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Jennifer Dressman - 40 years of Oral Drug Absorption

2021; Elsevier BV; Volume: 111; Issue: 1 Linguagem: Inglês

10.1016/j.xphs.2021.10.020

1520-6017

Bertil Abrahamsson, James Butler, Rodrigo Cristofoletti, Edmund Kostewicz, Christoph Saal, Christos Reppas,

Analytical Methods in Pharmaceuticals

Jenny (Boehm) Dressman grew up on a farm in Western Victoria, Australia, where she enjoyed riding horseback, playing field hockey and tennis, as well as reading. In school she developed an interest in maths and the sciences and, after completing her high school exams, she enrolled at the Victorian College of Pharmacy (VCP), which later became a part of Monash University. The excellent lectures given by Dr. Richard Oppenheim inspired her to pursue graduate studies in Pharmaceutics and after finishing her undergraduate studies with honours in several subjects, she enrolled in the Master's program at VCP under his supervision. The project involved formulating active charcoal for administration in childhood poisoning accidents,1Boehm J.J. Oppenheim R.C. An in vitro study of the adsorption of drugs by activated charcoal.Austr J Pharm Sci. 1977; 6: 107Google Scholar, 2Boehm J.J. Brown T.C.K. Oppenheim R.C. Flavored activated charcoal as an antidote.Austr J Pharm Sci. 1978; 7: 119Google Scholar, 3Boehm J.J. Brown T.C.K. Oppenheim R.C. Reduction of pheniramine toxicity using activated charcoal.Clin Toxicol. 1978; 12: 523Crossref PubMed Scopus (14) Google Scholar which was a significant public health issue at the time. During these studies, Professor Takeru Higuchi visited the VCP and, as part of the Intersearch cooperation between VCP and the University of Kansas (KU), Jenny was invited to transfer to Lawrence, Kansas to pursue doctoral studies, an invitation which she happily accepted due to the excellent reputation of the Department of Pharmaceutical Chemistry at KU and the chance to study with Higuchi, who has often been described as the „Father of Modern Pharmaceutics“. At KU she studied the influence of self-association of drugs and association on mass transfer4Dressman J.B. Himmelstein K.J. Higuchi T. Simultaneous self-association and diffusion of phenol in isooctane.J Pharm Sci. 1982; 71: 1226-1230Abstract Full Text PDF PubMed Scopus (3) Google Scholar,5Dressman J.B. Himmelstein K.J. Higuchi T. Diffusion of phenol in the presence of a complexing agent, tetrahydrofuran.J Pharm Sci. 1983; 72: 12-17Abstract Full Text PDF PubMed Scopus (3) Google Scholar which fostered her interest in diffusion as a mass transfer mechanism. After successfully defending her thesis, Jenny moved to North Carolina to take up a position as Research Pharmacist at Burroughs Wellcome, today part of GlaxoSmithKline. Here she returned to preformulation and formulation studies, including developing a sustained released dosage form of buproprion. But just a year after she had arrived in North Carolina, she got a call from Prof. Higuchi, asking her to come back to Lawrence to join the team at Interx, a small „think-tank“ belonging to Merck & Co. At Interx she was able to combine her interests in mass transfer and oral drug absorption. Over the next several years she published some key papers in this area with David Fleisher and Gordon Amidon,6Dressman J.B. Fleisher D. Amidon G.L. Physicochemical model for dose-dependent drug absorption.J Pharm Sci. 1984; 73: 1274-1279Abstract Full Text PDF PubMed Scopus (75) Google Scholar, 7Dressman J.B. Amidon G.L. Fleisher D. Absorption potential: estimating the fraction absorbed for orally administered compounds.J Pharm Sci. 1985; 74: 588-589Abstract Full Text PDF PubMed Scopus (196) Google Scholar, 8Dressman J.B. Fleisher D. Mixing-tank model for predicting dissolution rate control of oral absorption.J Pharm Sci. 1986; 75: 109-116Abstract Full Text PDF PubMed Scopus (150) Google Scholar one of which was awarded the Ebert Prize for the best paper in J Pharm Sci. In 1983, Jenny applied to and was accepted as the first woman to hold an Assistant Professor position in Pharmaceutics at the University of Michigan in Ann Arbor. At the tender age of 27, Jenny was barely older than either her graduate students or the Pharmacy students. Nevertheless, she commanded respect from her colleagues and students alike for her professional attitude, enthusiasm for teaching and research ideas. She quickly established an active research group. Notable collaborations at that time included a research partnership with Dr. James Meyer, a highly respected gastroenterologist from the VA in Sepulveda, with whom she worked on improving our understanding of the hydrodynamic interactions between gastrointestinal (GI) fluids and dosage forms,9Meyer J.H. Gu Y. Elashoff J. Reedy T. Dressman J.B. Amidon G.L. Effects of viscosity and fluid outflow on postcibal gastric emptying of solids.Am J Physiol. 1986; 193: G161-G164Google Scholar, 10Meyer J.H. Elashoff J. Porter-Fink V. Dressman J.B. Amidon G.L. Human postprandial gastric emptying of 1-3 millimeter spheres.Gastroenterology. 1988; 94: 1315-1325Abstract Full Text PDF PubMed Scopus (182) Google Scholar, 11Sirois P.J. Amidon G.L. Meyer J.H. Doty J. Dressman J.B. Gastric emptying of nondigestible solids in dogs: a hydrodynamic correlation.Am J Physiol. 1990; 258: G65-G72PubMed Google Scholar as well as a collaboration with Dr. Rosemary Berardi from the clinical faculty, with whom she published several papers on GI pH under the auspices of grants from the Cystic Fibrosis Foundation and NIH12Youngberg C.A. Berardi R.R. Howatt W.F. et al.Comparison of gastrointestinal pH in cystic fibrosis and healthy subjects.Dig Dis Sci. 1987; 32: 472-480Crossref PubMed Scopus (98) Google Scholar, 13Dressman J.B. Berardi R.R. Dermentzoglou L.C. et al.Upper gastrointestinal pH in young, healthy men and women.Pharm Res. 1990; 7: 756-761Crossref PubMed Scopus (622) Google Scholar, 14Russell T.L. Barnett J.L. Berardi R.R. et al.Upper gastrointestinal pH in seventy-nine healthy, North American men and women ≥ 65 years.Pharm Res. 1993; 10: 187-196Crossref PubMed Scopus (288) Google Scholar as well as running several oral drug absorption studies together. Teaching tablet coating at the University of Michigan At the same time, Jenny remained fascinated by the behavior of drugs in the GI tract. To understand this better, she teamed up again with her VCP mentor, Richard Oppenheim, to investigate the effects of bile components on solubility and dissolution of drugs from oral dosage forms. This work, carried out in the lab in large part by Vasso Bakatselou und Lori Naylor McMillan,15Bakatselou V. Oppenheim R.C. Dressman J.B. Solubilization and wetting effects of bile salts on the dissolution of steroids.Pharm Res. 1991; 8: 1461-1469Crossref PubMed Scopus (164) Google Scholar, 16Naylor L.J. Bakatselou V. Dressman J.B. Comparison of the mechanism of dissolution of hydrocortisone in simple and mixed micelle systems.Pharm Res. 1993; 10: 865-870Crossref PubMed Scopus (82) Google Scholar, 17Naylor L.J. Bakatselou V. Rodriguez-Hornedo N. Weiner N.D. Dressman J.B. Dissolution behavior of steroids in bile salt solutions is modified by the presence of lecithin.Eur J Pharm Biopharm. 1995; 41: 346-353Google Scholar, 18Mithani S.D. Bakatselou V. TenHoor C.N. Dressman J.B. Prediction of increase in solubility of drugs as a function of bile salt concentration.Pharm Res. 1996; 13: 163-167Crossref PubMed Scopus (289) Google Scholar together with the pH data from the clinical studies, later formed the basis of the “Biorelevant media“. Maintaining her interest in mathematical descriptions of pharmaceutical processes, she also teamed up with Prof. Bernard Palsson of the Chemical Engineering Departmentt at the University of Michigan to provide analytical solutions to problems such as the dissolution of ionizable compounds and enteric coatings.19Ozturk S.S. Palsson B.O. Dressman J.B. Dissolution of ionizable drugs in buffered and unbuffered solutions.Pharm Res. 1988; 5: 272-282Crossref PubMed Scopus (72) Google Scholar, 20Ozturk S.S. Palsson B.O. Donohoe B. Dressman J.B. Kinetics of release from enteric-coated tablets.Pharm Res. 1988; 5: 550-565Crossref PubMed Scopus (74) Google Scholar, 21Ozturk S.S. Dressman J.B. Palsson B.O. On the use of the quasi-equilibrium assumption for drug dissolution.Pharm Res. 1990; 7: 425-429Crossref PubMed Scopus (3) Google Scholar Further efforts in this period involved Christos Reppas, who spent several years in Jenny's labs at the University of Michigan collaborating as a Visiting Scientist, and a postdoc, Sahar Swidan, who worked together with Jenny on animal and clinical studies which demonstrated the benefits of high molecular weight HMPC in reducing glucose and lipid levels in patients with metabolic syndrome and Type 2 diabetics. The project was funded by the Dow Corporation and ultimately led to several papers22Dressman J.B. Adair C.H. Barnett J.L. et al.High molecular weight hydroxypropylmethylcellulose: a cholesterol lowering agent.Arch Int Med. 1993; 153: 1345-1353Crossref PubMed Scopus (37) Google Scholar, 23Reppas C. Adair C.H. Barnett J.L. et al.High viscosity hydroxypropylmethylcellulose reduces postprandial blood glucose concentrations in NIDDM patients.Diab Res Clin Pract. 1993; 22: 61-69Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 24Swidan S. Reppas C. Barnett J.L. et al.Ability of two comestible formulations of hydroxypropylmethylcellulose to lower serum cholesterol concentration.Eur J Pharm Sci. 1996; 4: 239-245Crossref Scopus (13) Google Scholar as well as a patent and the launch of Fortefiber®, a product which is used in various food items. In 1989, her excellence in research and teaching was rewarded with promotion to the position of Associate Professor with tenure. Amid all these activities, Jenny also found the time to support initiatives such as the founding of the American Association of Pharmaceutical Scientists in 1986 as a Charter Member. Later she filled several different posts at AAPS, including Chair of the Pharmaceutics and Drug Delivery Section, Chair of the Strategic Alliances Committee and as Member-At-Large on the Executive Council. In 1991 she became only the second female scientist (after Dr. Gertrude Elion, Nobel Prize 1988) to be made a Fellow of the AAPS. On sabbatical in 1992 at the University of Paris XI with Patrick Couvreur, Jenny was invited to give a seminar at the Johann Wolfgang Goethe University (GU) in Frankfurt, Germany, where an old friend from Kansas days, Jörg Kreuter, was Professor of Pharmaceutical Technology. To her surprise she was offered a professorial position at GU soon thereafter, even though she didn't speak any German. Having moved continents before, this seemed more like an adventure than a hurdle. She moved to Germany to take up the position at GU in 1994. However, she still had one foot in the USA and soon after she moved, Jenny was awarded an FDA grant to follow up on some dissolution aspects of the SUPAC guidances, with Vinod Shah as the collaboratingAAPS meeting, San Antonio, 2018partner at FDA. Drawing on ideas she had developed at the University of Michigan, this research led to the publication of two papers, one of which described the conditions necessary for biorelevant dissolution testing and the other, the application of these media to drug products. These were the seminal papers in the area of biorelevant dissolution testing and have been cited frequently over the years.25Dressman J.B. Amidon G.L. Reppas C. Shah V.P. Dissolution testing as a prognostic tool for oral drug absorption: immediate release dosage forms.Pharm Res. 1998; 15: 11-22Crossref PubMed Scopus (971) Google Scholar,26Galia E. Nicolaides E. Hörter D. Löbenberg R. Reppas C. Dressman J.B. Evaluation of various dissolution media for predicting in vivo performance of Class I and II drugs.Pharm Res. 1998; 15: 698-705Crossref PubMed Scopus (852) Google Scholar In the 1990s, Jenny was also welcomed into the “Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik“ (APV), serving as a member of the Executive Committee from 1997 to 2000 and continuing today as the Co-Chair of Pharmacokinetics and Biopharmaceutics with Prof. Peter Langguth from the University of Mainz. She also became active in the “Federation Internationale Pharmaceutique“ (FIP) in the Dissolution Group, working with Vinod Shah to initiate hands-on Dissolution Workshops throughout the world, the first of which was held in 1999. These workshops were designed to facilitate an even playing field in terms of dissolution expertise across the globe and were later augmented by topics related to bioavailability and bioequivalence as well as the Biopharmaceutics Classification Scheme (BCS). In 2000 together with her graduate student, Christian Leuner, Jenny wrote a review on solid dispersions,27Leuner C. Dressman J.B. Improving drug solubility for oral drug delivery using solid molecular dispersions. Invited review, 50th Anniversary edition.Eur J Pharm Biopharm. 2000; 50: 47-60Crossref PubMed Scopus (2233) Google Scholar which became widely cited in the pharmaceutical literature and still stands today in Google Scholar as her most cited paper. Following up on this work, many further papers and several patents were published on oral dosage forms that were designed to optimize release of the drug in the GI tract, with the aims ranging from improving the bioavailability of the drug, through targeting the drug to a certain site in the GI tract, to prolonging the duration of action (e.g.28Rudolph M.W. Klein S. Beckert T.E. Petereit H.-U. Dressman J.B. A new 5-aminosalicylic acid multi-unit dosage form for the therapy of ulcerative colitis.Eur J Pharm Biopharm. 2001; 51: 183-190Crossref PubMed Scopus (114) Google Scholar, 29Fürst T. Bott C. Stein J. Dressman J.B. Enteric coated cholylsarcosine granules for the treatment of short bowel syndrome.J Pharm Pharmacol. 2005; 57: 53-60Crossref PubMed Scopus (13) Google Scholar, 30Vogt M. Kunath K. Dressman J. Dissolution improvement of four poorly water-soluble drugs by cogrinding with commonly used excipients.Eur J Pharm Biopharm. 2008; 68: 330-337Crossref PubMed Scopus (117) Google Scholar, 31Nollenberger K. Gryczke A. Meier Ch Dressman J. Schmidt M.U. Brühne S. Pair distribution function x-ray analysis explains dissolution characteristics of felodipine melt extrusion products.J Pharm Sci. 2009; 98: 1476-1486Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). In complementary research, in collaboration with Christos Reppas, who by that time was an Associate Professor at the National and Kapodistrian University of Athens, the biorelevant media were refined and evolved to better reflect conditions in various segments of the GI tract,32Vertzoni M. Dressman J. Butler J. Hempenstall J. Reppas C. Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds.EurJ Pharm Biopharm. 2005; 60: 413-417Crossref PubMed Scopus (316) Google Scholar, 33Kalantzi L. Goumas K. Kalioras V. Abrahamsson B. Dressman J. Reppas C. Characterization of the human upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies.Pharm Res. 2006; 23: 165-176Crossref PubMed Scopus (543) Google Scholar, 34Jantratid E. Janßen N. Reppas C. Dressman J. Dissolution media simulating conditions in the proximal human gastrointestinal tract: an update.Pharm Res. 2008; 25: 1663-1676Crossref PubMed Scopus (629) Google Scholar while Sandra Klein, at that time a graduate student at GU (meanwhile Professor at the University of Greifswald), focused on developing specific methods for dosage forms with targeted release in the GI tract.35Klein S. Stein J. Dressman J.B. Site-specific release of anti-inflammatory drugs in the gastrointestinal tract.J Pharm Pharmacol. 2005; 57: 709-719Crossref PubMed Scopus (67) Google Scholar Additionally, as part of a collaboration with Boehringer Ingelheim, Dr. Edmund Kostewicz and Martin Wunderlich worked with Jenny to establish the so-called “Transfer Model“, which gives a first indication of whether weakly basic drugs can maintain a supersaturated state once they have passed from the stomach into the small intestine.36Kostewicz E. Wunderlich M. Becker R. Brauns U. Bock T. Dressman J.B. Predicting the precipitation of poorly soluble weak bases upon entry into the small intestine.J Pharm Pharmacol. 2004; 56: 43-51Crossref PubMed Scopus (266) Google Scholar This research enabled considerations of supersaturation and precipitation in the gut in an in vitro experimental design for the first time and spawned many further innovations in this area in the ensuing years. In addition to her research in this timeframe, Jenny also stepped up her participation in scientific organisations, being part of the CRS executive committee for several years, including a term as President in 2004/2005. Concurrently she became involved with the Biowaiver Monographs, which had been initiated by Dr. Dirk Barends of the “Rijksinstituut voor Volksgezondheid en Milieu“ (RIVM) in the Netherlands, as part of her work as Technical Advisor to WHO and member of the FIP dissolution working group. In 2006 she became Director of a WHO Collaborating Center for research on biopharmaceutics, which enabled her to continue classification of the WHO's List of Essential Medicines (EML) according to the BCS and cemented her involvement with the Biowaiver Monographs. When Dirk Barends sadly passed away after a short illness in 2012, Jenny took over responsibility for the Monographs, which aim to provide a scientifically based decision as to whether generic products containing the drug in question could be approved using the BCS-based Biowaiver rather than the more time-consuming and costly pharmacokinetic evaluation of bioequivalence. The BCS-based Biowaiver procedure is thus very important to ensuring that essential medicines are readily available at an affordable price across the globe, without sacrificing product quality. To date, over 50 drugs have been monographed, representing almost a third of the oral medicines on the EML, and the work is continuing. A current list of all monographs can be found at https://www.jpharmsci.org/biowaiver-monographs. In 2010, the biorelevant media were commercialized by the Phares company. This was a sea-change in the use of biorelevant media, as the instant powders saved a lot of time and effort in the preparation of the media while ensuring reproducibility.37Kloefer B. van Hoogevest P. Moloney R. Kuentz M. Leigh M. Dressman J. Study of a standardized taurocholate-lecithin powder for preparing the biorelevant media FaSSIF and FeSSIF.Dissolution Technologies. 2010; 17: 6-14Crossref Scopus (49) Google Scholar,38Mann J. Dressman J. Rosenblatt K. et al.Validation of dissolution testing with biorelevant media: an OrBiTo study.Mol Pharm. 2017; 14: 4192-4201Crossref PubMed Scopus (64) Google Scholar Later, the company's name was changed to biorelevant.com and over the years, Jenny has worked with the company to ensure that updates of the existing media, as well as new media to represent e.g. the colon are made available as ready-to-use products (https://biorelevant.com/). As a result of this availability, biorelevant media are now an essential part of the development paradigm for oral drug products across the pharmaceutical industry. In keeping with her opinion that pharmaceutics is an applied science and research in this area should therefore contribute to progress in industrial pharmaceutical development as well as in academic and regulatory research, Jenny has a long history of working with the pharmaceutical industry, in both longstanding bilateral collaborations with the pharmaceutical industry (F. Hoffmann-LaRoche, GSK, AstraZeneca and Janssen, to name just a few) and in European Union sponsored projects bringing together industrial with academic pharmaceutical sciences (OrBiTo, PEARRL and InPharma). To capitalize on the added-value of biorelevant dissolution testing in predicting absorption-related pharmacokinetic phenomena like food effects, it became apparent that it would be necessary to couple the results with a physiologically based pharmacokinetic (PBPK) model. Indeed, soon after the biorelevant media were first introduced, a team effort with the Reppas group in Athens demonstrated the importance of in silico modeling in simulating the impact of dosing conditions on plasma profile of poorly soluble, highly permeable drugs using rudimentary, self-built models.39Nicolaides E. Symillides M. Dressman J.B. Reppas C. Biorelevant dissolution testing to predict the plasma profile of lipophilic drugs after oral administration.Pharm Res. 2001; 18 (PMID: 11442280Y): 380-388https://doi.org/10.1023/a:1011071401306Crossref PubMed Scopus (0) Google Scholar The concept of the Nicolaides et al. paper (including introducing the z factor) was later extended to situations where drug precipitation and/or gut wall permeability was also playing a key role in the plasma profile.40Shono EJ Reppas C. Dressman J. Forecasting in vivo oral absorption and food effect of nanosized aprepitant formulation in humans.Eur J Pharm Biopharm. 2010; 76: 95-104Crossref PubMed Scopus (120) Google Scholar, 41Jünemann D. Jantratid E. Wagner C. Reppas C. Vertzoni M Dressman J. Biorelevant in vitro dissolution testing of micronized or nanosized products of fenofibrate with a view to predicting plasma profiles.Eur J Pharm Biopharm. 2010; 77: 257-264Crossref PubMed Scopus (91) Google Scholar, 42Shono Y. Jantratid E. Dressman J. Precipitation in the small intestine may play a more important role in the absorption of poorly soluble weak bases: case example nelfinavir.Eur J Pharm Biopharm. 2011; 79: 349-356Crossref PubMed Scopus (82) Google Scholar In the 2010s, it became apparent that a more sophisticated PBPK model would be needed to describe the GI physiology, permeability and first pass effects and the team adopted the use of commercially available PBPK models. In recent years, successful models to answer various questions around oral drug development, including some regulatory aspects, have been addressed by combining biorelevant dissolution testing with PBPK, e.g. identifying the rate limiting step to absorption, exploring the effect of salt form on in vivo behavior, investigating formulation effects, predicting food effects and mechanistically explaining drug interactions that result from drug-induced changes in GI physiology,43Kambayashi A. Dressman J. An in vitro-in silico-in vivo approach to predicting the oral pharmacokinetic profile of salts of weak acids: case example Dantrolene.Eur J Pharm Biopharm. 2013; 84: 200-207Crossref PubMed Scopus (39) Google Scholar, 44Litou C. Patel N. Turner D. Dressman J. Combining biorelevant in vitro and in silico tools to simulate and better understand the in vivo performance of a nano-sized formulation of aprepitant in the fasted and fed states.Eur J Pharm Sci. 2019; 138https://doi.org/10.1016/j.ejps.2019.105031Crossref PubMed Scopus (20) Google Scholar, 45Cristofoletti R. Dressman J. Dissolution methods to increasing discriminatory power of in vitro dissolution testing for ibuprofen free acid and its salts.J Pharm Sci. 2017; 106: 92-99Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 46Hansmann S. Miyaji Y. Dressman J. An in silico approach to determine challenges in the bioavailability of ciprofloxacin, a poorly soluble weak base with borderline solubility and permeability characteristics.Eur J Pharm Biopharm. 2018; 122: 186-196Crossref PubMed Scopus (21) Google Scholar, 47Paraiso R.L.M. Watanabe A. Andreas C.J. Turner D. Zane P. Dressman J. In-vitro–in-silico investigation of the negative food effect of zolpidem when administered as immediate-release tablets.J Pharm Pharmacol. 2019; 71: 1663-1676Crossref PubMed Scopus (8) Google Scholar, 48Otsuka K. Wagner C. Selen A. Dressman J. Prediction of in-vivo pharmacokinetic profile for immediate and modified release oral dosage forms of furosemide using an in-vitro-in-silico-in-vivo approach.J Pharm Pharmacol. 2015; 67: 651-665Crossref PubMed Scopus (23) Google Scholar, 49Cristofoletti R. Dressman J.B. Bridging the gap between in vitro dissolution and the time course of ibuprofen-mediating pain relief.J Pharm Sci. 2016; 105: 3658-3667Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 50Segregur D. Mann J. Moir A. Karlsson E.M. Dressman J. Prediction of plasma profiles of a weakly basic drug after adminnistration of omeprazole using PBPK modeling.Eur J Pharm Sci. 2020; 158105656Crossref PubMed Scopus (7) Google Scholar, 51Fiolka T. Van Den Abeele J. Augustijns P. Arora S. Dressman J. Biorelevant two-stage in vitro testing for rDCS classification and in PBPK modelling–Case example ritonavir.J Pharm Sci. 2020; 109: 2512-2526Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 52Komasaka T. Dressman J. Simulation of oral absorption from non-bioequivalent dosage forms of the salt of raltegravir, a poorly soluble acidic drug.Eur J Pharm Sci. 2020; 157105630Crossref PubMed Scopus (6) Google Scholar but it will be necessary to keep expanding the range of biorelevant testing as well as refining the PBPK models to achieve maximum scope and confidence in the approach. Most recently, together with her former graduate student, Rodrigo Cristofoletti (currently Assistant Professor at the University of Florida), first attempts were made to combine dissolution testing, PBPK and PD to link the lab with clinical performance.53Loisios-Konstantinidis I. Cristofoletti R. Fotaki N. Turner D.B. Dressman J. Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modelling.Eur J Pharm Sci. 2020; 143: 105-170Crossref Scopus (51) Google Scholar This quantitative modeling approach was further expanded in a follow-on EU project, PEARRL (www.pearrl.eu).54Cristofoletti R. Dressman J. Bridging the gap between in vitro dissolution and the time course of ibuprofen-mediating pain relief.J Pharm Sci. 2016; 105: 3658-3667Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar,55Loisios-Konstantinidis I. Cristofoletti R. Jamei M. Turner D. Dressman J. Physiologically based pharmacokinetic/pharmacodynamic modeling to predict the impact of CYP2C genetic polymorphism, comedication and formulation on the pharmacokinetics and pharmacodynamics of flurbiprofen.Pharmaceutics. 2020; 12: 1049Crossref Scopus (12) Google Scholar This would be an important breakthrough towards fulfilling the original aim and definition of bioequivalence, which is to ensure the equivalence of two drug products, or a drug product administered under different conditions, at the site of action.56Loisios-Konstantinidis I. Dressman J. Physiologically based pharmacokinetic/pharmacodynamic modeling to support waivers of in vivo clinical studies: current status, challenges, and opportunities.Mol Pharm. 2021; 18: 1-17Crossref PubMed Scopus (9) Google Scholar In a parallel effort to assist the pharmaceutical community in its attempts to bring new drugs to market, Jenny teamed up with James Butler of GlaxoSmithKline around 2010 to re-examine the BCS in the context of pharmaceutical development of oral drugs. By this time, it was recognized that although the BCS was a very good regulatory tool for generic drug and scale-up/post-approval changes, the cut-off points were too restrictive to be applied directly for decisions about whether a drug could be a candidate for oral delivery. In 2010 they published the Development Classification Scheme (DCS),57Butler J. Dressman J. The developability classification system: application of biopharmaceutics concepts to formulation development.J Pharm Sci. 2010; 99: 4940-4954Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar which was later revisited in the EU project OrBiTo (Oral Biopharmaceutics Tools) and published as the refined Development Classification System (rDCS) with an applications paper to demonstrate how to apply the rDCS in an industrial setting.58Rosenberger J. Butler J. Dressman J. A refined development classification scheme.J Pharm Sci. 2018; 107: 2020-2032Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 59Rosenberger J. Butler J. Muenster U. Dressman J. Application of a refined development classification scheme.J Pharm Sci. 2019; 108: 1090-1100Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Currently, in the latest EU project, InPharma (www.inpharma-network.eu) the rDCS is entering a beta-phase to verify the various steps and illustrate the applications on a broader basis. Although Jenny retired from GU in 2021, she is continuing her contributions to oral drug absorption through her association with the Fraunhofer Institute of Translational Medicine and Pharmacology (www.itmp.fraunhofer.de), where she is actively engaged in an innovative project to create an electronically based oral dosage form, the „e-Pille“ (https://www.itmp.fraunhofer.de/en/press/e-Pille.html), as well as collaborating with FDA, together with Jim Polli (U-Maryland) and Rodrigo Cristofoletti (U-Florida), on a virtual bioequivalence project. Watch this space for more exciting developments from Jenny‘s research group in the coming years!