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Lennernäs, Hans
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Publications (10 of 114) Show all publications
Bransford, P., Cook, J., Gupta, M., Haertter, S., He, H., Ju, R., . . . Wu, Y. (2020). ICH M9 Guideline in Development on Biopharmaceutics Classification System-Based Biowaivers: An Industrial Perspective from the IQ Consortium. Molecular Pharmaceutics, 17(2), 361-372
Open this publication in new window or tab >>ICH M9 Guideline in Development on Biopharmaceutics Classification System-Based Biowaivers: An Industrial Perspective from the IQ Consortium
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2020 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 17, no 2, p. 361-372Article in journal (Refereed) Published
Abstract [en]

In October 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH began efforts to provide recommendations to harmonize guidances for biopharmaceutics classification system (BCS)-based biowaivers. Topics to be addressed included consideration of the dose used to classify solubility, tests, and criteria for establishing highly permeable, dissolution conditions, the influence of excipients, and aspects of product strength. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader R&D community. Its members have substantial expertise in all scientific domains associated with BCS-based waivers and drug product quality, as well as considerable experience in the application of BCS-based biowaivers. The ICH process recognizes that harmonization is achieved through the development of guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side. Thus, to facilitate these efforts and to encourage open and transparent discussion of other perspectives that may exist, IQ offers their perspective on these and related topics.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2020
Keywords
biopharmaceutics classification system (BCS), bioequivalence (BE), biowaiver, permeability, solubility, dissolution, regulatory
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-406729 (URN)10.1021/acs.molpharmaceut.9b01062 (DOI)000511245300001 ()31846335 (PubMedID)
Available from: 2020-03-19 Created: 2020-03-19 Last updated: 2020-03-19Bibliographically approved
Dahlgren, D., Sjöblom, M., Hedeland, M. & Lennernäs, H. (2020). The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin. Pharmaceutics, 12(2), Article ID 99.
Open this publication in new window or tab >>The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin
2020 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 12, no 2, article id 99Article in journal (Refereed) Published
Abstract [en]

Permeation enhancers like sodium dodecyl sulfate (SDS) and caprate increase the intestinal permeability of small model peptide compounds, such as enalaprilat (349 Da). However, their effects remain to be investigated for larger low-permeability peptide drugs, such as hexarelin (887 Da). The objective of this single-pass perfusion study in rat was to investigate the effect of SDS at 5 mg/mL and of caprate administered at different luminal concentrations (5, 10, and 20 mg/mL) and pH (6.5 and 7.4). The small intestinal permeability of enalaprilat increased by 8- and 9-fold with SDS at 5 mg/mL and with caprate at 10 and 20 mg/mL but only at pH 7.4, where the free dissolved caprate concentration is higher than at pH 6.5 (5 vs. 2 mg/mL). Neither SDS nor caprate at any of the investigated luminal concentrations enhanced absorption of the larger peptide hexarelin. These results show that caprate requires doses above its saturation concentration (a reservoir suspension) to enhance absorption, most likely because dissolved caprate itself is rapidly absorbed. The absent effect on hexarelin may partly explain why the use of permeation enhancers for enabling oral peptide delivery has largely failed to evolve from in vitro evaluations into approved oral products. It is obvious that more innovative and effective drug delivery strategies are needed for this class of drugs.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
permeation enhancers, absorption-modifying excipients, oral peptide delivery, intestinal permeability, intestinal perfusion, pharmaceutical development
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-409915 (URN)10.3390/pharmaceutics12020099 (DOI)000519268500041 ()31991924 (PubMedID)
Available from: 2020-05-07 Created: 2020-05-07 Last updated: 2020-05-07Bibliographically approved
Roos, C., Dahlgren, D., Sjögren, E., Sjöblom, M., Hedeland, M. & Lennernäs, H. (2019). Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions. European journal of pharmaceutics and biopharmaceutics, 142, 387-395
Open this publication in new window or tab >>Effects of absorption-modifying excipients on jejunal drug absorption in simulated fasted and fed luminal conditions
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2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 387-395Article in journal (Refereed) Published
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.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396543 (URN)10.1016/j.ejpb.2019.07.012 (DOI)000488654000040 ()31306752 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Dahlgren, D., Roos, C., Peters, K., Lundqvist, A., Tannergren, C., Sjögren, E., . . . Lennernäs, H. (2019). Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model. European journal of pharmaceutics and biopharmaceutics, 142, 31-37
Open this publication in new window or tab >>Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model
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2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 31-37Article in journal (Refereed) Published
Abstract [en]

The rat single-pass intestinal perfusion (SPIP) model is commonly used to investigate gastrointestinal physiology and membrane drug transport. The SPIP model can be used with the intestinal segment inside or outside the abdomen. The rats can also be treated with parecoxib, a selective cycloxygenase-2 inhibitor that has been shown to affect some intestinal functions following abdominal surgery, such as motility, epithelial permeability, fluid flux and ion transport. However, the impact of extra-abdominal placement of the intestinal segment in combination with parecoxib on intestinal drug transport has not been investigated. There is also uncertainty how well intestinal permeability determinations based on luminal drug disappearance and plasma appearance correlate in the rat SPIP model. The main objective of this rat in vivo study was to investigate the effect of intra- vs. extra abdominal SPIP, with and without, pretreatment with parecoxib. The effect was evaluated by determining the difference in blood-to-lumen Cr-51-EDTA clearance, lumen-to-blood permeability of a cassette-dose of four model compounds (atenolol, enalaprilat, ketoprofen, and metoprolol), and water flux. The second objective was to compare the jejunal permeability values of the model drugs when determined based on luminal disappearance or plasma appearance. The study showed that the placement of the perfused jejunal segment, or the treatment with parecoxib, had minimal effects on membrane permeability and water flux. It was also shown that intestinal permeability of low permeability compounds should be determined on the basis of data from plasma appearance rather than lumina] disappearance. If permeability is calculated on the basis of luminal disappearance, it should preferably include negative values to increase the accuracy in the determinations.

Keywords
Intestinal perfusion, Intestinal permeability, Intestinal physiology, Intestinal fluid transport
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396541 (URN)10.1016/j.ejpb.2019.06.011 (DOI)000488654000004 ()31201856 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 115369
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Dahlgren, D., Sjöblom, M. & Lennernäs, H. (2019). Intestinal absorption-modifying excipients: A current update on preclinical in vivo evaluations. European journal of pharmaceutics and biopharmaceutics, 142, 411-420
Open this publication in new window or tab >>Intestinal absorption-modifying excipients: A current update on preclinical in vivo evaluations
2019 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 411-420Article in journal (Refereed) Published
Abstract [en]

Pharmaceutical excipients in drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase drug absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the intestinal drug absorption, it is defined as an absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase drug absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo intestinal absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the intestinal absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosa] recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect intestinal drug absorption.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-396544 (URN)10.1016/j.ejpb.2019.07.013 (DOI)000488654000043 ()31306749 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2019-11-07 Created: 2019-11-07 Last updated: 2019-11-07Bibliographically approved
Dahlgren, D. & Lennernäs, H. (2019). Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches. Pharmaceutics, 11(8), Article ID 411.
Open this publication in new window or tab >>Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches
2019 (English)In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, no 8, article id 411Article, review/survey (Refereed) Published
Abstract [en]

The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value P-eff) has been widely used to determine the rate and extent of the drug's intestinal absorption (F-abs) in humans. Preclinical gastrointestinal (GI) absorption models are currently in demand for the pharmaceutical development of novel dosage forms and new drug products. However, there is a strong need to improve our understanding of the interplay between pharmaceutical, biopharmaceutical, biochemical, and physiological factors when predicting F-abs and bioavailability. Currently, our knowledge of GI secretion, GI motility, and regional intestinal permeability, in both healthy subjects and patients with GI diseases, is limited by the relative inaccessibility of some intestinal segments of the human GI tract. In particular, our understanding of the complex and highly dynamic physiology of the region from the mid-jejunum to the sigmoid colon could be significantly improved. One approach to the assessment of intestinal permeability is to use animal models that allow these intestinal regions to be investigated in detail and then to compare the results with those from simple human permeability models such as cell cultures. Investigation of intestinal drug permeation processes is a crucial biopharmaceutical step in the development of oral pharmaceutical products. The determination of the intestinal P-eff for a specific drug is dependent on the technique, model, and conditions applied, and is influenced by multiple interactions between the drug molecule and the biological membranes.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
intestinal permeability, intestinal drug absorption, experimental and computational permeability methods
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-395363 (URN)10.3390/pharmaceutics11080411 (DOI)000484515100053 ()31412551 (PubMedID)
Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2019-10-22Bibliographically approved
Ahnfelt, E., Degerstedt, O., Lilienberg, E., Sjögren, E., Hansson, P. & Lennernäs, H. (2019). Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery: Effects of composition on stability and product quality. Journal of Drug Delivery Science and Technology, 53, Article ID UNSP 101143.
Open this publication in new window or tab >>Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery: Effects of composition on stability and product quality
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2019 (English)In: Journal of Drug Delivery Science and Technology, ISSN 1773-2247, Vol. 53, article id UNSP 101143Article in journal (Refereed) Published
Abstract [en]

Transarterial chemoembolization with emulsion-based formulations using doxorubicin hydrochloride (DOX) and Lipiodol (R) is the golden standard for the loco-regional treatment of unresectable hepatocellular carcinoma (HCC). However, from a pharmaceutical quality perspective these emulsions are poorly characterized. In this study, clinically relevant Lipiodol (R)-based emulsions were characterized in terms of emulsion stability, continuous phase classification and droplet-size distribution. Also, the solubility of DOX in the different emulsion components and the distribution of DOX to the lipid phase were investigated. These are key features to investigate due to the claimed tumor-seeking properties of Lipiodol (R). The in vitro release of DOX was studied in a miniaturized dialysis method and an empirical release model was applied to adjust for the passage of DOX across the dialysis membrane. The most stable emulsion ( > 72 h) was classified as water-in-oil (w/o), had the highest distribution of DOX to the lipid phase (20%) and an aqueous-to-lipid phase ratio of 1:4. The composition of the aqueous phase was a mixture (v/v) of iohexol (85%) and water (15%). Emulsions containing iohexol and a high aqueousto-lipid phase ratio (1:2-1:4) displayed prolonged in vitro release profiles of DOX. This study further emphasizes the medical need to standardize these emulsion-based drug delivery systems.

Place, publisher, year, edition, pages
ELSEVIER, 2019
Keywords
Emulsion, Lipiodol (R), Miniaturized dialysis method, In vitro release, Pharmaceutical quality, Liver cancer
National Category
Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-395729 (URN)10.1016/j.jddst.2019.101143 (DOI)000487963600044 ()
Funder
Swedish Research Council, 521-2011-373
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Dubbelboer, I. R., Pavlovic, N., Heindryckx, F., Sjögren, E. & Lennernäs, H. (2019). Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile. Cancers, 11(7), Article ID 1024.
Open this publication in new window or tab >>Liver Cancer Cell Lines Treated with Doxorubicin under Normoxia and Hypoxia: Cell Viability and Oncologic Protein Profile
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 7, article id 1024Article in journal (Refereed) Published
Abstract [en]

Hepatocellular carcinoma is often treated with a combination of doxorubicin and embolization, exposing it to high concentrations and hypoxia. Separation of the possible synergistic effect of this combination in vivo is difficult. Here, treatment with doxorubicin, under hypoxia or normoxia in different liver cancer cell lines, was evaluated. Liver cancer cells HepG2, Huh7, and SNU449 were exposed to doxorubicin, hypoxia, or doxorubicin + hypoxia with different duration. Treatment response was evaluated with cell viability, apoptosis, oxidative stress, and summarized with IC50. The protein profile of a 92-biomarker panel was analyzed on cells treated with 0 or 0.1 mu M doxorubicin during 6 or 72 h, under normoxia or hypoxia. Hypoxia decreased viability of HepG2 and SNU499. HepG2 was least and SNU449 most tolerant to doxorubicin treatment. Cytotoxicity of doxorubicin increased over time in HepG2 and Huh7. The combination of doxorubicin + hypoxia affected the cells differently. Normalized protein expression was lower for HepG2 than Huh7 and SNU449. Hierarchical clustering separated HepG2 from Huh7 and SNU449. These three commonly used cell lines have critically different responses to chemotherapy and hypoxia, which was reflected in their different protein expression profile. These different responses suggest that tumors can respond differently to the combination of local chemotherapy and embolization.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
IC50, doxorubicin, liver cancer, cell lines, hypoxia, normoxia
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-395927 (URN)10.3390/cancers11071024 (DOI)000479322800134 ()31330834 (PubMedID)
Funder
Swedish Cancer Society, CAN2018/602Swedish Cancer Society, CAN2017/518Swedish Cancer Society, CAN2013/1273Swedish Research Council, 2018-03301Swedish Society for Medical Research (SSMF), S17-0092
Available from: 2019-10-30 Created: 2019-10-30 Last updated: 2019-10-30Bibliographically approved
Garcia, L. P., Janzen, D., Kanebratt, K., Ericsson, H., Lennernäs, H. & Lundahl, A. (2019). Physiologically based pharmacokinetic model predictions of ivosidenib (AG-120) as a victim and perpetrator of drug–drug interactions. Drug Metabolism and Pharmacokinetics, 34(1), S70-S71
Open this publication in new window or tab >>Physiologically based pharmacokinetic model predictions of ivosidenib (AG-120) as a victim and perpetrator of drug–drug interactions
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2019 (English)In: Drug Metabolism and Pharmacokinetics, ISSN 1347-4367, E-ISSN 1880-0920, Vol. 34, no 1, p. S70-S71Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
JAPANESE SOC STUDY XENOBIOTICS, 2019
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-378239 (URN)10.1016/j.dmpk.2018.09.238 (DOI)000458519400233 ()
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-03-15Bibliographically approved
Eriksson, J., Thorn, H., Sjögren, E., Holmsten, L., Rubin, K. & Lennernäs, H. (2019). Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model. Molecular Pharmaceutics, 16(7), 3053-3064
Open this publication in new window or tab >>Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model
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2019 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 16, no 7, p. 3053-3064Article in journal (Refereed) Published
Abstract [en]

Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused 4 rat lung (IPL) model. Two particle size distributions (d50 = 1.2 mu m and d50 = 2.8 mu m) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter (K-ex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter (Kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 mu M), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 mu m). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between k(ex vivo) and k(in vitro). The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.

Keywords
inhalation, lung dissolution, isolated perfused lung model, pulmonary drug delivery, pulmonary drug absorption
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-390996 (URN)10.1021/acs.molpharmaceut.9b00289 (DOI)000474475400020 ()31136181 (PubMedID)
Funder
AstraZeneca
Available from: 2019-08-19 Created: 2019-08-19 Last updated: 2019-08-19Bibliographically approved
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