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Current Challenges and Future Perspectives in Oral Absorption Research: an Opinion of the UNGAP Network

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Current Challenges and Future Perspectives in Oral Absorption Research: an Opinion of the UNGAP Network Advanced Drug Delivery Reviews 171 (2021) 289–331 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network Zahari Vinarov a,b,BertilAbrahamssonc,PerArturssond,HannahBatchelore,PhilippeBerbenf, Andreas Bernkop-Schnürch g, James Butler h,JensCeulemansi, Nigel Davies j,DidierDupontk, Gøril Eide Flaten l,NikolettaFotakim, Brendan T. Griffin n, Vincent Jannin o, Janneke Keemink i,1, Filippos Kesisoglou p,MirkoKoziolekq, Martin Kuentz r, Alan Mackie s, Antonio J. Meléndez-Martínez t, Mark McAllister u, Anette Müllertz v, Caitriona M. O'Driscoll n,NeilParrottw, Jadwiga Paszkowska x, Petr Pavek y, Christopher J.H. Porter z, Christos Reppas aa,CordulaStillhartw, Kiyohiko Sugano ab, Elena Toader ac,Kateřina Valentová ad, Maria Vertzoni aa, Saskia N. De Wildt ae, Clive G. Wilson e, Patrick Augustijns a,2,⁎ a Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium b Department of Chemical and Pharmaceutical Engineering, Sofia University, Sofia, Bulgaria c Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden d Department of Pharmacy, Uppsala University, Uppsala, Sweden e Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom f Pharmaceutical Development, UCB Pharma SA, Braine- l'Alleud, Belgium g Department of Pharmaceutical Technology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria h GlaxoSmithKline Research and Development, Ware, United Kingdom i Janssen Pharmaceutica NV, Beerse, Belgium j Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden k INRAE, Institut Agro, STLO, Rennes, France l Department of Pharmacy, UiT The Arctic University of Norway, Tromsø, Norway m Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom n School of Pharmacy, University College Cork, Cork, Ireland o Lonza Pharma & Biotech, Colmar, France p Pharmaceutical Sciences, Merck & Co. Inc., Rahway, NJ, USA q Abbvie Deutschland GmbH & Co. KG, Ludwigshafen, Germany r Institute for Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland, Basel, Switzerland s School of Food Science & Nutrition, University of Leeds, Leeds, United Kingdom t Food Colour & Quality Laboratory, Area of Nutrition & Food Science, Universidad de Sevilla, Seville, Spain u Drug Product Design, Pfizer PGRD, Sandwich, United Kingdom v Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark w F. Hoffmann-La Roche Ltd, Basel, Switzerland x Physiolution Polska Sp. Z o.o., Wroclaw, Poland y Faculty of Pharmacy, Charles University, Hradec Králové, Czech Republic z Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia aa Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece ab College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan ac Faculty of Medicine, University of Medicine and Pharmacy of Iasi, Romania ad Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic ae Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, the Netherlands ⁎ 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 Current address: F. Hoffmann-La Roche Ltd., Basel, Switzerland. 2 Chairperson of the UNGAP network, COST CA16205 (www.ungap.eu). https://doi.org/10.1016/j.addr.2021.02.001 0169-409X/© 2021 The Author(s). 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, B. Abrahamsson, P. Artursson et al. Advanced Drug Delivery Reviews 171 (2021) 289–331 article info abstract Article history: Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug Received 27 November 2020 discovery and development pipelines challenge conventional formulation approaches and highlight the insuffi- Received in revised form 12 January 2021 cient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion Accepted 1 February 2021 of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, Available online 18 February 2021 (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, Keywords: Specific patient populations the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA Regional differences etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified con- Advanced formulations troversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to cre- Amorphous solid dispersions ate a roadmap for the future of oral drug absorption research. Lipid-based formulations © 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http:// Food-drug interactions creativecommons.org/licenses/by/4.0/). Microbiome In vitro tools PBPK modeling Contents 1. Introduction............................................................... 291 2. Specificpatientpopulations........................................................ 291 2.1. Introductionandscope...................................................... 291 2.2. Pediatricsandgeriatrics...................................................... 292 2.2.1. The role of GIT fluidvolumesinpediatricpopulations.................................... 292 2.2.2. Ontogenyofintestinaldrugtransportandmetabolisminpediatricpopulations.........................293 2.2.3. Oraldrugabsorptionininfantsincludingfoodeffects..................................... 293 2.2.4. Biorelevantdissolutiontestingandinsilicomodelingtopredictpharmacokineticsinneonatesandpediatrics........... 294 2.2.5. Oraldrugabsorptioninolderpeopleandgeriatricpatients.................................. 294 2.3. Disease-specificpopulations.................................................... 295 2.3.1. Cardiovascular,renalandmetabolismdiseases........................................ 295 2.3.2. Inflammatoryboweldisease................................................ 295 2.3.3. COVID-19........................................................ 296 3. Regionaldifferences........................................................... 296 3.1. Introductionandscope...................................................... 296 3.2. Targetingoforaldrugstothelowerintestineandcolonicdrugabsorption............................... 296 3.3. Predictionofcolonicabsorptionandphysiologicallybasedpharmacokineticmodels...........................297 3.4. Intestinaldrug-metabolizingenzymes................................................ 298 3.5. Theroleoflymphatictransportinoraldrugdelivery......................................... 299 4. Advancedformulations.......................................................... 300 4.1. Introductionandscope...................................................... 300 4.2. Poorlywater-solubledrugs..................................................... 300 4.2.1. Understandinglipid-baseddrugdeliverysystemsforincreasingabsorptionandreducingfoodeffects...............300 4.2.2. Understandingtheinvivoperformanceofamorphoussoliddispersions............................ 301 4.3. Biologicals............................................................ 303 4.3.1. Introductionandscope.................................................. 303 4.3.2. Oraldeliveryoftherapeuticnucleicacidsbynon-viralmethods................................ 303 4.3.3. Oralpeptidedelivery................................................... 304 5. In vitro and in silico toolsforexploringadvanceddrugformulations...................................... 307 5.1. Introductionandscope...................................................... 307 5.2. Biorelevantdissolutiontesting................................................... 307 5.3. Permeationmodels........................................................ 309 5.4. Combineddissolution-permeationmodels.............................................. 309 5.5. Novelreal-timeanalyticsforsupersaturatingformulations...................................... 310 5.6. Combining in vitro, in silico and in vivo data:ambitionsforpredictionoforalproductperformance.................... 311 Abbreviations list: A/V, Absorption surface to donor volume ratio; ACE2, Angiotensin converting enzyme 2; AhR, Aryl hydrocarbon receptor; AMI, Artificial membrane insert; ASD, Amorphous solid dispersions; BCS, Biopharmaceutics classification system; BE, Bioequivalence; CAR, Constitutive androstane receptor; CD, Crohn's disease; Cmax, Maximum plasma concentration; COVID-19, Coronavirus disease 2019; Cp, Plasma concentration; CPP, Cell penetrating peptides; CVRM, Cariovascular, renal and metabolism diseases; CYP, Cytochrome P450 enzymes; DDI, Drug-drug interactions; DGM, Dynamic gastric model; DLin-MC3-DMA, Heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate;
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