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  • 51. Langguth, P
    et al.
    Bermejo, M
    Lennernäs, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Preface.2006In: Eur J Pharm Sci, ISSN 0928-0987, Vol. 29, no 3-4, p. 173-Article in journal (Refereed)
  • 52.
    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.

  • 53. Lennernäs, B
    et al.
    Hedner, T
    Holmberg, M
    Bredenberg, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Nyström, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain.2005In: Br J Clin Pharmacol, ISSN 0306-5251, Vol. 59, no 2, p. 249-53Article in journal (Refereed)
  • 54.
    Lennernäs, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Drug transporters: Where is the research taking us?2004In: Eur J Pharm Sci, Vol. 23:S3-S4, Suppl 1Article in journal (Refereed)
  • 55.
    Lennernäs, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Intestinal permeability and its relevance for absorption and elimination2007In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 37, no 10-11, p. 1015-1051Article in journal (Refereed)
    Abstract [en]

    Human jejunal permeability (P-eff) is determined in the intestinal region with the highest expression of carrier proteins and largest surface area. Intestinal P-eff are often based on multiple parallel transport processes. Site-specific jejunal P-eff cannot reflect the permeability along the intestinal tract, but they are useful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunal P-eff > 1. 5 x 10(-4) cm s(-1) will be completely absorbed no matter which transport mechanism(s) are utilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinal absorption (i.e. > 85%) mediated by passive transcellular diffusion. The determined jejunal P-eff for drugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) will accurately predict the fraction of the dose absorbed as a consequence of the regional expression. The data also show that: (1) the human intestinal epithelium has a large resistance towards large and hydrophilic compounds; and (2) the paracellular route has a low contribution for compounds larger than approximately molecular weight 200. There is a need for more exploratory in vivo studies to clarify drug absorption and first-pass extraction along the intestine. One is encouraged to develop in vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This would stimulate the development of more relevant and complex in vitro absorption models and form the basis for an accurate physiologically based pharmacokinetic modelling of oral drug absorption.

  • 56.
    Lennernäs, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, B
    The biopharmaceutical classification system2006In: Comprehensive medicinal chemistry, Elsevier , 2006Chapter in book (Refereed)
  • 57.
    Lennernäs, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Lundgren, E
    Intestinal and blood-brain barrier drug transport: beyond involvement of a single transport function.2004In: Drug Discovery Today 1, Vol. 4, p. 417-Article in journal (Refereed)
  • 58.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Animal data: The contributions of the Ussing Chamber and perfusion systems to predicting human oral drug delivery in vivo2007In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 59, no 11, p. 1103-1120Article, review/survey (Refereed)
    Abstract [en]

    Oral administration dominates contemporary drug therapy and will most likely continue to do so as it is considered to be safe, efficient and easily accessible with minimal discomfort to the patient compared to other routes of administration such as intramuscular, subcutaneous, rectal and pulmonary delivery. However, despite these advantages, many of the mechanisms of drug uptake following oral administration remain to be fully characterized. In drug discovery and preclinical development there is a strong demand for the accurate and rapid characterization of processes such as absorption, distribution, metabolism and excretion. These biopharmaceutical/pharmacokinetic variables should also be related to pharmacodynamic and toxicological variables such potency and duration of effect. Although these processes are highly dynamic and complex, they are not yet fully characterized in vivo. Various in vitro pharmacokinetic screening methodologies have significantly increased the amount of experimental data generated in this part of the drug discovery process. In addition to these techniques, there is a strong need for in silico methods that may be used to accurately predict pharmacokinetic properties from molecular structure. For instance, pharmacokinetic filters that can sort out compounds with undesirable pharmacokinetic properties can be applied to virtual screening or compound design to reduce attrition rates. The aim of this review is to summarize reported human permeability values and to evaluate how they correlate to corresponding rat intestinal permeability data obtained in single-pass perfusion and Ussing Chamber experiments. The human permeability data are based on direct in vivo determinations in the human gastrointestinal tract with a single-pass perfusion system. The focus of this attention is particularly justified as the availability of directly determined in vivo permeability data in the literature is limited. In addition, there is a shortage of intestinal permeability studies in other mammals.

  • 59.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Human in Vivo Regional Intestinal Permeability: Importance for Pharmaceutical Drug Development2014In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 1, p. 12-23Article, review/survey (Refereed)
    Abstract [en]

    Both the development and regulation of pharmaceutical dosage forms have undergone significant improvements and development over the past 25 years, due primarily to the extensive application of the biopharmaceutical classification system (BCS). The Biopharmaceutics Drug Disposition Classification System, which was published in 2005, has also been a useful resource for predicting the influence of transporters in several pharmacokinetic processes. However, there remains a need for the pharmaceutical industry to develop reliable in vitro/in vivo correlations and in silica methods for predicting the rate and extent of complex gastrointestinal (GI) absorption, the bioavailability, and the plasma concentration time curves for orally administered drug products. Accordingly, a more rational approach is required, one in which high quality in vitro or in silico characterizations of active pharmaceutical ingredients and formulations are integrated into physiologically based in silica biopharmaceutics models to capture the full complexity of GI drug absorption. The need for better understanding of the in vivo GI process has recently become evident after an unsuccessful attempt to predict the GI absorption of BCS class II and IV drugs. Reliable data on the in vivo permeability of the human intestine (P-eff) from various intestinal regions is recognized as one of the key biopharmaceutical requirements when developing in silico GI biopharmaceutics Models with improved predictive accuracy. The P-eff values for human jejunum and ileum, based on historical open, single-pass, perfusion studies are presented in this review. The main objective of this review is to summarize and discuss the relevance and current status of these human in vivo regional intestinal permeability values.

  • 60.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Modeling gastrointestinal drug absorption requires more in vivo biopharmaceutical data: experience from in vivo dissolution and permeability studies in humans2007In: Current drug metabolism, ISSN 1389-2002, E-ISSN 1875-5453, Vol. 8, no 7, p. 645-657Article, review/survey (Refereed)
    Abstract [en]

    The majority (84%) of the 50 most-sold pharmaceutical products in the US and European markets are given orally. The dominating role of this route in drug therapy is a consequence of it being safe, efficient and easily accessible with minimal discomfort to the patient in comparison with other routes of drug administration. A successful drug discovery and development of oral pharmaceutical products require an in-depth understanding of multiple biochemical and physiological processes that determine the dissolution rate, intestinal permeability, gastrointestinal transit, first-pass extraction and systemic exposure-time profiles of drugs. It is crucial to realize that these basic biopharmaceutic and pharmacokinetic properties are crucial to focus on to allow successful drug development. Identification of the rate-limiting step(s) in order to overcome these barriers and understanding of the sources of variability are important in the selection of suitable candidate molecules in drug development. Several reports based on in vitro investigations in various cell models have suggested that carrier-mediated intestinal efflux may be a major reason for incomplete absorption and variable bioavailability of drugs, as well being a site for drug-drug and specific food-drug interactions. However, many drugs which were initially suggested to undergo significant efflux in vitro were later shown to be completely absorbed in vivo. This apparent discrepancy between in vitro and in vivo results may be due to several factors that will be discussed in this review. Novel data on solubility and dissolution in human gastrointestinal derived fluids will be reviewed. The effect of food intake on solubility and dissolution rate of a range of drugs including felodipine, danazol, griseofulvin, cyclosporine, probucol and ubiquinone in simulated and real intestinal fluids is discussed. The biopharmaceutic and physicochemical data discussed here can potentially be used as a benchmark set for validation of new experimental techniques or in silico models in future. Factors such as structural diversity, commercial availability, price and a suitable analytical technique for quantification were considered in the selection of a specific drug set. Using the compiled data set lipophilicity as determined by reverse phase HPLC and permeability across Caco-2 cell monolayers were determined; means to overcome the experimental difficulties due to the diversity of the data are also discussed.

  • 61.
    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.

  • 62.
    Lennernäs, Hans
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    The use of biopharmaceutic classification of drugs in drug discovery and development: current status and future extension.2005In: J Pharm Pharmacol, ISSN 0022-3573, Vol. 57, no 3, p. 273-85Article in journal (Refereed)
  • 63.
    Lennernäs, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Persson, EM
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Oral drug absorption and the biopharmaceutics classification system2007In: Journal of drug delivery science and technology, ISSN 1773-2247, Vol. 17, no 4, p. 237-244Article, review/survey (Refereed)
    Abstract [en]

    Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development and BE studies are presently being conducted for New Drug Application (NDAs) of new compounds, in supplementary NDAsfor new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs) of generic products and in applications for scale-up and post-approval changes. The Biopharmaceutics Classification System (BCS) has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediate release (IR) dosage form. The aim of BCS is to provide a regulatory tool for replacing certain BE studies by accurate in vitro dissolution tests. The aim of the present review is to present the status of BCS and discuss its future application in pharmaceutical product development. This will be discussed in relation to novel findings in human intestinal absorption, permeability and solubility. The future application of BCS is likely to be increasingly important if the BCS borders for certain Class II and III drugs are extended. The BCS is also a simple tool in early drug development to determine the rate-limiting step in the oral absorption process, which has facilitated the information between different experts involved in the overall drug development process. In the future, this increased awareness of a proper biopharmaceutical characterization of new drugs may result in drug molecules with a sufficiently high permeability, solubility and dissolution rate that will automatically increase the importance of BCS as a regulatory tool over time.

  • 64.
    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)
  • 65.
    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)
  • 66.
    Lennernäs, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lindahl, A.
    Med Prod Agcy, Uppsala, Sweden..
    Van Peer, A.
    Janssen Pharmaceut NV, Janssen Res & Dev, Turnhoutseweg 30, B-2340 Beerse, Belgium..
    Ollier, C.
    Sanofi US, 55 Corp Dr, Bridgewater, NJ 08807 USA..
    Flanagan, T.
    AstraZeneca R&D, Macclesfield, Cheshire, England..
    Lionberger, R.
    US FDA, Off Res & Stand, Off Gener Drugs, Ctr Drug Evaluat & Res, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA..
    Nordmark, A.
    Med Prod Agcy, Uppsala, Sweden..
    Yamashita, S.
    Setsunan Univ, Fac Pharmaceut Sci, Nagaotoge Cho 45-1, Hirakata, Osaka 5730101, Japan..
    Yu, L.
    US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA..
    Amidon, G. L.
    Univ Michigan, Coll Pharm, Ann Arbor, MI 48109 USA..
    Fischer, V.
    AbbVie, Drug Metab & Pharmacokinet, Res & Dev, N Chicago, IL 60064 USA..
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Zane, P.
    Sanofi US, 55 Corp Dr, Bridgewater, NJ 08807 USA..
    McAllister, M.
    GlaxoSmithKline, Pharmaceut Dev, New Frontiers Sci Pk, Harlow CM19 5AW, Essex, England..
    Abrahamsson, B.
    AstraZeneca R&D, Gothenburg, Sweden..
    In Vivo Predictive Dissolution (IPD) and Biopharmaceutical Modeling and Simulation: Future Use of Modern Approaches and Methodologies in a Regulatory Context2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 4, p. 1307-1314Article in journal (Refereed)
    Abstract [en]

    The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational Models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo meeting in 2015 was dedicated: to the presentation of the most recent progress in the development of the regulatory use of PBPK in silk() modeling, in vivo predictive dissolution (IPD) tests, and their application to biowaivers. There are still several areas for improvement of in vitro dissolution testing by means of generating results relevant for the intraluminal conditions in the GI tract. The major opportunity is probably in combining IPD testing and physiologically based in silico models where the in vitro data provide input to the absorption predictions. The OrBiTo project and other current research projects include-definition of test media representative for the more distal parts of the GI tract, models capturing supersaturation and precipitation phenomena, and influence of motility waves on shear and other forces of hydrodynamic origin, addressing the inter individual variability in composition and characteristics of GI fluids, food effects, definition of biorelevant buffer systems, and intestinal water volumes. In conclusion, there is currently a mismatch between the extensive industrial usage of modern in vivo predictive tools and very limited inclusion of such data in regulatory files. However, there is a great interest among all stakeholders to introduce recent progresses in prediction of in vivo GI drug absorption into regulatory context.

  • 67.
    Lilienberg, Elsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dubbelboer, Ilse R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Karalli, Amar
    Karolinska Univ Hosp Huddinge, Dept Radiol, Stockholm, Sweden.; Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden..
    Axelsson, Rimma
    Karolinska Univ Hosp Huddinge, Dept Radiol, Stockholm, Sweden.; Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden..
    Brismar, Torkel B,
    Karolinska Univ Hosp Huddinge, Dept Radiol, Stockholm, Sweden.; Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden..
    Ebeling Barbier, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Norén, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Duraj, Frans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Hedeland, Mikael
    Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden..
    Bondesson, Ulf
    Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Stål, Per
    Karolinska Inst, Dept Internal Med Huddinge, Gastroenterol Unit, Stockholm, Sweden.; Karolinska Univ Hosp Huddinge, Dept Digest Dis, Stockholm, Sweden..
    Nyman, Rickard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In vivo Drug Delivery Performance of Lipiodol-based Emulsion or Drug-eluting Beads in Patients with Hepatocellular Carcinoma2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 2, p. 448-458Article in journal (Refereed)
    Abstract [en]

    Doxorubicin (DOX) delivered in a lipiodol-based emulsion (LIPDOX) or in drug-eluting beads (DEBDOX) is used as palliative treatment in patients with intermediate-stage hepatocellular carcinoma (HCC). The primary objective of this study was to evaluate the in vivo delivery performance of DOX from LIPDOX or DEBDOX in HCC patients using the local and systemic pharmacokinetics of DOX and its main metabolite doxorubicinol (DOXol). Urinary excretion of DOX and DOXol, and their short-term safety and anti-tumor effects were also evaluated. In this open, prospective, non-randomized multi-center study, LIPDOX (n=13) or DEBDOX (n=12) were injected into the feeding arteries of the tumor. Local (vena cava/hepatic vein orifice) and systemic (peripheral vein) plasma concentrations of DOX and DOXol were determined in samples obtained up to 6 h and 7 days after treatment. Tumor response was assessed using computed tomography or magnetic resonance imaging. The Cmax and AUC0-24 h for DOX were 5.6-fold and 2.4-fold higher in LIPDOX vs DEBDOX recipients, respectively (p <0.001). After 6 h, the respective mean proportions of the dose remaining in the liver or drug-delivery system (DDS) were 49% for LIPDOX and 88% for DEBDOX. LIPDOX releases DOX faster than DEBDOX in HCC patients and provides more extensive local and systemic exposure (AUC) to DOX and DOXol initially (0-7 days). DEBDOX formulation has a release and distribution of DOX that is more restricted and rate controlled than LIPDOX.

  • 68.
    Lilienberg, Elsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dubbelboer, Ilse R
    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.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lipiodol does not affect the tissue distribution of intravenous doxorubicin infusion in pigs2017In: Journal of Pharmacy and Pharmacology (JPP), ISSN 0022-3573, E-ISSN 2042-7158, Vol. 69, no 2, p. 135-142Article in journal (Refereed)
    Abstract [en]

    ObjectivesIn liver cancer treatment, lipiodol is used as a pharmaceutical excipient to improve delivery of the cytostatic drug doxorubicin (DOX). As DOX and its metabolite doxorubicinol (DOXol) cause serious off-target adverse effects, we investigated the effects of drug-free lipiodol or ciclosporin (CsA) on the tissue distribution (K-p) of DOX and DOXol in relevant pig tissues. MethodsFour treatment groups (TI-TIV) all received an intravenous DOX solution at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), lipiodol (TII), CsA (TIII) or lipiodol and CsA (TIV). After 6 h, the pigs were euthanised, and liver, kidney, heart and intestine samples were collected and analysed. Key findingsThe tissue DOX concentrations were highest in the kidney (TI-TIV). All the investigated tissues showed extensive DOX K-p. Lipiodol had no effect on the K-p of DOX to any of the tissues. However, the tissue concentrations of DOX were increased by CsA (in liver, kidney and intestine, P < 0.05). ConclusionLipiodol injected into the portal vein does not affect the tissue distribution of DOX and DOXol.

  • 69.
    Lilienberg, Elsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ebeling-Barbier, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Nyman, Rickard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    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.
    Axén, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernas, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Investigation of Hepatobiliary Disposition of Doxorubicin Following Intrahepatic Delivery of Different Dosage Forms2014In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 1, p. 131-144Article in journal (Refereed)
    Abstract [en]

    Unresectable, intermediate stage hepatocellular carcinoma (HCC) is often treated palliatively in humans by doxorubicin (DOX). The drug is administered either as a drug-emulsified-in-Lipiodol (DLIP) or as drug loaded into drug eluting beads (DEB), and both formulations are administered intrahepatically. However, several aspects of their in vivo performance in the liver are still not well-understood. In this study, DLIP and DEB were investigated regarding the local and systemic pharmacokinetics (PK) of DOX and its primary metabolite doxorubicinol (DOXol). An advanced PK-multisampling site acute in vivo pig model was used for simultaneous sampling in the portal, hepatic, and femoral veins and the bile duct. The study had a randomized, parallel design with four treatment groups (TI–TIV). TI (n = 4) was used as control and received an intravenous (i.v.) infusion of DOX as a solution. TII and TIII were given a local injection in the hepatic artery with DLIP (n = 4) or DEB (n = 4), respectively. TIV (n = 2) received local injections of DLIP in the hepatic artery and bile duct simultaneously. All samples were analyzed for concentrations of DOX and DOXol with UPLC-MS/MS. Compared to DLIP, the systemic exposure for DOX with DEB was reduced (p < 0.05), in agreement with a slower in vivo release. The approximated intracellular bioavailability of DOX during 6 h appeared to be lower for DEB than DLIP. Following i.v. infusion (55 min), DOX had a liver extraction of 41 (28–53)%, and the fraction of the dose eliminated in bile of DOX and DOXol was 20 (15–22)% and 4.2 (3.2–5.2)%, respectively. The AUCbile/AUCVP for DOX and DOXol was 640 (580–660) and 5000 (3900–5400), respectively. In conclusion, DLIP might initially deliver a higher hepatocellular concentration of DOX than DEB as a consequence of its higher in vivo release rate. Thus, DLIP delivery results in higher intracellular peak concentrations that might correlate with better anticancer effects, but also higher systemic drug exposure and safety issues.

  • 70. Lindahl, A
    et al.
    Sjöberg, Å
    Bredberg, U
    Ungell, A-L
    Lennernäs, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Regional intestinal absorption and biliary excretion of fluvastatin in the rat: Possible involvement of mrp2.2004In: Molecular Pharmaceutics 1, Vol. 5, p. 347-Article in journal (Refereed)
  • 71.
    Lindell, Monica
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lang, Matti
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Biokemi.
    Lennernäs, Hans
    Department of Pharmacy.
    Expression of genes encoding for drug metabolising cytochrome P450 enzymes and P-glycoprotein in the rat small intestine: comparison to the liver2003In: Eur. J. Drug Metab. & Pharmacokin., Vol. 28, p. 41-48Article in journal (Refereed)
  • 72.
    Lundahl, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Åberg, Annica Tevell
    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.
    Lennernäs, Hans
    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.
    High-resolution mass spectrometric investigation of the phase I and II metabolites of finasteride in pig plasma, urine and bile2014In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 44, no 6, p. 498-510Article in journal (Refereed)
    Abstract [en]

    1. The metabolite profile of the 5 alpha-reductase type II inhibitor finasteride has been studied in pig plasma, urine and bile using high-resolution mass spectrometry. The porcine biotransformation products were compared to those formed by human liver microsomes and to literature data of recently identified human in vivo metabolites. The objective of this study was to gain further evidence for the validity of using pigs for advanced, invasive drug-drug interaction studies that are not possible to perform in humans. 2. The use of high-resolution mass spectrometry with accurate mass measurements enabled identification of the metabolites by calculation of their elemental compositions as well as their fragmentation patterns. 3. There was an excellent match between the porcine and human metabolic profiles, corroborating the pig as a model of human drug metabolism. The glucuronides of the two recently described human hydroxylated metabolites MX and MY and the carboxylated metabolite M3 were identified as the major biotransformation products of finasteride in pig urine and bile. 4. Furthermore, the CYP enzymes involved in the formation of the hydroxylated metabolites were characterized. Human recombinant CYP3A4 could produce the two major hydroxylated metabolites MX and MY, whereas human recombinant CYP2D6 formed MY only.

  • 73.
    Malm-Erjefalt, Monika
    et al.
    Novo Nordisk AS, DK-2860 Soborg, Denmark..
    Ekblom, Marianne
    Novo Nordisk AS, DK-2860 Soborg, Denmark..
    Vouis, Jan
    Quintiles AB, Phase Serv 1, SE-75323 Uppsala, Sweden..
    Zdravkovic, Milan
    Novo Nordisk AS, DK-2860 Soborg, Denmark..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect on the Gastrointestinal Absorption of Drugs from Different Classes in the Biopharmaceutics Classification System, When Treating with Liraglutide2015In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 12, no 11, p. 4166-4173Article in journal (Refereed)
    Abstract [en]

    Like other GLP-1 receptor agonists used for treatment of type 2 diabetes, liraglutide delays gastric emptying. In this clinical absorption study, the primary objective was to investigate the effect of liraglutide (at steady state) on the rate and/or extent of gastrointestinal (GI) absorption of concomitantly orally taken drugs from three classes of the Biopharmaceutics Classification System (BCS). To provide a general prediction on liraglutide drugdrug absorption interaction, single-dose pharmacokinetics of drugs representing BCS classes II (low solubility-high permeability; atorvastatin 40 mg and griseofulvin 500 mg), III (high solubilitylow permeability; lisinopril 20 mg), and IV (low solubility-low permeability; digoxin 1 mg) were studied in healthy subjects at steady state of liraglutide 1.8 mg, or placebo, in a two-period crossover design. With liraglutide, the oral drugs atorvastatin, lisinopril, and digoxin showed delayed t(max) (by <= 2 h) and did not meet the criterion for bioequivalence for C-max (reduced C-max by 27-38%); griseofulvin had similar tmax and 37% increased C-max. Although the prespecified bioequivalence criterion was not met by all drugs, the overall plasma exposure (AUC) of griseofulvin, atorvastatin, lisinopril, and digoxin only exhibited minor changes and was not considered to be of clinical relevance.

  • 74.
    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.

  • 75.
    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.

  • 76.
    Matsson, Elin M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Eriksson, Ulf G.
    Palm, Johan E.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lazorova, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Brannstrom, Marie
    Ekdahl, Anja
    Duner, Kristina
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Johansson, Susanne
    Schutzer, Kajs-Marie
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Combined in Vitro-in Vivo Approach To Assess the Hepatobiliary Disposition of a Novel Oral Thrombin Inhibitor2013In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 10, no 11, p. 4252-4262Article in journal (Refereed)
    Abstract [en]

    Two clinical trials and a large set of in vitro transporter experiments were performed to investigate if the hepatobiliary disposition of the direct thrombin inhibitor prodrug AZD0837 is the mechanism for the drug-drug interaction with ketoconazole observed in a previous clinical study. In Study 1, [H-3]AZD0837 was administered to healthy male volunteers (n = 8) to quantify and identify the metabolites excreted in bile. Bile was sampled directly from the jejunum by duodenal aspiration via an oro-enteric tube. In Study 2, the effect of ketoconazole on the plasma and bile pharmacokinetics of AZD0837, the intermediate metabolite (AR-H069927), and the active form (AR-H067637) was investigated (n = 17). Co-administration with ketoconazole elevated the plasma exposure to AZD0837 and the active form approximately 2-fold compared to placebo, which may be explained by inhibited CYP3A4 metabolism and reduced biliary clearance, respectively. High concentrations of the active form was measured in bile with a bile-to-plasma AUC ratio of approximately 75, indicating involvement of transporter-mediated excretion of the compound. AZD0837 and its metabolites were further investigated as substrates of hepatic uptake and efflux transporters in vitro. Studies in MDCK-MDRI cell monolayers and P-glycoprotein (P-gp) expressing membrane vesicles identified AZD0837, the intermediate, and the active form as substrates of P-gp. The active form was also identified as a substrate of the multidrug and toxin extrusion 1 (MATE!) transporter and the organic cation transporter 1 (OCT1), in HEK cells transfected with the respective transporter. Ketoconazole was shown to inhibit all of these three transporters; in particular, inhibition of P-gp and MATE1 occurred in a clinically relevant concentration range. In conclusion, the hepatobiliary transport pathways of AZD0837 and its metabolites were identified in vitro and in vivo. Inhibition of the canalicular transporters P-gp and MATE1 may lead to enhanced plasma exposure to the active form, which could, at least in part, explain the clinical interaction with ketoconazole.

  • 77. Meijer, Dirk K F
    et al.
    Lennernäs, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    EUFEPS conference on drug transporters at Copenhagen: integrative approaches in ADME research.2005In: Eur J Pharm Sci, ISSN 0928-0987, Vol. 26, no 1, p. 130-43Article in journal (Refereed)
  • 78. Nilsson, A. G.
    et al.
    Marelli, C.
    Fitts, D.
    Bergthorsdottir, R.
    Burman, P.
    Dahlqvist, P.
    Ekman, B.
    Engstrom, B. Eden
    Olsson, T.
    Ragnarsson, O.
    Ryberg, M.
    Wahlberg, J.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Skrtic, S.
    Johannsson, G.
    Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency2014In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 171, no 3, p. 369-377Article in journal (Refereed)
    Abstract [en]

    Objective: The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). Design: Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. Methods: Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20-40 mg once daily and hydrocortisone 20-40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). Results: In stage 1, patients had a median 1.5 (range, 1-9) intercurrent illness events with DR-HC and 1.0 (1-8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1-3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. Conclusions: This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy. European Journal of Endocrinology

  • 79.
    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.

  • 80.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Gomes-Trolin, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Knutson, Tina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nyström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets2003In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 26, no 3, p. 156-163Article in journal (Refereed)
    Abstract [en]

    Continuous duodenal infusion of carbidopa/levodopa has been shown to control motor fluctuations in advanced Parkinson's disease (PD). The authors compared the pharmacokinetics of levodopa and 3-O-methyldopa in patients with advanced PD after administration of an oral sustained-release levodopa preparation and after continuous intestinal levodopa infusion with a new formulation as a gel suspension. A randomized crossover trial was carried out in 12 patients. Carbidopa/levodopa was administered as an oral sustained-release tablet and by nasoduodenal continuous infusion for 3-week periods for each treatment. Plasma levodopa concentrations and motor performance were evaluated every 30 minutes during 3 test days of each treatment period. The average intraindividual coefficient of variation for the plasma levodopa concentrations after oral therapy was 34% and was significantly lower (14%, p < 0.01) during continuous infusion. Hourly video evaluations showed a significant increase in ON time during infusion and a significant decrease in OFF time and dyskinesia. Continuous intraduodenal delivery of a new carbidopa/levodopa formulation offers a means for markedly improved control of motor fluctuations in late stages of PD.

  • 81.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Johansson, Anders
    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.
    Hellquist, Elisabeth
    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.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Complexity of Motor Response to Different Doses of Duodenal Levodopa Infusion in Parkinson Disease2012In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 35, no 1, p. 6-14Article, review/survey (Refereed)
    Abstract [en]

    OBJECTIVE:

    The aim was to elaborately describe individual pharmacokinetic-pharmacodynamic profiles in patients with difficult-to-treat dyskinesias treated with levodopa/carbidopa intestinal gel infusion.

    METHODS:

    A nonrandomized, partly blinded, investigator-initiated trial was conducted in 5 patients with idiopathic Parkinson disease who were difficult to keep in "on" state without dyskinesia. Levodopa/carbidopa intestinal gel (Duodopa) doses of 80% to 120% of individually and clinically optimized dosage were infused during five 4-hour periods. Pharmacokinetic profiling, blinded assessment of video recordings, and objective movement analysis were applied every 20 to 30 minutes.

    RESULTS:

    Individual correlations between plasma levodopa concentrations and corresponding motor scores 20 to 30 minutes after the sampling time were significant in all patients (P < 0.05 and P < 0.001). Motor scores were generally stable during the 4-hour periods. The objective test revealed that motor performance was faster the more dyskinetic the patients were. Mean individual Treatment Response Scale scores were positive in 24 of the 25 steady-state periods. Dystonia was always combined with choreic dyskinesias.

    CONCLUSIONS:

    Motor response from different doses of levodopa/carbidopa intestinal gel is in a broad sense predictable even in dyskinetic patients although major interindividual differences in dose requirement, plasma levels, and motor response are found. That motor performance was faster the more dyskinetic the patients were implies that motor performance may be better with moderate dyskinesia than with mild dyskinesia. This may explain why patients with persistent dyskinesias choose to keep their doses above the dyskinesia threshold. There is no ideal therapeutic window in such patients, but levodopa infusion offers stable motor response.

  • 82.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Johansson, Anders
    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.
    Askmark, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Levodopa infusion combined with entacapone or tolcapone in Parkinson disease: a pilot trial2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no 6, p. 820-826Article in journal (Refereed)
    Abstract [en]

    Background and purpose: 

    Catechol-O-methyltransferase inhibitors may be used to decrease levodopa requirement. The objective was to investigate whether the levodopa/carbidopa intestinal gel infusion dose can be reduced by 20% without worsening of motor fluctuations and levodopa concentration stability when oral catechol-O-methyltransferase inhibitors are added.

    Methods: 

    A short-term, randomized, partly blinded, crossover, investigator-initiated clinical trial was performed, with levodopa/carbidopa intestinal gel combined with oral entacapone and tolcapone on two different days in 10 patients. The primary outcome measure was difference in coefficient of variation of levodopa in plasma between levodopa/carbidopa, levodopa/carbidopa/entacapone, and levodopa/carbidopa/tolcapone. The secondary outcome measures other pharmacokinetic variables, patient-reported outcome, and blinded analysis of motor performance.

    Results:

    Variation of plasma levodopa concentrations did not differ significantly between the treatments. The treatments did not differ regarding motor performance. Levodopa concentrations were significantly higher using tolcapone. Concentrations of the metabolite 3-O-methyldopa decreased gradually during catechol-O-methyltransferase inhibition.

    Conclusions: 

    According to this small, short-term pilot study, oral catechol-O-methyltransferase inhibitors administered in 5-h intervals may be useful in cases where levodopa/carbidopa intestinal gel dose reduction is wanted. Stability of plasma levodopa levels is not significantly altered, and off-time is not increased when decreasing the levodopa/carbidopa intestinal gel dose by 20%. Rather, the dose should probably be decreased more than 20%, especially under tolcapone co-treatment, to avoid increased dyskinesias with time.

  • 83.
    Nyholm, Dag
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gomes-Trolin, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Aquilonius, Sten-Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson's disease on individual drug combinations2002In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 25, no 2, p. 89-96Article in journal (Refereed)
    Abstract [en]

    Pharmacokinetics and pharmacodynamics of levodopa were evaluated at a high-resolution level in a heterogeneous group of 10 patients with idiopathic Parkinson's disease during their normal daily activity. A physician and a nurse spent 10 hours with each patient from the first morning dose of levodopa during daily activities at home and at work. Plasma samples were obtained every 20 minutes for analysis of levodopa and 3-O-methyldopa by high-performance liquid chromatography. To assess clinical response, mobility was rated on every test occasion by patients and by investigators. Food and fluid intake and physical activity were also monitored. There was a large intra- and interindividual variability in the pharmacokinetics of levodopa regardless of the different drug combinations used. Mean plasma levodopa concentration ranged between 0.45 to 7.07 µg/mL and peak concentrations between 0.95 to 13.75 µg/mL. In 44 of 58 dosing events, an oral dose of levodopa was related to a peak in plasma concentration. Assessment of the clinical effects was more sensitive when given by patients than when given by the investigators. The fluctuations of the levodopa concentration in plasma had a clear effect on the clinical parameters assessed, even during early disease stages. Variation in levodopa concentration is the determining factor for motor fluctuations also in patients on clinically optimized combinations with dopamine agonists and enzyme inhibitors.

  • 84.
    Nyholm, 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.
    Johansson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Estrada, Matias
    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.
    Circadian rhythmicity in levodopa pharmacokinetics in patients with Parkinson disease2010In: Clinical neuropharmacology, ISSN 0362-5664, E-ISSN 1537-162X, Vol. 33, no 4, p. 181-185Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:: The purpose of this study was to compare daytime and nighttime plasma pharmacokinetics (PK) of levodopa in patients with Parkinson disease. METHODS:: Four-hour plasma profiles of levodopa were captured in 8 patients with Parkinson disease after the second daily levodopa dose and after the identical dose at bedtime. Patients were fasting 2 hours before and 2 hours after dose intakes, except standardized amounts of tap water. Body position was upright during daytime testing and supine during nighttime testing. Four patients were additionally tested at daytime in supine position. RESULTS:: The absorption rate was significantly delayed at nighttime dosing. The time at which the maximum peaks occurred was delayed from 25 (15-240) to 105 (20-240) minutes, respectively. Maximum concentrations were significantly lower at night, but the plasma exposure (area under the curve, 0-4 hours) was unaffected. Supine daytime plasma PK was in between day and night results. CONCLUSIONS:: There is a slower absorption rate of levodopa during nighttime, probably related to delayed gastric emptying. However, the extent of absorption and bioavailability were unaffected. As the effect of posture on plasma PK was less than the effect of nighttime, this study suggests that the circadian rhythm has a pronounced effect on gastric emptying and absorption rate. Nevertheless, body position may also be an important factor, and it can be recommended that levodopa tablets be taken in upright position that probably should be sustained for at least 30 minutes.

  • 85.
    Olivares-Morales, Andres
    et al.
    Univ Manchester, Manchester Pharm Sch, Ctr Appl Pharmacokinet Res, Manchester M13 9PT, Lancs, England..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Aarons, Leon
    Univ Manchester, Manchester Pharm Sch, Ctr Appl Pharmacokinet Res, Manchester M13 9PT, Lancs, England..
    Rostami-Hodjegan, Amin
    Univ Manchester, Manchester Pharm Sch, Ctr Appl Pharmacokinet Res, Manchester M13 9PT, Lancs, England.;Certara, Blades Enterprise Ctr, Sheffield, S Yorkshire, England..
    Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption2015In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 17, no 5, p. 1177-1192Article in journal (Refereed)
    Abstract [en]

    Regional intestinal effective permeability (P-eff) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P-eff values. These new intestinal Peff values or "intrinsic" P-eff(P-eff,P-int) were subsequently employed for the prediction of the ileal absorption clearance (CLabs,ileum) for a set of structurally diverse compounds. Additionally, the method was combined with a semi-mechanistic absorption PBPK model for the prediction of the fraction absorbed (f(abs)). The results showed that Peff, int can successfully be employed for the prediction of the ileal CLabs and the f(abs). P-eff,P-int also showed to be a robust predictor of the f(abs) when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f(abs) observed for lowly permeable compounds when using the historical P-eff values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.

  • 86.
    Persson, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Löfgren, Lars
    Hansson, Göran
    Abrahamsson, Bertil
    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.
    Nilsson, Ralf
    Simultaneous assessment of lipid classes and bile acids in human intestinal fluid by solid-phase extraction and HPLC methods2007In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 48, no 1, p. 242-251Article in journal (Refereed)
    Abstract [en]

    The purpose of the study reported here was to develop a method for the determination of lipid classes in intestinal fluids, including bile acids (BAs). A solid-phase extraction (SPE) method using C18 and silica columns for the separation of BAs, phospholipids (PLs), and neutral lipids (NLs), including free fatty acids, has been developed and validated. Fed-state small intestinal fluid collected from humans was treated with orlistat to inhibit lipolysis and mixed with acetic acid and methanol before SPE to maximize lipid recoveries. BAs, PLs, and NLs were isolated using lipophilic and polar solvents to promote elution from the SPE columns. The different lipid classes were subsequently analyzed using three separately optimized HPLC methods with evaporative light-scattering detectors. High recoveries (>90%) of all lipids evaluated were observed, with low coefficients of variation (<5%). The HPLC methods developed were highly reproducible and allowed baseline separation of nearly all lipid classes investigated. In conclusion, these methods provide a means of lipid class analysis of NLs, PLs, and BAs in human fed-state small intestinal fluid, with potential use in other fluids from the intestinal tract and animals.

  • 87.
    Persson, Eva M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gustafsson, Ann-Sofie
    Carlsson, Anders S
    Nilsson, Ralf G
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Forsell, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hanisch, Gunilla
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids2005In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 22, no 12, p. 2141-2151Article in journal (Refereed)
    Abstract [en]

    Purpose  This study was conducted to determine the effect of food on drug solubility and dissolution rate in simulated and real human intestinal fluids (HIF). Methods  Dissolution rate obtained via the rotating disk method and saturation solubility studies were carried out in fed and fasted state HIF, fed dog (DIF), and simulated (FeSSIF) intestinal fluid for six aprotic low solubility drugs. The intestinal fluids were characterized with respect to physical–chemical characteristics and contents. Results  Fed HIF provided a 3.5- to 30-times higher solubility compared to fasted HIF and FeSSIF, whereas fed DIF corresponded well (difference of less than 30%) to fed HIF. The increased solubility of food could mainly be attributed to dietary lipids and bile acids. The dissolution rate was also 2 to 7 times higher in fed HIF than fasted HIF. This was well predicted by both DIF and FeSSIF (difference of less than 30%). Conclusions  Intestinal solubility is higher in fed state compared to fasted state. However, the dissolution rate does not increase to the same extent. Dog seems to be a good model for man with respect to dissolution in the small intestine after intake of a meal, whereas FeSSIF is a poorer means of determining intestinal saturation solubility in the fed state.

  • 88.
    Persson, Eva M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Nilsson, Ralf G
    Hansson, Göran I
    Löfgren, Lars J
    Libäck, Fredrik
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Abrahamsson, Bertil
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A clinical single-pass perfusion investigation of the dynamic in vivo secretory response to a dietary meal in human proximal small intestine2006In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 23, no 4, p. 742-751Article in journal (Refereed)
    Abstract [en]

    Purpose  To investigate the gastrointestinal secretory and enzymatic responses to a liquid meal during in vivo perfusion of the proximal human jejunum. Methods  Human intestinal fluid was collected from the proximal jejunum by single-pass in vivo perfusion (Loc-I-Gut). The fluid was quantitatively collected at 10-min intervals during 90 min while perfusing a nutritional drink at 2 mL/min. Quantification of lipids in the fluid leaving the segment was performed by using novel chromatographic methods. Results  The overall bile acid concentration varied between 0.5 and 8.6 mM with a peak level 40 min after the start of the liquid meal perfusion. The total concentration of phospholipids was between 0.1 and 3.9 mM and there was a rapid degradation of phosphatidylcholine to lysophosphatidylcholine. The tri-, di-, monoglycerides and free fatty acid levels increased sharply in the beginning and reached steady-state levels between 7 and 9.5 mM. Conclusions  There is a rapid secretion of bile in response to food. Most of the dietary lipids are found in the form of their degradation products in vivo in human jejunum. This novel in vivo characterization, based on direct and high-recovery sampling of intestinal fluids, forms a basis for further development of improved in vitro drug dissolution test media.

  • 89.
    Petri, N
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Borga, O
    Nyberg, L
    Hedeland, M
    Bondesson, U
    Department of Medicinal Chemistry. Analytisk Farmaceutisk Kemi.
    Lennernas, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Effect of erythromycin on the absorption of fexofenadine in the jejunum, ileum and colon determined using local intubation in healthy volunteers.2006In: Int J Clin Pharmacol Ther, ISSN 0946-1965, Vol. 44, no 2, p. 71-9Article in journal (Refereed)
  • 90.
    Petri, Niclas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Bergman, Ebba
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Forsell, Patrik
    Hedeland, Mikael
    Bondesson, Ulf
    Department of Medicinal Chemistry. Analytisk Farmaceutisk Kemi.
    Knutson, Lars
    Lennernäs, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    First-pass effects of verapamil on the intestinal absorption and liver disposition of fexofenadine in the porcine model.2006In: Drug Metab Dispos, ISSN 0090-9556, Vol. 34, no 7, p. 1182-9Article in journal (Refereed)
  • 91.
    Petri, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Tannergren, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rungstad, David
    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.
    Transport characteristics of fexofenadine in the Caco-2 cell model2004In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 21, no 8, p. 1398-1404Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    To investigate the membrane transport mechanisms of fexofenadine in the Caco-2 model.

    METHODS:

    Transport studies were performed in Caco-2 cell monolayers 21-25 days after seeding. The apparent permeability (Papp) of fexofenadine was determined in the concentration range 10-1000 microM in the basolateral-to-apical (b-a) and 50-1000 microM in the apical-to-basolateral (a-b) direction. The concentration-dependent effects of various inhibitors of P-glycoprotein (P-gp) (GF120918, ketoconazole, verapamil, erythromycin), multidrug resistant associated protein (MRP) (indomethacin, probenecid), and organic anion transporting polypeptide (OATP) (rifamycin SV) on the bidirectional transport of 150 microM fexofenadine were also examined.

    RESULTS:

    Fexofenadine displayed polarized transport, with the Pappb-a being 28- to 85-fold higher than the Papp(a-b). The Papp(a-b) was independent of the concentration applied, whereas Pappb-a decreased with increasing concentration (Vmax = 5.21 nmol cm(-2)s(-1) and K(M) = 150 microM), suggesting saturation of an apical efflux transporter. All four P-gp inhibitors had a strong, concentration-dependent effect on the Papp of fexofenadine in both directions, with GF 120918 being the most specific among them. The IC50 of verapamil was 8.44 microM on the P-gp-mediated secretion of fexofenadine. The inhibitors of OATP or MRP appeared not to affect the Papp(a-b) of fexofenadine in the Caco-2 model.

    CONCLUSIONS:

    This study clearly indicates that P-gp was the main transport protein of fexofenadine in the Caco-2 model. Even though P-gp was completely inhibited, fexofenadine was predicted to have a low fraction dose absorbed in humans due to poor intestinal permeability, and low passive diffusion seems to be the major absorption mechanism.

  • 92.
    Roos, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dahlgren, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Berg, Staffan
    AstraZeneca R&D, S-43150 Molndal, Sweden..
    Westergren, Jan
    Wendelsbergs Berakningskemi AB, Kyrkvagen 7B, S-43535 Molnlycke, Sweden..
    Abrahamsson, Bertil
    AstraZeneca R&D, S-43150 Molndal, Sweden..
    Tannergren, Christer
    AstraZeneca R&D, S-43150 Molndal, Sweden..
    Sjögren, Erik
    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.
    In Vivo Mechanisms of Intestinal Drug Absorption from Aprepitant Nanoformulations2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4233-4242Article in journal (Refereed)
    Abstract [en]

    Over recent decades there has been an increase in the proportion of BCS class II and IV drug candidates in industrial drug development. To overcome the biopharmaceutical challenges associated with the less favorable properties of solubility and/or intestinal permeation of these substances, the development of formulations containing nanosuspensions of the drugs has been suggested. The intestinal absorption of aprepitant from two nanosuspensions (20 mu M and 200 mu M total concentrations) in phosphate buffer, one nanosuspension (200 mu M) in fasted-state simulated intestinal fluid (FaSSIF), and one solution (20 mu M) in FaSSIF was investigated in the rat single-pass intestinal perfusion model. The disappearance flux from the lumen (J(disapp)) was faster for formulations containing a total concentration of aprepitant of 200 mu M than for those containing 20 mu M, but was unaffected by the presence of vesicles. The flux into the systemic circulation (J(app)) and, subsequently, the effective diffusion constant (D-eff) were calculated using the plasma concentrations. J(app) was, like J(disapp), faster for the formulations containing higher total concentrations of aprepitant, but was also faster for those containing vesicles (ratios of 2 and 1.5). This suggests that aprepitant is retained in the lumen when presented as nanoparticles in the absence of vesicles. In conclusion, increased numbers of nanoparticles and the presence of vesicles increased the rate of transport and availability of aprepitant in plasma. This effect can be attributed to an increased rate of mass transport through the aqueous boundary layer (ABL) adjacent to the gut wall.

  • 93.
    Roos, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dahlgren, David
    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.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 387-395Article in journal (Refereed)
    Abstract [en]

    Oral administration of drug products is the preferred administration route. In recent decades there has been an increase in drug candidates with low solubility and/or low permeability. To increase the possibility of oral administration for the poorly permeating drugs, the use of absorption modifying excipients (AMEs) has been proposed. These types of AMEs may also affect the regulatory assessment of a novel drug delivery system if they affect the absorption of a drug from any of the four BCS classes. The effects of AMEs have previously been investigated in various animal models, including the single-pass intestinal perfusion (SPIP) in rats. To further improve the biorelevance and the in vivo predictiveness of the SPIP model, four compounds (atenolol, enalaprilat, ketoprofen, metoprolol) were perfused in fasted or fed state simulated intestinal fluid (FaSSIF or FeSSIF) together with the AMEs N-acetyl-cysteine, caprate, or sodium dodecyl sulfate. For the highly soluble and poorly permeating compounds enalaprilat and atenolol (BCS class III), the flux was increased the most by the addition of SDS in both FaSSIF and FeSSIF. For ketoprofen (BCS class II), the flux decreased in the presence of all AMEs in at least one of the perfusion media. The flux of metoprolol (BCS class I) was not affected by any of the excipients in none of simulated prandial states. The changes in magnitude in the absorption of the compounds were in general smaller in FeSSIF than in FaSSIF. This may be explained by a reduced free concentration AMEs in FeSSIF. Further, the results in FeSSIF were similar to those from intrajejunal bolus administration in rat in a previous study. This suggests that the biorelevance of the SPIP method may be increased when investigating the effects of AMEs, by the addition of intraluminal constituents representative to fasted and/or fed state to the inlet perfusate.

  • 94.
    Roos, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dahlgren, David
    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.
    Tannergren, Christer
    AstraZeneca R&D, Pharmaceut Technol & Dev, S-43183 Gothenburg, Sweden..
    Abrahamsson, Bertil
    AstraZeneca R&D, Pharmaceut Technol & Dev, S-43183 Gothenburg, Sweden..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Regional Intestinal Permeability in Rats: A Comparison of Methods2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4252-4261Article in journal (Refereed)
    Abstract [en]

    Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (P-eff) and apparent (P-app) permeability in all three regions and at both pH levels. Metoprolol had high P-eff in all regions and at both pHs and high P-app at both pHs and in all regions except the jejunum, where P-app was low. Atenolol had low P-eff in all regions and at both pHs, but had high P-app at pH 6.5 and low P-app at pH 7.4. There were good correlations between these rat in situ P-eff (SPIP) and human in vivo P-eff determined previously for the same compounds by both intestinal perfusion of the jejunum and regional intestinal dosing. The results of this study indicate that both investigated models are suitable for determining the regional permeability of the intestine; however, the SPIP model seems to be the more robust and accurate regional permeability model.

  • 95.
    Roos, Carl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Westergren, Jan
    Dahlgren, David
    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.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mechanistic modelling of intestinal drug absorption: the in vivo effects of nanoparticles, hydrodynamics, and colloidal structures2018In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 133, p. 70-76Article in journal (Refereed)
    Abstract [en]

    Particle size reduction is a traditional approach to increase the intestinal absorption of active pharmaceutical ingredients with poor intestinal solubility, by increasing the particle dissolution rate. However, an increase in the dissolution rate cannot always fully explain the effects of nanoformulations, and a method of assessing the potential benefits of a nanoformulation in vivo would hence be of great value in drug development. A novel mathematical model of a nanoformulation, including interlinked descriptions of the hydrodynamics, particle dissolution and diffusion of particles and colloidal structures (CS), was developed to predict the combined in vivo effects of these mechanisms on drug absorption. The model successfully described previously reported in vivo observations of nanoformulated aprepitant in rats, at various drug concentrations and in the presence or absence of CS. The increase in absorption rate was explained as a direct consequence of the increased drug concentration at the membrane, caused by the contributing effects of the diffusion of both nanoparticles and CS into which the drug had partitioned. Further simulations supported the conclusion that the model can be applied during drug development to provide a priori assessments of the potential benefits of nanoformulations.

  • 96. Selen, Arzu
    et al.
    Dickinson, Paul A.
    Mullertz, Anette
    Crison, John R.
    Mistry, Hitesh B.
    Cruanes, Maria T.
    Martinez, Marilyn N.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wigal, Tim L.
    Swinney, David C.
    Polli, James E.
    Serajuddin, Abu T. M.
    Cook, Jack A.
    Dressman, Jennifer B.
    The Biopharmaceutics Risk Assessment Roadmap for Optimizing Clinical Drug Product Performance2014In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 103, no 11, p. 3377-3397Article in journal (Refereed)
    Abstract [en]

    The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate learning and confirming studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile.

  • 97.
    Sjögren, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    Augustijns, Patrick
    Becker, Dieter
    Bolger, Michael B.
    Brewster, Marcus
    Brouwers, Joachim
    Flanagan, Talia
    Harwood, Matthew
    Heinen, Christian
    Holm, Rene
    Juretschke, Hans-Paul
    Kubbinga, Marlies
    Lindahl, Anders
    Lukacova, Viera
    Munster, Uwe
    Neuhoff, Sibylle
    Nguyen, Mai Anh
    van Peer, Achiel
    Reppas, Christos
    Hodjegan, Amin Rostami
    Tannergren, Christer
    Weitschies, Werner
    Wilson, Clive
    Zane, Patricia
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Langguth, Peter
    In vivo methods for drug absorption - Comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, p. 99-151Article in journal (Refereed)
    Abstract [en]

    This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in today's knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing. (c) 2014 Elsevier B.V. All rights reserved.

  • 98.
    Sjögren, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bredberg, Ulf
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The pharmacokinetics and hepatic disposition of repaglinide in pigs: mechanistic modeling of metabolism and transport2012In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, no 4, p. 823-841Article in journal (Refereed)
    Abstract [en]

    The predictive power of using in vitro systems in combination with physiologically based pharmacolcinetic (PBPK) modeling to elucidate the relative importance of metabolism and carrier-mediated transport for the pharmacokinetics was evaluated using repaglinide as a model compound and pig as the test system. Repaglinide was chosen as model drug as previous studies in humans have shown that repaglinide is subject to both carrier-mediated influx to the liver cells and extensive hepatic metabolism. A multiple sampling site model in pig was chosen since it provides detailed in vivo information about the liver disposition. The underlying assumption was that both metabolism and carrier-mediated transport are also important for the hepatic disposition of repaglinide in pigs. Microsomes and primary hepatocytes were used for in vitro evaluation of enzyme kinetics and cellular disposition, respectively. In vitro data were generated both with and without metabolism inhibitors (ketoconazole, bezafibrate and trimethoprim) and transport inhibitors (diclofenac and quinine) providing input into a semi-PBPK model. In vivo data were also generated with and without the same enzyme and transporter inhibitors, alone and in combination. The pigs were given repaglinide as intravenous infusions with and without inhibitors in a sequential manner, i.e., a control phase and a test phase. Parameters describing the passive and carrier-mediated flux as well as metabolism were estimated in the control phase. The result from test phase was used to gain further knowledge of the findings from the control phase. The in vivo pig model enabled simultaneous sampling from plasma (pre- and postliver and peripheral) as well as from bile and urine. A semi-PBPK model consisting of 11 compartments (6 tissues + 5 sampling sites) was constructed for the mechanistic elucidation of the liver disposition, in vitro based in vivo predictions, sensitivity analyses and estimations of individual pharmacolcinetic parameters. Both in vitro and in vivo results showed that carrier-mediated influx was important for the liver disposition. The in vivo findings were supported by the result from the test phase where hepatic clearance (4.3 mL min(-1) kg(-1)) was decreased by 29% (metabolism inhibition), 43% (transport inhibition) and 57% (metabolism + transport inhibition). These effects were in good agreement with predicted levels. This study suggests that both metabolism and carrier-mediated uptake are of significant importance for the liver disposition of repaglinide in pigs.

  • 99.
    Sjögren, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dahlgren, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernas, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Human in Vivo Regional Intestinal Permeability: Quantitation Using Site-Specific Drug Absorption Data2015In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 12, no 6, p. 2026-2039Article in journal (Refereed)
    Abstract [en]

    Application of information on regional intestinal permeability has been identified as a key aspect of successful pharmaceutical product development. This study presents the results and evaluation of an approach for the indirect estimation of site-specific in vivo intestinal effective permeability (P-eff) in humans. Plasma concentrationtime profiles from 15 clinical studies that administered drug solutions to specific intestinal regions were collected and analyzed. The intestinal absorption rate for each drug was acquired by deconvolution, using historical intravenous data as reference, and used with the intestinal surface area and the dose remaining in the lumen to estimate the Peff. Forty-three new Peff values were estimated (15 from the proximal small intestine, 11 from the distal small intestine, and 17 from the large intestine) for 14 active pharmaceutical ingredients representing a wide range of biopharmaceutical properties. A good correlation (r(2) = 0.96, slope = 1.24, intercept = 0.030) was established between these indirect jejunal P-eff estimates and jejunal P-eff measurements determined directly using the single-pass perfusion double balloon technique. On average, P-eff estimates from the distal small intestine and large intestine were 90% and 40%, respectively, of those from the proximal small intestine. These results support the use of the evaluated deconvolution method for indirectly estimating regional intestinal P-eff in humans. This study presents the first comprehensive data set of estimated human regional intestinal permeability values for a range of drugs. These biopharmaceutical data can be used to improve the accuracy of gastrointestinal absorption predictions used in drug development decision-making.

  • 100.
    Sjögren, Erik
    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.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effects of verapamil on the pharmacokinetics and hepatobiliary disposition of fexofenadine in pigs2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, p. 214-223Article in journal (Refereed)
    Abstract [en]

    The pharmacokinetics (PK) of fexofenadine (FEX) in pigs were investigated with the focus on exploring the interplay between hepatic transport and metabolism when administered intravenously (iv) alone or with verapamil. The in vivo pig model enabled simultaneous sampling from plasma (pre-liver, post-liver and peripheral), bile and urine. Each animal was administered FEX 35mg iv alone or with verapamil 35mg. Plasma, bile and urine were analyzed with liquid chromatography-tandem mass spectrometry. Non-compartmental analysis (NCA) was used to estimate traditional PK parameters. In addition, a physiologically based pharmacokinetic (PBPK) model consisting of 11 compartments (6 tissues +5 sample sites) was applied for mechanistic elucidation and estimation of individual PK parameters. FEX had a terminal half-life of 1.7h and a liver extraction of 3%. The fraction of the administered dose of unchanged FEX excreted into the bile was 25% and the bile exposure was more than 100 times higher than the portal vein total plasma exposure, indicating carrier-mediated (CM) disposition processes in the liver. 23% of the administered dose of FEX was excreted unchanged in the urine. An increase in FEX plasma exposure (+50%) and a decrease in renal clearance (-61%) were detected by NCA as a direct effect of concomitant administration of verapamil. However, analysis of the PBPK model also revealed that biliary clearance was significantly inhibited (-53%) by verapamil. In addition, PBPK analysis established that metabolism and CM uptake were important factors in the disposition of FEX in the liver. In conclusion, this study demonstrated that CM transport of FEX in both liver and kidneys was inhibited by a single dose of verapamil.

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