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  • 1. Agerso¸, Henrik
    et al.
    Koechling, Wolfgang
    Knutsson, Magnus
    Hjortkjaer, Rolf
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The dosing solution influence on the pharmacokinetics of degarelix, a new GnRH antagonist, after s.c. administration to beagle dogs.2003In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 20, no 3, p. 335-340Article in journal (Refereed)
    Abstract [en]

    Objective

    Degarelix (FE200486) is a new GnRH-receptor antagonist intended for the treatment of prostate cancer. The objective of the present analysis was to evaluate the pharmacokinetics of degarelix after subcutaneous (s.c.) and intra-muscular (i.m.) administration to male beagle dogs, and to determine the influence of the different dosing conditions on the absorption profile of degarelix.

    Methods

    Degarelix was administered to 27 dogs and plasma concentrations were measured. The dosing conditions varied with respect to route (s.c. or i.m.), dose (0.25–1.5 mg/kg), solution strength (1.25–40 mg/ml) and volume administered (0.15–2.9 ml). Data were analysed by use of non-linear mixed effect modelling to characterize the pharmacokinetics, in particular the relationship between dosing conditions and rate, and extent of absorption.

    Results

    After s.c. and i.m. administration of degarelix, the plasma concentration versus time profile was best described by applying a two-compartment model, with two input functions: a fast first-order input function to describe the rapid initial increase in the plasma concentration levels, and a slow first-order input function to describe the prolonged absorption profile of degarelix. Intra-muscular as opposed to s.c. administration led to a more rapid absorption of degarelix, reaching a mean maximum concentration of 64 and 31 ng/ml roughly 2.0 and 3.7 h after administration, respectively. The slow absorption half-life was found to be 268 h (∼11 days). The relative fraction absorbedwas found to vary with the concentration of the dosing solution. The present analysis suggested that the absorbed fractionwas reduced by approximately 50% when the concentration in dosing solution was increased from 1.25 to 40 mg/ml. The rate of the initial absorption component was also dependent on the concentration in the dosing solution, with slower absorption at higher concentrations.

    Conclusion

    Through varying the dosing conditions and by applying a joint analysis of all data, the important factors determining the complex absorption of degarelix could be described.

  • 2.
    Alterman, Mathias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sjöbom, Hans
    Säfsten, Pär
    Markgren, Per-Olof
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Hämäläinen, Markku
    Löfås, Stefan
    Hultén, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Classon, Björn
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    P1/P1' modified HIV protease inhibitors as tools in two new sensitive surface plasmon resonance biosensor screening assays2001In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 13, no 2, p. 203-212Article in journal (Refereed)
    Abstract [en]

    The commonly used HIV-1 protease assays rely on measurements of the effect of inhibitions on the hydrolysis rate of synthetic peptides. Recently an assay based on surface plasmon resonance (SPR) was introduced. We have taken advantage of the fact that the SPR signal is proportional to the mass of the analyte interacting with the immobilised molecule and developed two new improved efficient competition assay methods. Thus, high molecular weight binders were used as amplifiers of the surface plasmon resonance signal. Linkers were attached by a Heck reaction to the para-positions of the P1/P1′ benzyloxy groups of a linear C2-symmetric C-terminal duplicated inhibitor to enable (a) biotin labelling or (b) direct immobilisation of the inhibitor to the biosensor surface matrix. The interaction properties of a series of 17 structurally diverse inhibitors was assessed and compared to previously reported data. The most sensitive assay was obtained by immobilising the enzyme and amplifying the signal with an antibody, giving a detection range between 0.1 nM and 10 μM. Immobilisation of the inhibitor resulted in a stable and durable surface but a narrower detection range (1–100 nM). The two competition assays are anticipated to be very suitable for fast screening of potential HIV inhibitors.

  • 3.
    Bergström, Christel A. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Andersson, Sara B. E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fagerberg, Jonas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ragnarsson, Gert
    Lindahl, Anders
    Is the full potential of the biopharmaceutics classification system reached?2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, p. 224-231Article in journal (Refereed)
    Abstract [en]

    In this paper we analyse how the biopharmaceutics classification system (BCS) has been used to date. A survey of the literature resulted in a compilation of 242 compounds for which BCS classes were reported. Of these, 183 compounds had been reported to belong to one specific BCS class whereas 59 compounds had been assigned to multiple BCS classes in different papers. Interestingly, a majority of the BCS class 2 compounds had fraction absorbed (FA) values >85%, indicating that they were completely absorbed after oral administration. Solubility was computationally predicted at pH 6.8 for BCS class 2 compounds to explore the impact of the pH of the small intestine, where most of the absorption occurs, on the solubility. In addition, the solubilization capacity of lipid aggregates naturally present in the intestine was studied computationally and experimentally for a subset of 12 compounds. It was found that all acidic compounds with FA > 85% were completely dissolved in the pH of the small intestine. Further, lipids at the concentration used in fasted state simulated intestinal fluid (FaSSIF) dissolved the complete dose given of the most lipophilic (logD(6.5) >3) compounds studied. Overall, biorelevant dissolution media (pure buffer of intestinal pH or FaSSIF) identified that for 20 of the 29 BCS class 2 compounds with FA > 85% the complete dose given orally would be dissolved. These results indicate that a more relevant pH restriction for acids and/or dissolution medium with lipids present better forecast solubility-limited absorption in vivo than the presently used BCS solubility criterion. The analysis presented herein further strengthens the discussion on the requirement of more physiologically relevant dissolution media for the in vitro solubility classification performed to reach the full potential of the BCS. (C) 2013 Elsevier B.V. All rights reserved.

  • 4.
    Bergström, Christel A S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bolin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rönn, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hepatitis C virus NS3 protease inhibitors: large, flexible molecules of peptide origin show satisfactory permeability across Caco-2 cells2009In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 38, no 5, p. 556-563Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the intestinal absorption of tripeptide-based compounds intended for treatment of hepatitis C virus (HCV) infection. The intestinal permeability of 11 HCV NS3 protease inhibitors (Mw 687-841, ClogD(pH 7.4) 1.2-7.3 and 10-13 hydrogen bond donors/acceptors) was measured using Caco-2 cells. Each compound was investigated in the apical to basolateral (a-b) and basolateral to apical (b-a) direction at pH 7.4. For compounds displaying efflux the experiment was repeated in the presence of 1 microM GF120918 to investigate possible involvement of P-glycoprotein (Pgp; ABCB1). All compounds displayed intermediate to high permeability. Seven of them showed extensive efflux, with 31-114-fold higher permeability in the b-a direction than the a-b direction. Addition of the Pgp inhibitor GF120918 reduced the b-a transport rate for the effluxed compounds. However, for inhibitors with a C-terminal carboxylic acid and the acidic bioisosteres thereof the efflux was still significant. Hence, the negative charge resulted in efflux by other ABC-transporters than Pgp. From this study it can be concluded that small changes in the overall structure can lead to a large variation in permeability and efflux as shown by the inhibitors herein, properties that also may influence the resulting inhibition potency of the compounds when performing cell-based pharmacological assays.

  • 5.
    Bergström, Christel A. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Holm, Rene
    Jorgensen, Soren Astrup
    Andersson, Sara B. E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Beato, Stefania
    Borde, Anders
    Box, Karl
    Brewster, Marcus
    Dressman, Jennifer
    Feng, Kung-I.
    Halbert, Gavin
    Kostewicz, Edmund
    McAllister, Mark
    Muenster, Uwe
    Thinnes, Julian
    Taylor, Robert
    Mullertz, Anette
    Early pharmaceutical profiling to predict oral drug absorption: Current status and unmet needs2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, p. 173-199Article in journal (Refereed)
    Abstract [en]

    Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silica and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered. (C) 2013 Elsevier B.V. All rights reserved.

  • 6. Brokjaer, Anne
    et al.
    Kreilgaard, Mads
    Olesen, Anne Estrup
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Christrup, Lona Louring
    Dahan, Albert
    Drewes, Asbjorn Mohr
    Population pharmacokinetics of morphine and morphine-6-glucuronide following rectal administration - A dose escalation study2015In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 68, p. 78-86Article in journal (Refereed)
    Abstract [en]

    Introduction: To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. Material and methods: This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10 mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. Results: A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 h, clearance 78 L/h [relative standard error (RSE) 12%1 and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed. Conclusion: A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated. (C) 2014 Elsevier B.V. All rights reserved.

  • 7.
    Bäckström, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Taipalensuu, Jan
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Svensson, Ann-Cathrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Genetic variation in the ATP-binding cassette transporter gene ABCG2(BCRP) in a Swedish population2003In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 18, no 5, p. 359-364Article in journal (Refereed)
    Abstract [en]

    The ATP-binding cassette transporter ABCG2 (also named breast cancer resistance protein, BCRP) functions as a drug efflux transporter and is expressed at high levels in the human small intestine. The aim of this study was to screen the human ABCG2 gene for genetic variation. The regions of the gene most likely to affect function, namely the coding parts, exon/intron boundaries, 5' untranslated region and 3' untranslated region and the proposed promoter region, were included in the screening. DNA was obtained from 60 Swedish individuals. The screening was performed using a polymerase chain reaction-denaturing high-performance liquid chromatography approach followed by sequence analysis. Eight sites of genetic variation were identified. The sequence variations considered to be most likely to affect transcription level or transport function were a CTCA deletion in the 5' flanking region, a single nucleotide polymorphism (SNP) in a 5' flanking CpG island, two non-synonymous SNPs, changing valine at amino acid position 12 to methionine and glutamine at position 141 to lysine, respectively. Genotyping of these sequence variations revealed linkage between the CTCA deletion and the SNP changing glutamine 141 for lysine. This information forms the basis for future association studies to investigate the genetic basis of differences of drug disposition due to sequence variation in the ABCG2 gene.

  • 8. Carlert, Sara
    et al.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    Evaluation of the use of Classical Nucleation Theory for predicting intestinal crystalline precipitation of two weakly basic BSC class II drugs2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 53, p. 17-27Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to evaluate an in vitro-in silico approach for prediction of small intestinal crystalline precipitation and drug absorption of two weakly basic model BCS class II drugs, AZD0865 and mebendazole. The crystallization rates were investigated in an in vitro method using simulated gastric and intestinal media, and the result was modeled by using Classical Nucleation Theory (CNT). The effect of varying in vitro parameters (initial drug concentration, rate of mixing gastric and intestinal fluid, stirring and filtration) on the interfacial tension gamma, being a key parameter in CNT, was investigated. The initial drug concentration had the most significant effect on gamma for both substances tested, although gamma is a fundamental parameter independent of concentration according to CNT. In the subsequent in silico prediction of drug absorption, by use of a Compartmental and Transit intestinal model, an empirical approach was used where gamma was allowed to vary with simulated small intestinal concentrations. The in silico predictions were compared to published human in vivo plasma drug concentration data for different doses of AZD0865 and dog intestinal drug concentrations, amount precipitated in intestine and plasma concentrations for mebendazole. The results showed that lack of significant crystallization effects on absorption in man of the model drug AZD0865 up to doses of 4 mg/kg could be predicted which was in accordance with in vivo data. Mebendazole intestinal precipitation in canines was also well described by the model, where mean predicted amount precipitated was 136% (range 111-164%) of measured solid amount, and mean predicted intestinal concentration was 94% (range 59-147%) of measured concentration. In conclusion, the in vitro-in silico approach can be used for predictions of absorption effects of crystallization, but the model could benefit from further development work on the theoretical crystallization model and in vitro experimental design.

  • 9.
    Chen, Chunli
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ortega, Fatima
    GlaxoSmithKline, DDW, Med Dev Campus,Severo Ochoa 2, Madrid 28760, Spain..
    Alameda, Laura
    GlaxoSmithKline, DDW, Med Dev Campus,Severo Ochoa 2, Madrid 28760, Spain..
    Ferrer, Santiago
    GlaxoSmithKline, DDW, Med Dev Campus,Severo Ochoa 2, Madrid 28760, Spain..
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Population pharmacokinetics, optimised design and sample size determination for rifampicin, isoniazid, ethambutol and pyrazinamide in the mouse2016In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 93, p. 319-333Article in journal (Refereed)
    Abstract [en]

    The current first-line therapy for drug-susceptible tuberculosis consists of rifampicin (RIF), isoniazid (INH), pyrazinamide (PZA) and ethambutol (EMB). In this study, we determined the population pharmacokinetics (PopPK) of RIF, INH, EMB and PZA using original experimental sampling designs for single-dose intravenous (IV) and single- and multiple-dose oral administration studies in the mouse model, and used these PopPK models to develop and evaluate new, more informative sampling designs with the aim of reducing the number of animals required for each drug. The RIF, INH, EMB and PZA blood concentrations after single oral and IV doses and multiple-dose oral administrations based on the original designs were used in the PopPK analysis using NONMEM software. The final PopPK models described the data well, Stochastic simulation and estimation were used to optimise the designs. The relative bias and relative imprecision of each pharmacokinetic parameter for each drug were derived and assessed to choose the final designs. The final single-dose IV and oral designs included up to eight samples per mouse with a total of 24 mice required for RIF and EMB and 33 mice for INH and PZA. In the new multiple-dose (zipper) oral designs, the mice were divided into two groups of three per dose, and four samples were taken from each mouse to cover all seven or eight sampling time points. The final number of mice required for the multiple-dose oral designs was 30 for RIF, INH and EMB, 36 for PZA. The number of mice required in the new designs for RIF, INH and EMB was decreased by up to 7-fold and the relative bias and relative imprecision in the parameter estimates were at least similar to those in the original designs.

  • 10.
    Claussen, Anetta
    et al.
    Certara Strateg Consulting, Basel, Switzerland.;Novo Nordisk AS, Quantitat Clin Pharmacol, Vandtarnvej 108-110, Soborg, Denmark..
    Möller, Jonas B.
    Novo Nordisk AS, New Prod Planning, Soborg, Denmark..
    Kristensen, Niels R.
    Novo Nordisk AS, Quantitat Clin Pharmacol, Vandtarnvej 108-110, Soborg, Denmark..
    Klim, Sören
    Novo Nordisk AS, Biostat, Soborg, Denmark..
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ingwersen, Steen H.
    Novo Nordisk AS, Quantitat Clin Pharmacol, Vandtarnvej 108-110, Soborg, Denmark..
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Impact of demographics and disease progression on the relationship between glucose and HbA1c2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 104, p. 417-423Article in journal (Refereed)
    Abstract [en]

    Context: Several studies have shown that the relationship between mean plasma glucose (MPG) and glycated haemoglobin (HbA1c) may vary across populations. Especially race has previously been referred to shift the regression line that links MPG to HbA1c at steady-state (Herman & Cohen, 2012).

    Objective: To assess the influence of demographic and disease progression-related covariates on the intercept of the estimated linear MPG-HbA1c relationship in a longitudinal model.

    Data: Longitudinal patient-level data from 16 late-phase trials in type 2 diabetes with a total of 8927 subjects was used to study covariates for the relationship between MPG and HbA1c. The analysed covariates included age group, HMI, gender, race, diabetes duration, and pre-trial treatment. Differences between trials were taken into account by estimating a trial-to-trial variability component.

    Participants: Participants included 47% females and 20% above 65 years. 77% were Caucasian, 9% were Asian, 5% were Black and the remaining 9% were analysed together as other races.

    Analysis: Estimates of the change in the intercept of the MPG-HbA1c relationship due to the mentioned covariates were determined using a longitudinal model.

    Results: The analysis showed that pre-trial treatment with insulin had the most pronounced impact associated with a 0.34% higher HbA1c at a given MPG. However, race, diabetes duration and age group also had an impact on the MPG-HbA1c relationship.

    Conclusion: Our analysis shows that the relationship between MPG and HbA1c is relatively insensitive to covariates, but shows small variations across populations, which may be relevant to take into account when predicting HbA1c response based on MPG measurements in clinical trials.

  • 11.
    Conrado, Daniela J.
    et al.
    Crit Path Inst, Quantitat Med, Tucson, AZ USA..
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Romero, Klaus
    Crit Path Inst, Quantitat Med, Tucson, AZ USA..
    Sarr, Celine
    Pharmetheus, Uppsala, Sweden..
    Wilkins, Justin J.
    Occams, Amstelveen, Netherlands..
    Open innovation: Towards sharing of data, models and workflows2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 109, p. S65-S71Article, review/survey (Refereed)
    Abstract [en]

    Sharing of resources across organisations to support open innovation is an old idea, but which is being taken up by the scientific community at increasing speed, concerning public sharing in particular. The ability to address new questions or provide more precise answers to old questions through merged information is among the attractive features of sharing. Increased efficiency through reuse, and increased reliability of scientific findings through enhanced transparency, are expected outcomes from sharing. In the field of pharmacometrics, efforts to publicly share data, models and workflow have recently started. Sharing of individual-level longitudinal data for modelling requires solving legal, ethical and proprietary issues similar to many other fields, but there are also pharmacometric-specific aspects regarding data formats, exchange standards, and database properties. Several organisations (CDISC, C-Path, IMI, ISoP) are working to solve these issues and propose standards. There are also a number of initiatives aimed at collecting disease-specific databases-Alzheimer's Disease (ADNI, CAMD), malaria (WWARN), oncology (PDS), Parkinson's Disease (PPMI), tuberculosis (CPTR, TB-PACTS, ReSeqTB)-suitable for drug-disease modelling. Organized sharing of pharmacometric executable model code and associated information has in the past been sparse, but a model repository (DDMoRe Model Repository) intended for the purpose has recently been launched. In addition several other services can facilitate model sharing more generally. Pharmacometric workflows have matured over the last decades and initiatives to more fully capture those applied to analyses are ongoing. In order to maximize both the impact of pharmacometrics and the knowledge extracted from clinical data, the scientific community needs to take ownership of and create opportunities for open innovation.

  • 12. Cui, J.
    et al.
    Eneroth, P.
    Bruhn, J. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Gynostemma pentaphyllum: identification of major sapogenins and differentiation from Panax species1999In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 8, no 3, p. 187-191Article in journal (Refereed)
    Abstract [en]

    Four main dammarane-type aglycones of gypenosides, extracted from the aerial parts of Gynostemma pentaphyllum were identified by gas chromatography-mass spectrometry. By detecting these aglycones as well as the aglycones of ginsenosides, a difference in sapogenin composition between Gynostemma pentaphyllum and Panax species was observed, which can be used in the differentiation of these plant drugs.

  • 13.
    Darwich, Adam S.
    et al.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Margolskee, Alison
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Pepin, Xavier
    AstraZeneca, London, England;Sanofi, Paris, France.
    Aarons, Leon
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Galetin, Aleksandra
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Rostami-Hodjegan, Amin
    Univ Manchester, Manchester M13 9PL, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England.
    Carlert, Sara
    AstraZeneca, Gothenburg, Sweden.
    Hammarberg, Maria
    AstraZeneca, Gothenburg, Sweden.
    Hilgendorf, Constanze
    AstraZeneca, Gothenburg, Sweden.
    Johansson, Pernilla
    AstraZeneca, Gothenburg, Sweden.
    Karlsson, Eva
    AstraZeneca, Gothenburg, Sweden.
    Murphy, Donal
    AstraZeneca, London, England.
    Tannergren, Christer
    AstraZeneca, Gothenburg, Sweden.
    Thorn, Helena
    AstraZeneca, Gothenburg, Sweden.
    Yasin, Mohammed
    AstraZeneca, London, England.
    Mazuir, Florent
    Sanofi, Paris, France.
    Nicolas, Olivier
    Sanofi, Paris, France.
    Ramusovic, Sergej
    Sanofi, Frankfurt, Germany.
    Xu, Christine
    Sanofi, Bridgewater, NJ USA.
    Pathak, Shriram M.
    Simcyp Ltd, Sheffield, S Yorkshire, England.
    Korjamo, Timo
    Orion Pharma, Espoo, Finland.
    Laru, Johanna
    Orion Pharma, Espoo, Finland;AstraZeneca, London, England.
    Malkki, Jussi
    Orion Pharma, Espoo, Finland.
    Pappinen, Sari
    Orion Pharma, Espoo, Finland.
    Tuunainen, Johanna
    Orion Pharma, Espoo, Finland.
    Dressman, Jennifer
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Hansmann, Simone
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Kostewicz, Edmund
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    He, Handan
    Novartis, New York, NY USA.
    Heimbach, Tycho
    Novartis, New York, NY USA.
    Wu, Fan
    Novartis, New York, NY USA.
    Hoft, Carolin
    AbbVie, Wiesbaden, Germany.
    Pang, Yan
    AbbVie, Wiesbaden, Germany.
    Bolger, Michael B.
    Simulat Plus Inc, Lancaster, CA USA.
    Huehn, Eva
    Simulat Plus Inc, Lancaster, CA USA.
    Lukacova, Viera
    Simulat Plus Inc, Lancaster, CA USA.
    Mullin, James M.
    Simulat Plus Inc, Lancaster, CA USA.
    Szeto, Ke X.
    Simulat Plus Inc, Lancaster, CA USA.
    Costales, Chester
    Pfizer, New York, NY USA.
    Lin, Jian
    Pfizer, New York, NY USA.
    McAllister, Mark
    Pfizer, Tadworth, Middx, England.
    Modi, Sweta
    Pfizer, New York, NY USA.
    Rotter, Charles
    Pfizer, New York, NY USA.
    Varma, Manthena
    Pfizer, Tadworth, Middx, England.
    Wong, Mei
    Pfizer, Tadworth, Middx, England.
    Mitra, Amitava
    Merck Sharp & Dohme Ltd, Hoddesdon, Herts, England.
    Bevernage, Jan
    Janssen, Beerse, Belgium.
    Biewenga, Jeike
    Janssen, Beerse, Belgium.
    Van Peer, Achiel
    Janssen, Beerse, Belgium.
    Lloyd, Richard
    GlaxoSmithKline, Brentford, Middx, England.
    Shardlow, Carole
    GlaxoSmithKline, Brentford, Middx, England.
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Mishenzon, Irina
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Nguyen, Mai Anh
    Brown, Jonathan
    Bristol Myers Squibb, Uxbridge, Middx, England.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    AstraZeneca, Gothenburg, Sweden.
    IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 96, p. 626-642Article in journal (Refereed)
    Abstract [en]

    Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.

  • 14.
    Dencker, Lennart
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hellmann, K.
    Klifovet AG, Geyerspergerstr 27, D-80689 Munich, Germany..
    Mochel, J.
    Leiden Acad Ctr Drug Res, Dept Pharmacol, NL-2300 Leiden, Netherlands..
    Senel, S.
    Hacettepe Univ, Fac Pharm, Dept Pharmaceut Technol, TR-06100 Ankara, Turkey..
    Tyden, E.
    Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Div Parasitol, Box 7036, S-75007 Uppsala, Sweden..
    Vendrig, J. C.
    Univ Utrecht, Fac Vet Med, Inst Risk Assessment Sci Vet Pharmacol Pharmacoth, Yalelaan 104,Postbus 80152, NL-3584 CM Utrecht, Netherlands..
    Linden, H.
    EUFEPS, Veddesta Business Ctr, SE-17572 Jarfalla, Stockholm, Sweden..
    Schmerold, I.
    Univ Vet Med Vienna, A-1020 Vienna, Austria.;Obere Donaustr 21-3-4, A-1020 Vienna, Austria..
    Position Paper: EUFEPS Network on Veterinary Medicines Initiative: An interdisciplinary forum to support Veterinary Pharmacology and promote the development of new pharmaceuticals for Animal Health2016In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 91, p. I-VIIArticle in journal (Refereed)
    Abstract [en]

    Veterinary medicines account for a substantial portion of the production, sale, and consumption of medicines in Europe, and probably world-wide. This calls our attention to the fact that only healthy farm animals can ensure safe and sufficient livestock products to meet the growing demand for animal protein. Human and veterinary medicine share many common features - expressed and symbolised by the "One Health Concept". This concept forms the logical basis for the maintenance of healthy livestock by the control of zoonoses and foodborne diseases, the prevention of poor sanitary conditions, and the reduction of microbial and parasitic threats, including resistance to antibiotics and anti-parasitic drugs. Achieving these aims will require international cooperation and interdisciplinary action. A new initiative of the European Federation for Pharmaceutical Sciences (EUFEPS) - the Network on Veterinary Medicines - has the potential to manage and overcome these challenges. A number of EUFEPS expertise networks have already been established, and some will be instrumental in supporting the activities of the Network on Veterinary Medicines, e.g., the European Network on PharmacoGenomics Research and Implementation (EPRIN), as well as the Network on Bioavailability and Biopharmaceutics, and the envisioned Network on Systems Pharmacology. Notably, the EUFEPS Networks on Safety Sciences, on Environment and Pharmaceuticals and on NanoMedicine as well as on Regulatory Science, represent promising partners. New technologies are being introduced to veterinary medicine for the treatment of numerous and frequently species-specific conditions. Scientific input from different areas is required to evaluate the potential benefitrisk profiles of these novel products, drug delivery techniques, and medical attention for animals as a whole. Drug treatment of food-producing animals inevitably affects consumer safety and public health, as any administration of medicines to animals may result in the presence of drug residues in edible tissues or products such as milk, eggs, and honey. The many questions surrounding the risks to human health and to the environment posed by exposure to veterinary drug residues cause great concern among health authorities as well as the public. In particular, the shared use of many classes of antimicrobials in both veterinary and human medicine, the emergence and spread of resistant microbes from animals or animal-derived products to humans, and the presence of contaminated manure in the environment are all provoking deep concern throughout the world. The Network on Veterinary Medicines initiative sees itself as broadly positioned. Among its most important goals are contributing to legislative issues in veterinary medicine and to the development of new pharmaceuticals for animal health, including novel drug delivery systems. Efforts to support the academic teaching and training of veterinary professionals and formulators for veterinary drug delivery are also considered imperative objectives of the network. The pursuit of these tasks will depend on interdisciplinary cooperation among experts from pharmaceutical and veterinary sciences, concentrating on issues where scientists from academia, industry and regulatory agencies can collaborate. National and international healthcare bodies, as well as organisations dedicated to the endorsement of teaching and training of scientists in pharmaceutical and veterinary sciences, are also key partners. Major objectives of the network include the following: strengthening academic research to promote the emergence of new concepts, principles and mechanisms of action to develop innovative new veterinary medicinal products, supporting the education and training of future healthcare professionals in veterinary practice, pharmacy and industrial research, including continuing professional development, and supporting Veterinary Universities. Further efforts of the Network will encourage the European Commission to initiate calls for research in the area of veterinary medicines, such as Horizon 2020. Once these calls are in place, the formation of strong consortia to apply for funding (IMI, EU-funding) is projected. The success of the Network depends on the engagement and expertise of cooperating specialists. It will benefit from the experience and means of other EUFEPS networks.

  • 15. Diakidou, A
    et al.
    Vertzoni, M
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dressman, J
    Reppas, C
    Simulation of gastric lipolysis and prediction of felodipine release from a matrix tablet in the fed stomach2009In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 37, no 2, p. 133-140Article in journal (Refereed)
    Abstract [en]

    The importance of intragastric lipolysis to felodipine release from a hydrophilic, extended release tablet in the fed stomach was assessed in USP II apparatus with the tablet fixed on a steel wire above the paddle. The release medium, homogenized long-life milk, was gradually digested with shots of acidic solutions of pepsin over the course of the experiment in absence and in presence of biorelevant concentrations of a lipase that was similar to human gastric lipase. Percentage tablet erosion at specific times in the same media was measured in separate experiments. The data were compared to published data for intragastric release in fed healthy adults. In all cases, felodipine release occurred under sink conditions. Lipase facilitated felodipine release from the eroded polymer, bringing the release profile closer to the in vivo data. Likewise, the relationship between tablet erosion and amount of released felodipine reflected the in vivo data only when lipase was added to the medium. It was concluded that modelling intragastric lipolysis is necessary in order to simulate felodipine release from the extended release tablets in the fed stomach.

  • 16.
    Englund, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lazorova, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gråsjö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Regional levels of drug transporters along the human intestinal tract: Co-expression of ABC and SLC transporters and comparison with Caco-2 cells2006In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 29, no 3-4, p. 269-277Article in journal (Refereed)
    Abstract [en]

    A vast number of drugs are subjected to active or facilitated transport and multiple transport mechanism may contribute to the net flux during drug absorption. The main objective of this study was to quantify the regional mRNA expression and determine the co-expression of drug transporters from the ABC (Pgp, BCRP, MRP2, MRP3) and SLC (PEPT1, MCT1, OATPB, OCTN2, OCT1) families along the human intestine (duodenum, jejunum, ileum, and colon). A second objective was to compare the transporter expression between the different intestinal regions and Caco-2 cells. Eight out of nine of the investigated transporters exhibited significant regional differences in expression. OATPB was the only transporter that did not show a region-dependency in the expression along the human intestinal canal. The expression of Pgp, BCRP, OCTN2 and MCT1 differed along the small intestine, but the expression differences were greater than five-fold only for Pgp. The rank order of transcript prevalence was identical in the ileum and the jejunum. Between the ileum and colon, seven transcripts were differentially expressed, and MCT1, OCTN2 and MRP3 were expressed at higher levels in the colon than in the small intestine. The expression of transporters in Caco-2 was closest to the expression pattern in the small intestine, although the expression of OATPB, BCRP and MRP2 differed more than five-fold between the Caco-2 cells and ileum. In conclusion, this study provides quantitative data on the expression of transporters from the ABC and SLC families along the human intestine, which can be useful in the interpretation of clinical studies where more than one intestinal transporter contribute to the net transport and in the computer modelling of drug absorption.

  • 17.
    Fagerberg, Jonas H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Concomitant intake of alcohol may increase the absorption of poorly soluble drugs2015In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 67, p. 12-20Article in journal (Refereed)
  • 18. Fermer, C
    et al.
    Nilsson, P
    Larhed, M
    Microwave-assisted high-speed PCR2003In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 18, no 2, p. 129-132Article in journal (Refereed)
    Abstract [en]

    PCR amplification has emerged as a very important tool in biological research. The utility of the PCR is, however, hampered by the fact that it is a slow technique. Faster heating cycles are therefore needed, both to enhance the activity of the enzyme, and to enable shortening of the reaction times. In this paper, polymerase chain reactions with focused microwave irradiation as the source of heat were demonstrated for the first time. Thus, it was established that continuous microwave heating does not terminate the enzymatic function of the polymerase. The results indicate the possibility to shorten the total reaction time. In addition, the technique may give the possibility to perform PCR reactions in millilitre scale. (C) 2002 Elsevier Science B.V. All rights reserved.

  • 19. Franek, F.
    et al.
    Jarlfors, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Larsen, F.
    Holm, P.
    Steffansen, B.
    In vitro solubility, dissolution and permeability studies combined with semi-mechanistic modeling to investigate the intestinal absorption of desvenlafaxine from an immediate- and extended release formulation2015In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 77, p. 303-313Article in journal (Refereed)
    Abstract [en]

    Desvenlafaxine is a biopharmaceutics classification system (BCS) class 1 (high solubility, high permeability) and biopharmaceutical drug disposition classification system (BDDCS) class 3, (high solubility, poor metabolism; implying low permeability) compound. Thus the rate-limiting step for desvenlafaxine absorption (i.e. intestinal dissolution or permeation) is not fully clarified. The aim of this study was to investigate whether dissolution and/or intestinal permeability rate-limit desvenlafaxine absorption from an immediate-release formulation (IRF) and Pristiq (R), an extended release formulation (ERF). Semi-mechanistic models of desvenlafaxine were built (using SimCyp (R)) by combining in vitro data on dissolution and permeation (mechanistic part of model) with clinical data (obtained from literature) on distribution and clearance (non-mechanistic part of model). The model predictions of desvenlafaxine pharmacokinetics after IRF and ERF administration were compared with published clinical data from 14 trials. Desvenlafaxine in vivo dissolution from the IRF and ERF was predicted from in vitro solubility studies and biorelevant dissolution studies (using the USP3 dissolution apparatus), respectively. Desvenlafaxine apparent permeability (P-app) at varying apical pH was investigated using the Caco-2 cell line and extrapolated to effective intestinal permeability (P-eff) in human duodenum, jejunum, ileum and colon. Desvenlafaxine pK(a)-values and octanol-water partition coefficients (D-o:w) were determined experimentally. Due to predicted rapid dissolution after IRF administration, desvenlafaxine was predicted to be available for permeation in the duodenum. Desvenlafaxine D-o:w and P-app increased approximately 13-fold when increasing apical pH from 5.5 to 7.4. Desvenlafaxine P-eff thus increased with pH down the small intestine. Consequently, desvenlafaxine absorption from an IRF appears rate-limited by low P-eff in the upper small intestine, which "delays" the predicted time to the maximal plasma concentration (t(max)), consistent with clinical data. Conversely, desvenlafaxine absorption from the ERF appears rate-limited by dissolution due to the formulation, which tends to negate the influence of pH-dependent permeability on absorption. We suggest that desvenlafaxine P-eff is mainly driven by transcellular diffusion of the unionized form. In the case of desvenlafaxine, poor metabolism does not imply low intestinal permeability, as indicated by the BDDCS, merely low duodenal/jejunal permeability.

  • 20.
    Friberg, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Hassan, Saadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Pharmacokinetic-Pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model2005In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, no 1, p. 163-173Article in journal (Refereed)
    Abstract [en]

    N-(6-Chlorophenoxyhexyl)-N'-cyano-N''-4-pyridylguanidine (CHS 828) is a novel anticancer agent that shows schedule-dependent effects in vitro and in vivo, as well as in Phase I clinical trials. A rat hollow fibre model was used to investigate whether this dependency is due to pharmacokinetic and/or pharmacodynamic factors. The effect on two cell lines, MDA-MB-231 (breast cancer) and CCRF-CEM (leukaemia) were studied after CHS 828 was administered orally as a single dose or in a 5-day schedule, at different total dose levels. The 5-day schedules were associated with greater effects on both cell lines compared with single doses. A one-compartment pharmacokinetic model, with a half-life of 2.3h and a consecutive zero- and first-order process to describe dissolution and absorption, fit the concentration data. Pharmacokinetics were dose-dependent, as the fraction absorbed decreased with increasing dose. Clearance increased with accumulative exposure. Twenty hours after administration, concentrations started to increase again, probably due to coprophagy. Pharmacokinetic-pharmacodynamic models characterized the cell growth and cell kill over time and showed that schedule-dependent antitumour effects were present also when the dose-dependent pharmacokinetics were accounted for. The prolonged schedules of CHS 828 were therefore associated with greater antitumour effects than single doses of the same total exposure.

  • 21. Garbacz, Grzegorz
    et al.
    Golke, Berit
    Wedemeyer, Ralph-Steven
    Axell, Marie
    Söderlind, Erik
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Weitschies, Werner
    Comparison of dissolution profiles obtained from nifedipine extended release once a day products using different dissolution test apparatuses2009In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 38, no 2, p. 147-155Article in journal (Refereed)
    Abstract [en]

    In order to improve the predictability of dissolution testing new apparatuses have been proposed that mimic hydrodynamic and mechanical conditions in the gastrointestinal tract. In this study tested were four different nifedipine extended release (ER) formulations using the paddle apparatus and the reciprocating cylinder as pharmacopoeial test devices as well as two newly developed test apparatuses: the rotating beaker apparatus and the dissolution stress test apparatus. Investigated were Adalat OROS in strengths of 30 and 60 mg, and two hydrophilic matrix formulations: 60 mg nifedipine Coral and Nifedipin Sandoz 40 mg retard. The results demonstrate that the dissolution characteristic of the ER tablets is strongly dependent on the applied test conditions. The dosage form related food effects for Coral 60 mg tablets that were previously observed in human bioequivalence studies could be predicted with the two non-compendial dissolution test devices. The dissolution of Sandoz 40 mg tablets was very sensitive to all applied test conditions. The stable drug delivery characteristics of Adalat OROS observed in numerous in vivo studies was also observed in all of the dissolution tests. In conclusion, the present study shows that besides pH dependency the aspect of the mechanical robustness may be an essential factor affecting the dissolution characteristic of hydrogel matrix formulations.

  • 22. Gaspar, Rogerio
    et al.
    Aksu, Buket
    Cuine, Alain
    Danhof, Meindert
    Takac, Milena Jadrijevic-Mladar
    Linden, Hans H.
    Link, Andreas
    Muchitsch, Eva-Maria
    Wilson, Clive G.
    Öhrngren, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Dencker, Lennart
    Towards a European Strategy for Medicines Research (2014-2020): The EUFEPS Position Paper on Horizon 20202012In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 47, no 5, p. 979-987Article in journal (Refereed)
    Abstract [en]

    Executive summary: As to the alignment of "Horizon 2020", iris a more integrated approach to European science policy than expressed in the proposals previously drafted, and specifically considers: (i) promoting excellence in Science, (ii) establishing a sound industrial leadership and (iii) expressing an ambition to address current and future societal challenges. In this respect, the quest for a knowledge-based economy in Europe should result in proposals for industrial and employment policies that will consolidate the major European advantages in the biomedical, healthcare and pharmaceutical sectors. Horizon 2020 also provides the possibility of adopting a more flexible and simplified management route to drive European research through innovation, research and development. What should be additionally considered? Unmet medical needs, under pressure from demographic changes, await the generation of new medicines and health technologies which will evolve into a driver for a unified European policy. We believe that this should be focused on harnessing pharmaceutical knowledge for clinical use, as part of a response to accommodate patient needs and economic growth based on a robust, scientific approach. The bolder ambition for European research is to unlock key bottlenecks currently undermining European competitiveness. The historical lack of an appropriate business/innovation environment with reduced access to adequate risk finance instruments has severed the path for economic growth and industrial development. These issues are of critical importance and a solution is urgently needed to foster translation from the university to the healthcare sector through the generation and support of start-ups, spin-offs, university-industry consortia, and other platforms, which support translational research. The ultimate goal is implementation of holistic programmes: the 'bench to bedside' paradigm of medicines and other healthcare products. The European Research Council supports the basic biomedical research programmes of long term importance for development of medicines; however, fundamental research initiatives on medicines development will not be competitive in such an environment. In order to strengthen the long term outlook, we must foster innovative research within the university sector, EUFEPS proposes that a fund for such research be set up within Horizon 2020, which would be open for individual research groups and which would include Public-Public Partnerships (complementing already existing Public-Private Partnerships). How do we look for implementation? There is an established research agenda for medicines research that is globally focused, and which incorporates a cooperative model between universities and industry, facilitating integration of complex technologies. Regulatory Science will play an important role in this integration. This agenda uses tools arising from systems approaches (including discovery with systems biology and also systems pharmacology) and has the potential for providing better knowledge management, as well as technological innovation (including manufacturing). It also addresses the drive towards personalised medicines and can, with support from both public and private sectors, foster translation of knowledge to new technologies and from that, to new medicinal products and complex integrated systems. This is a part of a strategy capable of solving unmet medical needs, which would increase the quality of life of patients suffering from chronic and debilitating diseases. The instruments to allow the development of a research agenda should strengthen existing partnerships such as the IMI-JU model; allow for the creation of European-network infrastructures that can bring together existing competences with adequate European coordination, thus promoting advanced training and continuous professional development for the pharmaceutical sciences. This will be the cornerstone of a knowledge management strategy, providing education and training for healthcare professionals and scientists. A key role for EUFEPS is to help the research community to embrace these new holistic policies applied to the spectrum of pharmaceutical, medical and cognate sciences.

  • 23.
    Graffner-Nordberg, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Kolmodin, Karin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Queener, Sherry F
    Hallberg, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Design, synthesis, and computational affinity prediction of ester soft drugs as inhibitors of dihydrofolate reductase from Pneumocystis carinii2004In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 22, no 1, p. 43-54Article in journal (Refereed)
    Abstract [en]

    A series of dihydrofolate reductase (DHFR) inhibitors, where the methylenamino-bridge of non-classical inhibitors was replaced with an ester function, have been prepared as potential soft drugs intended for inhalation against Pneumocystis carinii pneumonia (PCP). Several of the new ester-based inhibitors that should serve as good substrates for the ubiquitous esterases and possibly constitute safer alternatives to metabolically stable DHFR inhibitors administered orally, were found to be potent inhibitors of P. carinii DHFR (pcDHFR). Although the objectives of the present program is to achieve a favorable toxicity profile by applying the soft drug concept, a high preference for inhibition of the fungal DHFR versus the mammalian DHFR is still desirable to suppress host toxicity at the site of administration. Compounds with a slight preference for the fungal enzyme were identified. The selection of the target compounds for synthesis was partly guided by an automated docking and scoring procedure as well as molecular dynamics simulations. The modest selectivity of the synthesized inhibitors was reasonably well predicted, although a correct ranking of the relative affinities was not successful in all cases.

  • 24. Gram, Luise K
    et al.
    Rist, Gerda Marie
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Steffansen, Bente
    Impact of carriers in oral absorption: Permeation across Caco-2 cells for the organic anions estrone-3-sulfate and glipizide2009In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 37, no 3-4, p. 378-386Article in journal (Refereed)
    Abstract [en]

    Carriers may mediate the permeation across enterocytes for drug substances being organic anions. Carrier mediated permeation for the organic anions estrone-3-sulfate (ES) and glipizide across Caco-2 cells were investigated kinetically, and interactions on involved carriers evaluated. Initial uptakes (P(UP)) at apical and basolateral membranes, apparent permeabilities (P(APP)) and corresponding intracellular end-point accumulations (P(EPA)) of radioactive labeled compounds were studied. Possible effects of other anionic compounds were investigated. Apical P(UP) and absorptive P(APP) for ES were inhibited and its absorptive P(EPA) prevented in presence of the investigated organic anions and apical P(UP) was saturable with K(m) 23microM. Basolateral P(UP) and exsorptive P(APP) were inhibited, its exsorptive P(EPA) was prevented, and basolateral P(UP) and exsorptive P(APP) were saturable with K(m) 44microM and 38microM, respectively. BCRP inhibition affected both absorptive an exsorptive P(EPA) and P(APP) for ES. Glipizide apical P(UP) and absorptive P(APP) were not inhibitable. Basolateral P(UP) for glipizide was inhibitable, its P(EPA) prevented, and P(UP) was saturable with K(m) 56microM, but exsorptive P(APP) was not affected. Carrier mediated exsorption kinetics for ES are seen at both apical and basolateral membranes, resulting in predominant exsorption despite presence of absorptive carrier(s). Carrier mediated basolateral P(UP) for glipizide was observed, but glipizide P(APP) was not described by carrier kinetics. However, glipizide is affecting exsorption for ES, due to interactions on basolateral carrier. The study confirms that estrone-3-sulfate can be used to characterize anionic carrier kinetics. Furthermore it is suggested that estrone-3-sulfate may be used to identify compounds which may interact on anionic carriers.

  • 25. Hayeshi, Rose
    et al.
    Hilgendorf, Constanze
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Augustijns, Patrick
    Brodin, Birger
    Dehertogh, Pascale
    Fisher, Karen
    Fossati, Lina
    Hovenkamp, Egbert
    Korjamo, Timo
    Masungi, Chantal
    Maubon, Nathalie
    Mols, Raf
    Müllertz, Anette
    Mönkkönen, Jukka
    O'Driscoll, Caitriona
    Oppers-Tiemissen, H M
    Ragnarsson, Eva G E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rooseboom, Martijn
    Ungell, Anna-Lena
    Comparison of drug transporter gene expression and functionality in Caco-2 cells from 10 different laboratories2008In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 35, no 5, p. 383-396Article in journal (Refereed)
    Abstract [en]

    Caco-2 cells, widely used to study carrier mediated uptake and efflux mechanisms, are known to have different properties when cultured under different conditions. In this study, Caco-2 cells from 10 different laboratories were compared in terms of mRNA expression levels of 72 drug and nutrient transporters, and 17 other target genes, including drug metabolising enzymes, using real-time PCR. The rank order of the top five expressed genes was: HPT1>GLUT3>GLUT5>GST1A>OATP-B. Rank correlation showed that for most of the samples, the gene ranking was not significantly different. Functionality of transporters and the permeability of passive transport markers metoprolol (transcellular) and atenolol (paracellular) were also compared. MDR1 and PepT1 function was investigated using talinolol and Gly-Sar transport, respectively. Sulfobromophthalein (BSP) was used as a marker for MRP2 and OATP-B functionality. Atenolol permeability was more variable across laboratories than metoprolol permeability. Talinolol efflux was observed by all the laboratories, whereas only five laboratories observed significant apical uptake of Gly-Sar. Three laboratories observed significant efflux of BSP. MDR1 expression significantly correlated to the efflux ratio and net active efflux of talinolol. PepT1 mRNA levels showed significant correlation to the uptake ratio and net active uptake of Gly-Sar. MRP2 and OATP-B showed no correlation to BSP transport parameters. Heterogeneity in transporter activity may thus be due to differences in transporter expression as shown for PepT1 and MDR1 which in turn is determined by the culture conditions. Absolute expression of genes was variable indicating that small differences in culture conditions have a significant impact on gene expression, although the overall expression patterns were similar.

  • 26.
    Hägerström, Helene
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Paulsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Edsman, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Evaluation of mucoadhesion for two polyelectrolyte gels in simulated physiological conditions using a rheological method2000In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 9, no 3, p. 301-309Article in journal (Refereed)
    Abstract [en]

    A rheological method to measure mucoadhesion was evaluated for two ion-sensitive polymers, Carbopol 934 and Gelrite((R)) (deacetylated gellan gum), in a simulated physiological environment using two commercially available mucins. The method simulates the interpenetration layer in the mucoadhesion process. The elastic modulus for a polymer/mucin mixture is compared with the elastic modulus for the polymer alone, and an increase in the elastic modulus for the mixture compared to the polymer is interpreted as a positive interaction caused by mucoadhesion. In this study the influence of polymer concentration, type of mucin and experimental rheological factors, such as gap width, were examined. The choice of polymer concentration was crucial, especially with the porcine gastric mucin. We found that one is more likely to obtain positive interactions with weak gels. It was also shown that the choice of mucin has a large influence on the results obtained. Carbopol 934 interacted more strongly with the bovine submaxillary gland mucin than with the porcine gastric mucin, whereas the gel structure of Gelrite((R)) was destroyed when mixed with the bovine mucin. Furthermore, it was concluded that with hydrogels consisting of gel particles (such as Carbopol 934), rheological measurements can give highly varying results, depending on, for example, the concentration and ion-sensitivity of the polymer, the quantity of ions present, as well as the gap width of the measuring system.

  • 27.
    Jönsson, Siv
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Estimation of dosing strategies aiming at maximizing utility or responder probability, using oxybutynin as an example drug2005In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, no 1, p. 123-132Article in journal (Refereed)
    Abstract [en]

    Methods for optimizing dosing strategies for individualization with a limited number of discrete doses, in terms of maximizing the expected utility of treatment or responder probability, are presented. The optimality criteria require models for both beneficial and adverse effects that are part of the utility definition and published population models describing those effects for oxybutynin (urge urinary incontinence episodes per week and severity of dry mouth, respectively) were used for illustration. Dosing strategies with two dosing categories were defined in terms of sizes of the daily doses (low and high dose) and the proportion of patients that can be expected to be preferentially treated at the low dose level. Utility and responder definitions were varied to investigate the influence on the resulting dosing strategy. By minimizing a risk function, describing the seriousness of deviations from the predefined target, optimal dosing strategies were estimated using mixture models in NONMEM. The estimated dose ranges for oxybutynin were similar to those recommended. The optimal individualization conditions were dependent on the definitions of responder and utility. The predicted gain of individualization given utility and responder definitions used was greater, when a responder criteria was maximized compared with maximizing utility.

  • 28. Kostewicz, Edmund S.
    et al.
    Aarons, Leon
    Bergstrand, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bolger, Michael B.
    Galetin, Aleksandra
    Hatley, Oliver
    Jamei, Masoud
    Lloyd, Richard
    Pepin, Xavier
    Rostami-Hodjegan, Amin
    Sjogren, Erik
    Tannergren, Christer
    Turner, David B.
    Wagner, Christian
    Weitschies, Werner
    Dressman, Jennifer
    PBPK models for the prediction of in vivo performance of oral dosage forms2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, no SI, p. 300-321Article, review/survey (Refereed)
    Abstract [en]

    Drug absorption from the gastrointestinal (GI) tract is a highly complex process dependent upon numerous factors including the physicochemical properties of the drug, characteristics of the formulation and interplay with the underlying physiological properties of the GI tract. The ability to accurately predict oral drug absorption during drug product development is becoming more relevant given the current challenges facing the pharmaceutical industry. Physiologically-based pharmacokinetic (PBPK) modeling provides an approach that enables the plasma concentration time profiles to be predicted from preclinical in vitro and in vivo data and can thus provide a valuable resource to support decisions at various stages of the drug development process. Whilst there have been quite a few successes with PBPK models identifying key issues in the development of new drugs in vivo, there are still many aspects that need to be addressed in order to maximize the utility of the PBPK models to predict drug absorption, including improving our understanding of conditions in the lower small intestine and colon, taking the influence of disease on GI physiology into account and further exploring the reasons behind population variability. Importantly, there is also a need to create more appropriate in vitro models for testing dosage form performance and to streamline data input from these into the PBPK models. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the current status of PBPK models available. The current challenges in PBPK set-ups for oral drug absorption including the composition of GI luminal contents, transit and hydrodynamics, permeability and intestinal wall metabolism are discussed in detail. Further, the challenges regarding the appropriate integration of results from in vitro models, such as consideration of appropriate integration! estimation of solubility and the complexity of the in vitro release and precipitation data, are also highlighted as important steps to advancing the application of PBPK models in drug development. It is expected that the "innovative" integration of in vitro data from more appropriate in vitro models and the enhancement of the GI physiology component of PBPK models, arising from the OrBiTo project, will lead to a significant enhancement in the ability of PBPK models to successfully predict oral drug absorption and advance their role in preclinical and clinical development, as well as for regulatory applications.

  • 29. Larsen, Anne T
    et al.
    Ohlsson, Anja G
    Polentarutti, Britta
    Barker, Richard A
    Phillips, Andrew R
    Abu-Rmaileh, Ragheb
    Dickinson, Paul A
    Abrahamsson, Bertil
    AstraZeneca, Pharmaceutical Development, Physical Science, Mölndal, Sweden.
    Ostergaard, Jesper
    Müllertz, Anette
    Oral bioavailability of cinnarizine in dogs: relation to SNEDDS droplet size, drug solubility and in vitro precipitation2013In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 48, no 1-2, p. 339-350Article in journal (Refereed)
    Abstract [en]

    The in vivo performance of self-nanoemulsifying drug delivery systems (SNEDDSs) with different in vitro physicochemical properties were determined with the purpose of elucidating the parameters determining the in vivo performance of SNEDDSs. The in vitro characterisation included the use of pulsed field gradient NMR and the dynamic lipolysis model. In vivo characterisation was carried out in dogs with elevated gastric pH. Four SNEDDSs containing cinnarizine were dosed orally, and the obtained PK profiles were related to in vitro characterisation data. The SNEDDSs with the lowest solubility of cinnarizine in the preconcentrates and the smallest droplet size had the highest AUC values after oral administration. No difference in C(max) and t(max) was observed between the SNEDDSs. Despite of precipitation occurring during in vitro lipolysis of one of the SNEDDS this SNEDDS performed as well in vivo as another SNEDDS that did not show any precipitation. The area under the colloidal dispersion curves as well as under the lipolysis curves could be used to rank order the in vivo performance of the SNEDDSs. Selection of in vitro optimisation parameters for SNEDDSs should be done carefully. It may not always be best to aim for the highest solubility in the preconcentrate and to avoid precipitation during in vitro lipolysis.

  • 30.
    Larsen, Malte Selch
    et al.
    Novo Nordisk AS, Global Res, Haemophilia Res, Haemophilia PK & ADME, Malov, Denmark.;Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg, Denmark..
    Juul, Rasmus Vestergaard
    Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark..
    Groth, Andreas Velsing
    Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark..
    Simonsson, Ulrika S H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kristensen, Annemarie T.
    Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg, Denmark..
    Knudsen, Tom
    Novo Nordisk AS, Global Res, Haemophilia Pharmacol, Translat Haemophilia Pharmacol, Malov, Denmark..
    Agersö, Henrik
    Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark..
    Kreilgaard, Mads
    Novo Nordisk AS, Global Res, Haemophilia Res, Haemophilia PK & ADME, Malov, Denmark..
    Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia2018In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 115, p. 196-203Article in journal (Refereed)
    Abstract [en]

    Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects. Three scaling principles were applied to predict human PK: proportional scaling to body weight from single species, scaling with fixed theory-based allometric exponents from single species, and allometric interspecies scaling with estimated allometric coefficients and exponents. The plasma concentration-time profile of rFVIIa and rFVIII in mice, rats, monkeys and dogs were accurately described by the developed species-specific PK models, accounting for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling revealed high predictive performance for human PK, and may promote rational decision-making in future first-in-human trials for rFVIIa and rFVIII variants.

  • 31.
    Lennernas, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Regional intestinal drug permeation: Biopharmaceutics and drug development2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, no SI, p. 333-341Article, review/survey (Refereed)
    Abstract [en]

    Over the last 25 years, profound changes have been seen in both the development and regulation of pharmaceutical dosage forms, due primarily to the extensive use of the biopharmaceutical classification system (BCS) in both academia and industry. The BCS and the FDA scale-up and post-approval change guidelines were both developed during the 1990s and both are currently widely used to claim biowaivers. The development of the BCS and its wide acceptance were important steps in pharmaceutical science that contributed to the more rational development of oral dosage forms. The effective permeation (P-eff) of drugs through the intestine often depends on the combined outcomes of passive diffusion and multiple parallel transport processes. Site-specific jejunal P-eff cannot reflect the permeability of the whole intestinal tract, since this varies along the length of the intestine, but is a useful approximation of the fraction of the oral dose that is absorbed. It appears that drugs with a jejunal P-eff > 1.5 x 10(-4) cm/s will be completely absorbed no matter which transport mechanisms are utilized. In this paper, historical clinical data originating from earlier open, single-pass perfusion studies have been used to calculate the P-eff of different substances from sites in the jejunum and ileum. More exploratory in vivo studies are required in order to obtain reliable data on regional intestinal drug absorption. The development of experimental and theoretical methods of assessing drug absorption from both small intestine and various sites in the colon is encouraged. Some of the existing human in vivo data are discussed in relation to commonly used cell culture models. It is crucial to accurately determine the input parameters, such as the regional intestinal P-eff, as these will form the basis for the expected increase in modeling and simulation of all the processes involved in GI drug absorption, thus facilitating successful pharmaceutical development in the future. It is suggested that it would be feasible to use open, single-pass perfusion studies for the in vivo estimation of regional intestinal TV, but that care should be taken in the study design to optimize the absorption conditions.

  • 32.
    Lennernäs, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Aarons, L.
    Augustijns, P.
    Beato, S.
    Bolger, M.
    Box, K.
    Brewster, M.
    Butler, J.
    Dressman, J.
    Holm, R.
    Frank, K. Julia
    Kendall, R.
    Langguth, P.
    Sydor, J.
    Lindahl, A.
    McAllister, M.
    Muenster, U.
    Mullertz, A.
    Ojala, K.
    Pepin, X.
    Reppas, C.
    Rostami-Hodjegan, A.
    Verwei, M.
    Weitschies, W.
    Wilson, C.
    Karlsson, C.
    Abrahamsson, B.
    Oral biopharmaceutics tools - Time for a new initiative - An introduction to the IMI project OrBiTo2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, no SI, p. 292-299Article, review/survey (Refereed)
    Abstract [en]

    OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silica biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.

  • 33.
    Lennernäs, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Peter
    Langguth, Bertil
    Oral biopharmaceutics-current status and identified gaps of understanding2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, European journal of pharmaceutical sciences, ISSN 0928-0987, Vol. 57, p. 98-98Article in journal (Refereed)
  • 34.
    Lennernäs, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Langguth, Peter
    Yamashita, Shinji
    Crommelin, Daan J. A.
    Theme Issue 5th World Conference on Drug Absorption, Transport and Delivery2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 61, p. 1-1Article in journal (Other academic)
  • 35.
    Lindqvist, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fridén, Markus
    AstraZeneca R&D, Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacokinetic Considerations of Nanodelivery to the Brain: Using Modeling and Simulations to Predict Outcome of Liposomal Formulations2016In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 92, p. 173-182Article in journal (Refereed)
    Abstract [en]

    The use of nanocarriers is an intriguing solution to increase the brain delivery of novel therapeutics. The aim of this paper was to use pharmacokinetic analysis and simulations to identify key factors that determine the effective drug concentration-time profile at the target site in the brain. Model building and simulations were based on experimental data obtained from the administration of the opioid peptide DAMGO in glutathione tagged PEGylated liposomes to rats. Different pharmacokinetic models were investigated to explore the mechanisms of increased brain delivery. Concentration time profiles for a set of formulations with varying compound and carrier characteristics were simulated. By controlling the release rate from the liposome, the time profile and the extent of brain delivery can be regulated. The modeling did not support a mechanism of the liposomes passing the brain endothelial cell membrane in an intact form through endocytosis or transcytosis. The most likely process was found to be fusion of the liposome with the endothelial luminal membrane. The simulations revealed that low permeable compounds, independent on efflux, will gain the most from a nanocarrier formulation. The present model based approach is useful to explore and predict possibilities and limitations of carrier-based systems to the brain.

  • 36.
    Lundahl, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The effect of St. John's wort on the pharmacokinetics, metabolism and biliary excretion of finasteride and its metabolites in healthy men2009In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 36, no 4-5, p. 433-443Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate what the consequences of induced drug metabolism, caused by St. John's wort (SJW, Hypericum perforatum) treatment, would have on the plasma, biliary and urinary pharmacokinetics of finasteride and its two previously identified phase I metabolites (hydroxy-finasteride and carboxy-finasteride). Twelve healthy men were administered 5mg finasteride directly to the intestine via a catheter with a multi-channel tubing system, Loc-I-Gut, before and after 14 days SJW (300mg b.i.d, hyperforin 4%) treatment. Bile samples were withdrawn via the Loc-I-Gut device from the proximal jejunum. LC-ESI-MS/MS was used to analyze finasteride and its metabolites in plasma, bile and urine. HPLC-UV was used to analyze hyperforin in plasma. The herbal treatment significantly reduced the peak plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC(0-24h)) and the elimination half-life (t(1/2)) of finasteride. The geometric mean ratios (90% CI) were 0.42 (0.36-0.49), 0.66 (0.56-0.79) and 0.54 (0.48-0.61), respectively. Finasteride was excreted unchanged to a minor extent into bile and urine. Hydroxy-finasteride was not detected in plasma, bile or urine. Carboxy-finasteride was quantified in all three compartments and its plasma pharmacokinetics was significantly affected by SJW treatment. Hyperforin concentration in plasma was 21+/-7ng/ml approximately 12h after the last dose of the 14 days SJW treatment. In conclusion, SJW treatment for 2 weeks induced the metabolism of finasteride and caused a reduced plasma exposure of the drug. New knowledge was gained about the biliary and urinary excretion or the drug and its metabolites.

  • 37.
    Mahlin, Denny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Early drug development predictions of glass-forming ability and physical stability of drugs2013In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 49, no 2, p. 323-332Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate if rapidly measured physical properties can predict glass-forming ability and glass stability of drug compounds. A series of 50 structurally diverse drug molecules were studied with respect to glass-forming ability and, for glass-formers (n = 24), the physical stability upon 1 month of storage was determined. Spray-drying and melt-cooling were used to produce the amorphous material and the solid state was analysed by Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction. Thermal properties and molecular weight (Mw) were used to develop predictive models of (i) glass-forming ability and (ii) physical stability. In total, the glass-forming ability was correctly predicted for 90% of the drugs from their Mw alone. As a rule of thumb, drugs with Mw greater than 300 g/mole are expected to be transformed to its amorphous state by using standard process technology. Glass transition temperature and Mw predicted the physical stability upon storage correctly for 78% of the glass-forming compounds. A strong sigmoidal relationship (R-2 of 0.96) was identified between crystallization temperature and stability. These findings have the potential to rationalize decisions schemes for utilizing and developing amorphous formulations, through early predictions of glass-forming ability from Mw and physical stability from simple DSC characterization.

  • 38.
    Mahmoodi, Foad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    An experimental evaluation of an effective medium based compaction equation2012In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 46, no 1-2, p. 49-55Article in journal (Refereed)
    Abstract [en]

    Tablet production involves compression of free flowing powder in an enclosed cavity of defined geometry. The complexity of the powder bed system necessitates that a way be found to better understand what occurs during compression. One such approach is by means of compaction equations, of which, the Heckel and Kawakita equations are the best known. This work attempts to experimentally evaluate the applicability of the effective medium (EM) equation introduced by Frenning et al. (2009) to powder systems. Two powder types (sodium chloride and lactose monohydrate), each consisting of three size fractions (<40, 125-212 and 212-300 mu m) were characterised and compressed to a pressure of 500 MPa. These powders were chosen because of their differing mechanical properties. An invariance which is inherent in the EM equation is exposed by varying the starting points of compression, and can yield insights into compression mechanisms. Such invariant regions were observed once plastic particle deformation started to dominate the compression behaviour, and enabled the determination of the point where particle rearrangement stops.

  • 39.
    Marelius, J.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Ljungberg, Kajsa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Åqvist, J
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Sensitivity of an Empirical Affinity Scoring Function to Changes in Receptor-Ligand Complex Conformations2001In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 14, no 1, p. 87-95Article in journal (Refereed)
    Abstract [en]

    A combination of empirical scoring and conformational sampling for ligand bindingaffinity prediction is examined. The behaviour of a scoring function with respect to thesensitivity to conformational changes is investigated using ensembles of structures generated by molecular dynamics simulation. The correlation between the calculated score and the coordinate deviation from the experimental structure is clear for the complex of arabinose with arabinose-binding protein, which is dominated by hydrogen bond interactions, while the score calculated for the hydrophobic complex between retinol and retinol binding protein is rather insensitive to ligand conformational changes. For typical ensembles of stuctures generated by molecular dynamics at 300 K. the variation of the calculated score is considerably smaller than that of the underlying molecular mechanics interaction energies.

  • 40.
    Margolskee, Alison
    et al.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Darwich, Adam S.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Pepin, Xavier
    AstraZeneca, London, England;Sanofi, Paris, France.
    Aarons, Leon
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Galetin, Aleksandra
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Rostami-Hodjegan, Amin
    Univ Manchester, Manchester M13 9PL, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England.
    Carlert, Sara
    AstraZeneca, Gothenburg, Sweden.
    Hammarberg, Maria
    AstraZeneca, Gothenburg, Sweden.
    Hilgendorf, Constanze
    AstraZeneca, Gothenburg, Sweden.
    Johansson, Pernilla
    AstraZeneca, Gothenburg, Sweden.
    Karlsson, Eva
    AstraZeneca, Gothenburg, Sweden.
    Murphy, Donal
    AstraZeneca, London, England.
    Tannergren, Christer
    AstraZeneca, Gothenburg, Sweden.
    Thorn, Helena
    AstraZeneca, Gothenburg, Sweden.
    Yasin, Mohammed
    AstraZeneca, London, England.
    Mazuir, Florent
    Sanofi, Paris, France.
    Nicolas, Olivier
    Sanofi, Paris, France.
    Ramusovic, Sergej
    Sanofi, Frankfurt, Germany.
    Xu, Christine
    Sanofi, Bridgewater, NJ USA.
    Pathak, Shriram M.
    Korjamo, Timo
    Orion Pharma, Espoo, Finland.
    Laru, Johanna
    Orion Pharma, Espoo, Finland;AstraZeneca, London, England.
    Malkki, Jussi
    Orion Pharma, Espoo, Finland.
    Pappinen, Sari
    Orion Pharma, Espoo, Finland.
    Tuunainen, Johanna
    Orion Pharma, Espoo, Finland.
    Dressman, Jennifer
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Hansmanni, Simone
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Kostewicz, Edmund
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    He, Handan
    Novartis, New York, NY USA.
    Heimbach, Tycho
    Novartis, New York, NY USA.
    Wu, Fan
    Novartis, New York, NY USA.
    Hoft, Carolin
    AbbVie, Wiesbaden, Germany.
    Laplanche, Loic
    AbbVie, Wiesbaden, Germany.
    Pang, Yan
    AbbVie, Wiesbaden, Germany.
    Bolger, Michael B.
    Simulat Plus Inc, Lancaster, CA USA.
    Huehn, Eva
    Simulat Plus Inc, Lancaster, CA USA.
    Lukacova, Viera
    Simulat Plus Inc, Lancaster, CA USA.
    Mullin, James M.
    Simulat Plus Inc, Lancaster, CA USA.
    Szeto, Ke X.
    Simulat Plus Inc, Lancaster, CA USA.
    Costales, Chester
    Pfizer, New York, NY USA.
    Lin, Jian
    Pfizer, New York, NY USA.
    McAllister, Mark
    Pfizer, Tadworth, England.
    Modi, Sweta
    Pfizer, New York, NY USA.
    Rotter, Charles
    Pfizer, New York, NY USA.
    Varma, Manthena
    Pfizer, Tadworth, England.
    Wong, Mei
    Pfizer, Tadworth, England.
    Mitra, Amitava
    Merck Sharp & Dohme Ltd, Hoddesdon, Herts, England.
    Bevernage, Jan
    Janssen, Beerse, Belgium.
    Biewenga, Jeike
    Janssen, Beerse, Belgium.
    Van Peer, Achiel
    Janssen, Beerse, Belgium.
    Lloyd, Richard
    GlaxoSmithKline, Brentford, Middx, England.
    Shardlow, Carole
    GlaxoSmithKline, Brentford, Middx, England.
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Mishenzon, Irina
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Nguyen, Mai Anh
    Brown, Jonathan
    Bristol Myers Squibb, Uxbridge, Middx, England.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    AstraZeneca, Gothenburg, Sweden.
    IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and overview of results2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 96, p. 610-625Article in journal (Refereed)
    Abstract [en]

    Orally administered drugs are subject to a number of barriers impacting bioavailability (F-oral), causing challenges during drug and formulation development. Physiologically-based pharmacokinetic (PBPK) modelling can help during drug and formulation development by providing quantitative predictions through a systems approach. The performance of three available PBPK software packages (GI-Sim, Simcyp (R), and GastroPlus (TM)) were evaluated by comparing simulated and observed pharmacokinetic (PK) parameters. Since the availability of input parameters was heterogeneous and highly variable, caution is required when interpreting the results of this exercise. Additionally, this prospective simulation exercise may not be representative of prospective modelling in industry, as API information was limited to sparse details. 43 active pharmaceutical ingredients (APIs) from the OrBiTo database were selected for the exercise. Over 4000 simulation output files were generated, representing over 2550 study arm-institution-software combinations and approximately 600 human clinical study arms simulated with overlap. 84% of the simulated study arms represented administration of immediate release formulations, 11% prolonged or delayed release, and 5% intravenous (i.v.). Higher percentages of i.v. predicted area under the curve (AUC) were within two-fold of observed (52.9%) compared to per oral (p.o.) (37.2%), however, F-oral and relative AUC (F-rel) between p.o. formulations and solutions were generally well predicted (64.7% and 75.0%). Predictive performance declined progressing from i.v. to solution and immediate release tablet, indicating the compounding error with each layer of complexity. Overall performance was comparable to previous large-scale evaluations. A general overprediction of AUC was observed with average fold error (AFE) of 1.56 over all simulations. AFE ranged from 0.0361 to 64.0 across the 43 APIs, with 25 showing overpredictions. Discrepancies between software packages were observed for a few APIs, the largest being 606, 171, and 81.7-fold differences in AFE between SimCYP and GI-Sim, however average performance was relatively consistent across the three software platforms.

  • 41.
    Margolskee, Alison
    et al.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Darwich, Adam S.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Pepin, Xavier
    AstraZeneca, London, England;Sanofi, Paris, France.
    Pathak, Shriram M.
    Simcyp Ltd, Sheffield, S Yorkshire, England.
    Bolger, Michael B.
    Simulat Plus Inc, Lancaster, CA USA.
    Aarons, Leon
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Rostami-Hodjegan, Amin
    Simcyp Ltd, Sheffield, S Yorkshire, England;Univ Manchester, Manchester M13 9PL, Lancs, England.
    Angstenberger, Jonas
    AbbVie, Wiesbaden, Germany.
    Graf, Franziska
    AbbVie, Wiesbaden, Germany.
    Laplanche, Loic
    AbbVie, Wiesbaden, Germany.
    Mueller, Thomas
    AbbVie, Wiesbaden, Germany.
    Carlert, Sara
    AstraZeneca, Gothenburg, Sweden.
    Daga, Pankaj
    AstraZeneca, New York, NY USA.
    Murphy, Donal
    AstraZeneca, London, England.
    Tannergren, Christer
    AstraZeneca, Gothenburg, Sweden.
    Yasin, Mohammed
    AstraZeneca, London, England.
    Greschat-Schade, Susanne
    Bayer Pharma AG, Berlin, Germany.
    Mueck, Wolfgang
    Bayer Pharma AG, Berlin, Germany.
    Muenster, Uwe
    Bayer Pharma AG, Berlin, Germany.
    van der Mey, Dorina
    Bayer Pharma AG, Berlin, Germany.
    Frank, Kerstin Julia
    Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany.
    Lloyd, Richard
    GlaxoSmithKline, Brentford, Middx, England.
    Adriaenssen, Lieve
    Janssen, Beerse, Belgium.
    Bevernage, Jan
    Janssen, Beerse, Belgium.
    De Zwart, Loeckie
    Janssen, Beerse, Belgium.
    Swerts, Dominique
    Janssen, Beerse, Belgium.
    Tistaert, Christophe
    Janssen, Beerse, Belgium.
    Van Den Bergh, An
    Janssen, Beerse, Belgium.
    Van Peer, Achiel
    Janssen, Beerse, Belgium.
    Beato, Stefania
    Novartis, Basel, Switzerland.
    Nguyen-Trung, Anh-Thu
    Bennett, Joanne
    Pfizer, Tadworth, Middx, England.
    McAllister, Mark
    Pfizer, Tadworth, Middx, England.
    Wong, Mei
    Pfizer, Tadworth, Middx, England.
    Zane, Patricia
    Sanofi, Bridgewater, NJ USA.
    Ollier, Celine
    Sanofi, Paris, France.
    Vicat, Pascale
    Sanofi, Paris, France.
    Kolhmann, Markus
    Sanofi, Frankfurt, Germany.
    Marker, Alexander
    Sanofi, Paris, France.
    Brun, Priscilla
    Sanofi, Paris, France.
    Mazuir, Florent
    Sanofi, Paris, France.
    Beilles, Stephane
    Sanofi, Paris, France.
    Venczel, Marta
    Sanofi, Frankfurt, Germany.
    Boulenc, Xavier
    Sanofi, Paris, France.
    Loos, Petra
    Sanofi, Frankfurt, Germany.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    AstraZeneca, Gothenburg, Sweden.
    IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 96, p. 598-609Article in journal (Refereed)
    Abstract [en]

    Predicting oral bioavailability (F-oral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9 L/h (interquartile range: 11.6-43.6 L/h; n = 23), volume of distribution was 80.8 L (54.5-239 L; n = 23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n = 22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.

  • 42.
    Mihajlica, Nebojsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmacokinetics of Pericyte Involvement in Small-Molecular Drug Transport Across the Blood-Brain Barrier2018In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 122, p. 77-84Article in journal (Refereed)
    Abstract [en]

    Pericytes are perivascular cells that play important roles in the regulation of the blood-brain barrier (BBB) properties. Pericyte-deficiency causes compromised BBB integrity and increase in permeability to different macromolecules mainly by upregulated transcytosis. The aim of the present study was to investigate pericyte involvement in the extent of small-molecular drug transport across the BBB. This was performed with five compounds: diazepam, digoxin, levofloxacin, oxycodone and paliperidone. Compounds were administered at low doses via subcutaneous injections as a cassette (simultaneously) to pericyte-deficient Pdgfb(ret/ret) mice and corresponding WT controls. Total drug partitioning across the BBB was calculated as the ratio of total drug exposures in brain tissue and plasma (K-p,K-brain). In addition, equilibrium dialysis experiments were performed to estimate unbound drug fractions in brain (f(u,brain)) and plasma (f(u,plasma)). This enabled estimation of unbound drug partitioning coefficients (K-p,K-uu,K-brain). The results indicated slight tendencies towards increase of total brain exposures in Pdgfb(ret/ret) mice as reflected in K-p,K-brain values, which were within the 2-fold limit. Part of these differences could be explained by differences in plasma protein binding. No difference was found in brain tissue binding. The combined in vivo and in vitro data resulted in no differences in BBB transport in pericyte-deficiency, as described by similar K-p,K-uu,K-brain Values in Pdgfb(ret/ret) and control mice. In conclusion, these findings imply no influence of pericytes on the extent of BBB transport of small-molecular drugs, and suggest preserved BBB features relevant for handling of this type of molecules irrespective of pericyte presence at the brain endothelium.

  • 43.
    Neuhoff, Sibylle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ungell, Anna-Lena
    Zamora, Ismael
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    pH-Dependent passive and active transport of acidic drugs across Caco-2 cell monolayers2005In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 25, no 2-3, p. 211-220Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate pH-dependent passive and active transport of acidic drugs across Caco-2 cells. Therefore, the bidirectional pH-dependent transport of two acidic drugs, indomethacin and salicylic acid, across Caco-2 cells was studied in the physiological pH range of the gastrointestinal tract. The transport of both drugs decreased with increased pH, as expected from the pH-partition hypothesis. Net absorption occurred when the basolateral pH exceeded the apical pH. Concentration dependence and transporter inhibition studies indicated passive transport for indomethacin and a mixture of pH-dependent passive and active influx for salicylic acid. Unexpectedly, active and passive drug transport results were indistinguishable in temperature dependency studies. The transport of salicylic acid (apical pH 5.0; basolateral pH 7.4) was partly blocked by inhibitors of the proton-dependent transporters MCT1 (SLC16A1) and OATP-B (SLC21A9, SLCO2B1). This study shows that the asymmetry in bidirectional transport of acidic drugs is affected by both passive and active components in the presence of pH gradients across Caco-2 cells. Thus, combined studies of concentration-dependency and transport-inhibition are preferred when acidic drug transport is studied in a pH gradient. The findings of this in vitro study can be extrapolated to in vivo situations involving an acidic microclimate.

  • 44.
    Nilsson, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fasth, Karl Johan
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Tedroff, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Hartvig, Per
    Långström, Bengt
    Absorption of L-DOPA from the proximal small intestine studied in the rhesus monkey by positron emission tomography1999In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 7, no 3, p. 185-189Article in journal (Refereed)
    Abstract [en]

    Positron emission tomography (PET) seems to be a valuable method for the understanding of intestinal absorption mechanisms, for simultaneous quantitation of absorption rate and distribution kinetics to the tissues of interest after oral drug delivery. PET was evaluated in three Rhesus monkeys for quantitation of the absorption rate from the gastrointestinal tract and the distribution kinetics into different organs. To obtain optimal standardized conditions for the measurement of absorption the drug was administered via a naso-duodenal catheter directly to the absorption site in the proximal small intestine. l-DOPA was used as study drug given in a suspension together with carbidopa and the radiomarker l-[beta-11C]DOPA. The l-DOPA suspension was given into the duodenum without and after administration of a suspension of six l-amino acids (120 mM) in order to investigate any interaction on the intestinal absorption and distribution of l-DOPA into the liver and brain tissue. Intestinal absorption was in general minor during the first study period and higher together with administered l-amino acids. The somewhat contradictory result with increased absorption when amino acids were present in the intestinal lumen, may be a consequence of increased intestinal motility initiated by the nutrient load.

  • 45. Nyberg, Lars
    et al.
    Månsson, Wiking
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Seidegård, Janeric
    Borgå, Olof
    A convenient method for local drug administration at predefined sites in the entire gastrointestinal tract: experiences from 13 phase I studies2007In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 30, no 5, p. 432-440Article in journal (Refereed)
    Abstract [en]

    For local administration of drugs or enzyme inhibitors in the human gut, a small-bore, smooth tube was introduced through the nose, retrieved from the pharynx, equipped with a firm radio-opaque capsule, and swallowed. Peristalsis moves the capsule to the desired location in the gut where it is anchored before administration via the tube. Drug uptake is followed by plasma sampling.

    One capsule type is used for solutions, another for solid formulations. With solutions, repeated administrations could be done with the capsule being anchored for 24 h or longer or, alternatively, at several locations along the gut.

    This communication presents the method and an overview of 13 uptake and enzyme/transporter localization studies. Altogether, 268 intubations were undertaken in a total of 128 subjects. Plasma concentrations found with terbutaline and metoprolol are presented showing that terbutaline has its best uptake in the upper small intestine, whereas metoprolol shows the same bioavailability along the whole gut.

    Subjects could undertake most of their normal activities while carrying the equipment. No serious adverse events (AEs) occurred. Possibly intubation-related AEs were abdominal pain (n = 8) and constipation (n = 5).

    In conclusion, the method has been found to be safe, convenient and multifunctional for studies of drug uptake at predetermined gut locations in healthy subjects.

  • 46.
    Paulsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rheological studies of the gelation of deacetylated gellan gum (Gelrite®) in physiological conditions1999In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 9, no 1, p. 99-105Article in journal (Refereed)
    Abstract [en]

    Gels have been successfully used to increase the mucosal contact time and hence the bioavailability of nasal and ophthalmic formulations. The use of in situ gelling polymers requires a rapid sol-gel transition that produces a strong gel for an optimal contact time. In this study, the rheological behaviour of deacetylated gellan gum (Gelrite) was analysed in order to better understand the reasons for the good performance in humans. Thermal scans were used to study gel formation and other changes in the structure of the samples when the macromolecular and ionic contents were altered. The effect the different ions in tear fluid (Na+, K+, Ca2+) had on the gel strength and the consequences of dilution due to the ocular protective mechanisms were examined. Na+ was found to be the most important gel-promoting ion in vivo. It was also found that gels are formed in tear fluid even when the concentration of Gelrite) is only 0.1%. Samples with concentrations of Gelrite of 0.5-1% do not require more ions than 10-25% of those in tear fluid to form gels. These two findings can partly explain the good performance of Gelrite in vivo. Gels with a high elastic modulus can thus be formed even though dilution of instilled drops takes place.

  • 47.
    Paulsson, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hägerström, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Edsman, Katarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rheological studies of the gelation of deacetylated gellan gum (Gelrite®) in physiological conditions1999In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 9, no 1, p. 99-105Article in journal (Refereed)
    Abstract [en]

    Gels have been successfully used to increase the mucosal contact time and hence the bioavailability of nasal and ophthalmic formulations. The use of in situ gelling polymers requires a rapid sol-gel transition that produces a strong gel for an optimal contact time. In this study, the rheological behaviour of deacetylated gellan gum (Gelrite) was analysed in order to better understand the reasons for the good performance in humans. Thermal scans were used to study gel formation and other changes in the structure of the samples when the macromolecular and ionic contents were altered. The effect the different ions in tear fluid (Na+, K+, Ca2+) had on the gel strength and the consequences of dilution due to the ocular protective mechanisms were examined. Na+ was found to be the most important gel-promoting ion in vivo. It was also found that gels are formed in tear fluid even when the concentration of Gelrite) is only 0.1%. Samples with concentrations of Gelrite of 0.5-1% do not require more ions than 10-25% of those in tear fluid to form gels. These two findings can partly explain the good performance of Gelrite in vivo. Gels with a high elastic modulus can thus be formed even though dilution of instilled drops takes place.

  • 48.
    Pazesh, Samaneh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Persson, Ann-Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Berggren, Jonas
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect of milling on the plastic and the elastic stiffness of lactose particles2018In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 114, p. 138-145Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the effect of degree of amorphisation of a series of lactose powders, prepared by milling α-lactose monohydrate powders for different time periods, on the plastic stiffness of the particles. As references, a series of physical mixtures consisting of original crystalline particles and amorphous particles obtained by spray-drying was used. In addition, the effect of powder pre-storage humidity on the mechanical properties was investigated. The particle plastic stiffness was assessed by the Heckel yield pressure derived from the relationship between porosity of the powder column and the applied compression pressure during confined powder compression.

     

    For milled particles of a low degree of disorder, a decreased particle size increased the particle plastic stiffness. For milled particles of constant particle size, the plastic stiffness decreased with an increased degree of disorder while the elastic stiffness seemed independent of the degree of disorder. The presence of moisture caused a recrystallization of milled particles with low degree of disorder which increased their plastic stiffness.

     

    For the physical mixtures of crystalline and amorphous particles, similar relationships between plastic stiffness and amorphous content as for the milled powders were obtained. A reasonable explanation is that the nature of the milled particles is represented by a two-state system with crystalline and amorphous domains.

  • 49.
    Pedersen, Jenny M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. QPS LLC, Durham, NC USA..
    Khan, Elin K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Palm, Johan
    AstraZeneca R&D Gothenburg, Pharmaceut Technol & Dev, SE-43183 Molndal, Sweden..
    Hoogstraate, Janet
    AstraZeneca R&D, CNS, Sodertalje, Sweden.;AstraZeneca R&D, Pain Innovat Med DMPK, Sodertalje, Sweden.;Valneva Sweden AB, Solna, Sweden..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Substrate and method dependent inhibition of three ABC-transporters (MDR1, BCRP, and MRP2)2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 103, p. 70-76Article in journal (Refereed)
    Abstract [en]

    Drug transport and drug-drug interactions (DDI) with human ABC transporters are generally investigated in mammalian cell lines or inverted membrane vesicles from insect cells (Sf9) overexpressing the transporter of interest. In this study, we instead used membrane vesicles from human embryonic kidney cells (HEK293) overexpressing wild type MDR1/Pgp (ABCB1), BCRP (ABCG2), and MRP2 (ABCC2) with the aim to study the concentration dependent inhibition of shared and prototypic probe substrates. We first investigated 15 substrates and identified estrone-17-beta-glucorinide (E17G) as shared substrate. Nine specific and general inhibitors were then studied using El7G and prototypic probe substrates. The results were compared with those previously obtained in Sf9 vesicles and cell lines of canine (MDCKII) and human (Saos-2) origin. For the majority of inhibitors, K-i; values differed <10-fold between EI7G and probe substrates. Significant differences in K-i; values were observed for about one third of the inhibitors. The transport inhibition potencies in HEK293 vesicles were in good agreement with those obtained in Sf9 vesicles. Large differences were found in the inhibition potencies observed in the vesicular systems compared to the cellular systems. Nevertheless, the rank order correlations between the different experimental systems were generally good. Our study provides further information on substrate dependent inhibition of ABC-transporters, and suggests that simple ranking of compounds can be used as a tier one approach to bridge results obtained in different experimental systems.

  • 50.
    Persson, Ann-Sofie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alderborn, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Frenning, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Flowability of surface modified pharmaceutical granules: A comparative experimental and numerical study2011In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 42, no 3, p. 199-209Article in journal (Refereed)
    Abstract [en]

    Flowability - as measured by hopper discharge rate, angle of repose and Carr's index (CI) - of surface modified microcrystalline cellulose granules was investigated experimentally. Three-dimensional simulations of the granule flow were performed, using the discrete element method (DEM), including either sliding and rolling friction or sliding friction and cohesion in the model. Granule surface modification with polymer coating and lubrication was found to have a significant effect on the sliding friction coefficient. This effect was also reflected in the ensuing flow behaviour, as quantified by the experimental discharge rate and angle of repose, whereas the results for the Cl were inconclusive. The numerical results demonstrated that granular flow was qualitatively different for non-cohesive and cohesive granules, occurring in the form of individual particles for the former and in larger clusters for the latter. Rolling friction and cohesion nevertheless affected the simulated discharge rate in a similar manner, producing results comparable to those observed experimentally and calculated with the Beverloo equation. The numerical results for the cohesive granules demonstrated that cohesion alone was sufficient to produce stable heaps. However, the agreement with experimental data was satisfactory only for the non-cohesive granules, demonstrating the importance of rolling friction.

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