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Impact of Gastrointestinal Tract Variability Onłoral Drug Absorption and Pharmacokinetics

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Impact of Gastrointestinal Tract Variability Onłoral Drug Absorption and Pharmacokinetics European Journal of Pharmaceutical Sciences 162 (2021) 105812 Contents lists available at ScienceDirect European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps Impact of gastrointestinal tract variability on oral drug absorption and pharmacokinetics: An UNGAP review Zahari Vinarov a,b, Mohammad Abdallah c, Jos´e A.G. Agundez d, Karel Allegaert e,f, Abdul W. Basit g, Marlies Braeckmans a, Jens Ceulemans h, Maura Corsetti i,j, Brendan T. Griffin k, Michael Grimm l, Daniel Keszthelyi m, Mirko Koziolek n, Christine M. Madla g, Christophe Matthys o,p, Laura E. McCoubrey g, Amitava Mitra q, Christos Reppas r, Jef Stappaerts h, Nele Steenackers o, Natalie L. Trevaskis c, Tim Vanuytsel s, Maria Vertzoni r, Werner Weitschies l, Clive Wilson t, Patrick Augustijns a,u,1,* a Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium b Department of Chemical and Pharmaceutical Engineering, Sofia University, Sofia, Bulgaria c Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia d University Institute of Molecular Pathology Biomarkers, UEx. ARADyAL, Instituto de Salud Carlos III, Caceres,´ Spain e Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands f Department of Development and Regeneration and Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium g UCL School of Pharmacy, University College London, London, United Kingdom h Pharmaceutical Sciences, Janssen Research & Development, Beerse, Belgium i NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom j Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom k School of Pharmacy, University College Cork, Cavanagh Pharmacy Building, Cork, Ireland l Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport, University of Greifswald, Greifswald, Germany m Division of Gastroenterology-Hepatology, Department of Internal Medicine, NUTRIM, Maastricht University Medical Center, Maastricht, the Netherlands n NCE Formulation Sciences, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany o Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium p Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium q Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, Spring House, Pennsylvania, United States r Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Athens, Greece s Translational Research Centre for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (ChroMeTa), KU Leuven, Leuven, Belgium t Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), University of Strathclyde, United Kingdom u Chairperson of the UNGAP network, COST CA 16205 Abbreviations: 5-FU, 5-fluorouracil; ADME, Absorption, distribution, metabolism and excretion; AIDS, Acquired immunodeficiency syndrome; AUC, Area under the curve; BCS, Biopharmaceutics classification system; BMI, Body mass index; CD, Cyclodextrin; CETP, Cholesterylester transfer protein; CI, Confidence interval; CIPO, Chronic intestinal pseudoobstruction; Cmax, Maximum plasma concentration; CRA, Cannabinoid receptor agonist; CTT, Colon transit times; CV, Coefficientof variance; CYP, Cytochrome P450; DAG, Diacylglycerides; DDI, Drug-drug interactions; Dv50, Median particle size by volume; EHC, Enterohepatic circulation; FaHIF, Fasted state human intestinal fluids; FaSSIF, Fasted state simulated intestinal fluids; FDA, U.S. Food and drug administration agency; FFA, Free fatty acids; GC, Glycocholate; GCDC, Glycochenodeoxycholate; GDC, Glycodeoxycholate; GET, Gastric emptying time; GIT, Gastrointestinal tract; HIV, Human immunodeficiency virus; HPMC, Hydroxypropyl methylcellulose; HPMC-AS, Hydroxypropyl methylcellulose acetate succinate; HPMCP, Hydroxypropyl methylcellulose phtalate; IBD, Inflammatory bowel disease; IMMC, Inter-digestive migrating motor complex; IR, Immediate release; L-DOPA, Levodopa; Lyso-PC, Lyso-phosphatidylcholine; MAG, Monoacylglycerides; MRI, Magnetic resonance imaging; NAPQI, N-acetyl-p-benzoquinone imine; NSAID, Nonsteroidal anti-inflammatory drug; OHM, 1-hydroxy- midazolam; PBPK, Physiologically based pharmacokinetic modelling; PC, Phosphatidylcholine; PD, Pharmacodynamic(s); PEG, Polyethylene glycol; PK, Pharma­ cokinetic(s); PPI, Proton pump inhibitors; RYGB, Roux-en-Y gastric bypass; SBWC, Small bowel water content; SIBO, Small intestinal bacterial overgrowth; SITT, Small intestinal transit time; TAG, Triacylglycerides; TC, Taurocholate; TCDC, Taurochenodeoxycholate; TDC, Taurodeoxycholate; TKI, Tyrosine kinase inhibitors; tmax, Time to reach maximum plasma concentration; UDC, Ursodeoxycholate; UNGAP, European network on understanding gastrointestinal absorption-related processes; VEGF-C, Vascular endothelial growth factor C. * Corresponding author at: Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Gasthuisberg O&N II, Herestraat 49, Box 921, 3000 Leuven, Belgium. E-mail address: [email protected] (P. Augustijns). 1 www.ungap.eu. https://doi.org/10.1016/j.ejps.2021.105812 Received 5 December 2020; Received in revised form 19 February 2021; Accepted 16 March 2021 Available online 20 March 2021 0928-0987/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Z. Vinarov et al. European Journal of Pharmaceutical Sciences 162 (2021) 105812 ARTICLE INFO ABSTRACT Keywords: The absorption of oral drugs is frequently plagued by significant variability with potentially serious therapeutic Variation consequences. The source of variability can be traced back to interindividual variability in physiology, differ- Fasted and fed state ences in special populations (age- and disease-dependent), drug and formulation properties, or food-drug in- Physiology teractions. Clinical evidence for the impact of some of these factors on drug pharmacokinetic variability is Pediatrics and geriatrics mounting: e.g. gastric pH and emptying time, small intestinal fluid properties, differences in pediatrics and the Diseases Drug formulation elderly, and surgical changes in gastrointestinal anatomy. However, the link of colonic factors variability (transit time, fluid composition, microbiome), sex differences (male vs. female) and gut-related diseases (chronic con- stipation, anorexia and cachexia) to drug absorption variability has not been firmlyestablished yet. At the same time, a way to decrease oral drug pharmacokinetic variability is provided by the pharmaceutical industry: clinical evidence suggests that formulation approaches employed during drug development can decrease the variability in oral exposure. This review outlines the main drivers of oral drug exposure variability and potential approaches to overcome them, while highlighting existing knowledge gaps and guiding future studies in this area. 1. Introduction perform a meta-analysis of the available data. However, as most results available in the literature are based on small scale explorative clinical The oral intake of drugs remains the preferred administration route studies, a statistical comparison is usually not justified. In addition, because of its non-invasive character and convenience for the patient, differences in the experimental protocols and instrumentation used to which increases drug regimen compliance. However, ensuring sufficient gather the data would undermine any attempts at such analysis. and predictable systemic drug exposure when developing oral drug Therefore, results are reported in a descriptive way. products is not straightforward (Basavaraj and Betageri, 2014; Kor- Furthermore, the impact of methodology, clinical study design and stanje, 2003; Li et al., 2016): issues with bioavailability and pharma- statistics on the measurement and quantificationof variability is an issue cokinetics (PK) are among the top 3 reasons for attrition of oral on its own (Augustijns et al., 2020; Evans, 2010; Pocock et al., 2015) and small-molecule new drug candidates. In particular, the effectiveness of will not be addressed in the current paper. The effect of drug absorption oral drug products in clinical practice can be plagued by significant variability on clinical performance and therapeutic outcome is also not variability in drug exposure with serious therapeutic consequences in the scope of the current review. (Pasipanodya et al., 2012). It is logical to expect that the factors, which control drug absorption 2. Physiological inter- and intraindividual variability in the and PK, are also responsible for the variability of drug exposure fasted and fed state observed in the clinic. Hence, the impact of physiological differences (in special populations and gastrointestinal tract (GIT) regions), drug and 2.1. Gastric conditions formulation properties, and food-drug interactions on drug absorption was recognized and described by the European Network on Under- This section focuses on the variability of data in healthy fasted and standing Gastrointestinal Absorption-related Processes (UNGAP)(Boyd fed
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