Edmund Kostewicz received a BSc. from the University of Adelaide (Australia). His Honours Degree was awarded at Flinders University (Australia) and his PhD from the University of South Australia (Australia) under the supervision of Prof. Lloyd Sansom.

Following completion of his PhD, he held a Post Doc position in the Institute for Pharmaceutical Technology at the Goethe University (Germany). He then took up a position as Research Scientist within the Department of Biopharmaceutics at AstraZeneca (Sweden) and then as Project Coordinator within the Centre for Drug Candidate Optimisation at Monash University (Australia). Edmund has held his current position in the Institute for Pharmaceutical Technology at Goethe University since 2009.

Research Interest:  Tools for predicting oral drug absorption in humans

  • In vitro and in vivo models for predicting oral drug absorption in humans
  • In vivo prediction of gastrointestinal (GI) precipitation using the transfer model
  • Use of physiologically based pharmacokinetic modeling to simulate drug absorption

A variety of factors can limit the rate and extent of absorption following oral drug absorption. These include solubility, dissolution from a pharmaceutical dosage form and stability within the GI tract, permeability and first pass metabolism across the gut wall and/or liver. Poor biopharmaceutical properties are therefore a major cause for the failure of potential drug candidates. A reliable assessment of a drug’s biopharmaceutical properties is important not only at an early stage when the most suitable drug candidate is selected but also at a later stage in the subsequent pharmaceutical development of the candidate.

Solubility and dissolution relationships in the GI tract can be critical for the oral bioavailability of poorly soluble drugs. In order to assess potential solubility or dissolutions limitations, biorelevant GI media have proven to be a useful tool (Kostewicz et al. 2000). Media simulating pre and post prandial conditions in the stomach and intestine have been successfully applied to establish in vitro – in vivo correlations for oral dosage formulations.

In the case of poorly soluble weak bases, the possibility of drug precipitation upon entry into the small intestine may also impact on the amount of drug available for absorption. Given the high number of drug candidates exhibiting little or insufficient aqueous solubility, precipitation along the GI tract may be an important factor limiting their further development. During drug discovery and development, avoidance of drug precipitation for poorly soluble drugs is an important factor that needs to be considered and assessed.

To date, few in vitro methods have been used to characterize in vivo GI precipitation. The “transfer model” is an in vitro method (Kostewicz et al., 2004) using a modified USP dissolution approach containing 2 compartments that simulates the stomach and intestine, respectively. This dynamic system has demonstrated its utility in evaluating the degree of supersaturation and precipitation of poorly soluble weak bases as they transit out of the stomach and into the intestine.

In order to facilitate the simulation and prediction of oral drug absorption, the in vitro biorelevant solubility, dissolution and precipitation results can be coupled with in silico Physiologically Based Pharmacokinetic (PBPK) modeling to simulate plasma profiles. The important elements of these models are that all physiological and anatomical parameters relevant to the absorption process and their interaction with the characteristics of the drug and dosage formulation are appropriately dealt with and allows for a mechanistic examination of the absorption process for the drug from the particular dosage form.

Current Research

Transfermodel edmund

Optimization and validation of the transfer model to evaluate the influence of supersaturation and precipitation on the oral absorption of poorly soluble drugs. Mr Aaron Ruff, PhD student (Project funded by OrBiTo)

http://www.imi.europa.eu/content/orbito   

Orbito edmund

Refereed Publications

Refereed Publications

(1-26)

 

  1. P.J. O'Dwyer, C. Litou, K.J. Box, J.B. Dressman, E.S. Kostewicz, M. Kuentz, and C. Reppas. In vitro methods to assess drug precipitation in the fasted small intestine - a PEARRL review. J Pharm Pharmacol (2018).
  2. C. Litou, A. Effinger, E.S. Kostewicz, K.J. Box, N. Fotaki, and J.B. Dressman. Effects of medicines used to treat gastrointestinal diseases on the pharmacokinetics of coadministered drugs: a PEARRL Review. J Pharm Pharmacol (2018).
  3. M. Koziolek, E. Kostewicz, and M. Vertzoni. Physiological Considerations and In Vitro Strategies for Evaluating the Influence of Food on Drug Release from Extended-Release Formulations. AAPS PharmSciTech. 19:2885-2897 (2018).
  4. L.J. Henze, N.J. Koehl, J.P. O'Shea, E.S. Kostewicz, R. Holm, and B.T. Griffin. The pig as a preclinical model for predicting oral bioavailability and in vivo performance of pharmaceutical oral dosage forms: a PEARRL review. J Pharm Pharmacol (2018).
  5. M. Santillo, S. Young, K. Bracht, D. Elder, A. Zeitler, J. Butler, K. Box, E. Kostewicz, and J. Mann. Meeting Report: Dissolution Testing: Current and Future Considerations. Dissolut Technol. 24:62-67 (2017).
  6. A. Ruff, R. Holm, and E.S. Kostewicz. Evaluating the predictability of the in vitro transfer model and in vivo rat studies as a surrogate to investigate the supersaturation and precipitation behaviour of different Albendazole formulations for humans. Eur J Pharm Sci. 105:108-118 (2017).
  7. A. Ruff, T. Fiolka, and E.S. Kostewicz. Prediction of Ketoconazole absorption using an updated in vitro transfer model coupled to physiologically based pharmacokinetic modelling. Eur J Pharm Sci. 100:42-55 (2017).
  8. S.M. Pathak, A. Ruff, E.S. Kostewicz, N. Patel, D.B. Turner, and M. Jamei. Model-Based Analysis of Biopharmaceutic Experiments To Improve Mechanistic Oral Absorption Modeling: An Integrated in Vitro in Vivo Extrapolation Perspective Using Ketoconazole as a Model Drug. Mol Pharm. 14:4305-4320 (2017).
  9. A. Margolskee, A.S. Darwich, X. Pepin, L. Aarons, A. Galetin, A. Rostami-Hodjegan, S. Carlert, M. Hammarberg, C. Hilgendorf, P. Johansson, E. Karlsson, D. Murphy, C. Tannergren, H. Thorn, M. Yasin, F. Mazuir, O. Nicolas, S. Ramusovic, C. Xu, S.M. Pathak, T. Korjamo, J. Laru, J. Malkki, S. Pappinen, J. Tuunainen, J. Dressman, S. Hansmann, E. Kostewicz, H. He, T. Heimbach, F. Wu, C. Hoft, L. Laplanche, Y. Pang, M.B. Bolger, E. Huehn, V. Lukacova, J.M. Mullin, K.X. Szeto, C. Costales, J. Lin, M. McAllister, S. Modi, C. Rotter, M. Varma, M. Wong, A. Mitra, J. Bevernage, J. Biewenga, A. Van Peer, R. Lloyd, C. Shardlow, P. Langguth, I. Mishenzon, M.A. Nguyen, J. Brown, H. Lennernas, and B. Abrahamsson. IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 2: An introduction to the simulation exercise and overview of results. Eur J Pharm Sci. 96:610-625 (2017).
  10. A.S. Darwich, A. Margolskee, X. Pepin, L. Aarons, A. Galetin, A. Rostami-Hodjegan, S. Carlert, M. Hammarberg, C. Hilgendorf, P. Johansson, E. Karlsson, D. Murphy, C. Tannergren, H. Thorn, M. Yasin, F. Mazuir, O. Nicolas, S. Ramusovic, C. Xu, S.M. Pathak, T. Korjamo, J. Laru, J. Malkki, S. Pappinen, J. Tuunainen, J. Dressman, S. Hansmann, E. Kostewicz, H. He, T. Heimbach, F. Wu, C. Hoft, Y. Pang, M.B. Bolger, E. Huehn, V. Lukacova, J.M. Mullin, K.X. Szeto, C. Costales, J. Lin, M. McAllister, S. Modi, C. Rotter, M. Varma, M. Wong, A. Mitra, J. Bevernage, J. Biewenga, A. Van Peer, R. Lloyd, C. Shardlow, P. Langguth, I. Mishenzon, M.A. Nguyen, J. Brown, H. Lennernas, and B. Abrahamsson. IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes. Eur J Pharm Sci. 96:626-642 (2017).
  11. J.P. O'Shea, W. Faisal, T. Ruane-O'Hora, K.J. Devine, E.S. Kostewicz, C.M. O'Driscoll, and B.T. Griffin. Lipidic dispersion to reduce food dependent oral bioavailability of fenofibrate: In vitro, in vivo and in silico assessments. Eur J Pharm Biopharm. 96:207-216 (2015).
  12. E.S. Kostewicz, B. Abrahamsson, M. Brewster, J. Brouwers, J. Butler, S. Carlert, P.A. Dickinson, J. Dressman, R. Holm, S. Klein, J. Mann, M. McAllister, M. Minekus, U. Muenster, A. Mullertz, M. Verwei, M. Vertzoni, W. Weitschies, and P. Augustijns. In vitro models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci. 57:342-366 (2014).
  13. E.S. Kostewicz, L. Aarons, M. Bergstrand, M.B. Bolger, A. Galetin, O. Hatley, M. Jamei, R. Lloyd, X. Pepin, A. Rostami-Hodjegan, E. Sjogren, C. Tannergren, D.B. Turner, C. Wagner, W. Weitschies, and J. Dressman. PBPK models for the prediction of in vivo performance of oral dosage forms. Eur J Pharm Sci. 57:300-321 (2014).
  14. B.T. Griffin, M. Kuentz, M. Vertzoni, E.S. Kostewicz, Y. Fei, W. Faisal, C. Stillhart, C.M. O'Driscoll, C. Reppas, and J.B. Dressman. Comparison of in vitro tests at various levels of complexity for the prediction of in vivo performance of lipid-based formulations: case studies with fenofibrate. Eur J Pharm Biopharm. 86:427-437 (2014).
  15. C.A. Bergstrom, R. Holm, S.A. Jorgensen, S.B. Andersson, P. Artursson, S. Beato, A. Borde, K. Box, M. Brewster, J. Dressman, K.I. Feng, G. Halbert, E. Kostewicz, M. McAllister, U. Muenster, J. Thinnes, R. Taylor, and A. Mullertz. Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs. Eur J Pharm Sci. 57:173-199 (2014).
  16. Y. Fei, E.S. Kostewicz, M.T. Sheu, and J.B. Dressman. Analysis of the enhanced oral bioavailability of fenofibrate lipid formulations in fasted humans using an in vitro-in silico-in vivo approach. Eur J Pharm Biopharm. 85:1274-1284 (2013).
  17. E. Buscato, J.M. Wisniewska, C.B. Rodl, A. Bruggerhoff, A. Kaiser, F. Rorsch, E. Kostewicz, M. Wurglics, M. Schubert-Zsilavecz, S. Grosch, D. Steinhilber, B. Hofmann, and E. Proschak. Structure-activity relationship and in vitro pharmacological evaluation of imidazo[1,2-a]pyridine-based inhibitors of 5-LO. Future Med Chem. 5:865-880 (2013).
  18. B.L. Flynn, G.S. Gill, D.W. Grobelny, J.H. Chaplin, D. Paul, A.F. Leske, T.C. Lavranos, D.K. Chalmers, S.A. Charman, E. Kostewicz, D.M. Shackleford, J. Morizzi, E. Hamel, M.K. Jung, and G. Kremmidiotis. Discovery of 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105), a tubulin polymerization inhibitor with potent antiproliferative and tumor vascular disrupting properties. J Med Chem. 54:6014-6027 (2011).
  19. K.D. Johnstone, T. Karoli, L. Liu, K. Dredge, E. Copeman, C.P. Li, K. Davis, E. Hammond, I. Bytheway, E. Kostewicz, F.C. Chiu, D.M. Shackleford, S.A. Charman, W.N. Charman, J. Harenberg, T.J. Gonda, and V. Ferro. Synthesis and biological evaluation of polysulfated oligosaccharide glycosides as inhibitors of angiogenesis and tumor growth. J Med Chem. 53:1686-1699 (2010).
  20. G.A. Holloway, W.N. Charman, A.H. Fairlamb, R. Brun, M. Kaiser, E. Kostewicz, P.M. Novello, J.P. Parisot, J. Richardson, I.P. Street, K.G. Watson, and J.B. Baell. Trypanothione reductase high-throughput screening campaign identifies novel classes of inhibitors with antiparasitic activity. Antimicrob Agents Chemother. 53:2824-2833 (2009).
  21. M. Vertzoni, N. Fotaki, E. Kostewicz, E. Stippler, C. Leuner, E. Nicolaides, J. Dressman, and C. Reppas. Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects. J Pharm Pharmacol. 56:453-462 (2004).
  22. E.S. Kostewicz, M. Wunderlich, U. Brauns, R. Becker, T. Bock, and J.B. Dressman. Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine. J Pharm Pharmacol. 56:43-51 (2004).
  23. A. Scholz, E. Kostewicz, B. Abrahamsson, and J.B. Dressman. Can the USP paddle method be used to represent in-vivo hydrodynamics? J Pharm Pharmacol. 55:443-451 (2003).
  24. A. Scholz, B. Abrahamsson, S.M. Diebold, E. Kostewicz, B.I. Polentarutti, A.L. Ungell, and J.B. Dressman. Influence of hydrodynamics and particle size on the absorption of felodipine in labradors. Pharm Res. 19:42-46 (2002).
  25. E.S. Kostewicz, U. Brauns, R. Becker, and J.B. Dressman. Forecasting the oral absorption behavior of poorly soluble weak bases using solubility and dissolution studies in biorelevant media. Pharm Res. 19:345-349 (2002).
  26. E. Kostewicz, L. Sansom, R. Fishlock, A. Morella, and T. Kuchel. Examination of two sustained release nifedipine preparations in humans and in pigs. European Journal of Pharmaceutical Sciences. 4:351-357 (1996).

 

Abstracts and Conference Proceedings

Abstracts and Conference Proceedings

  1. Kostewicz E and Mackenzie P. Expression of Bilirubin UDP Glucuronosyltransferase in Rat Tissues. Clinical and Experimental Pharmacology and Physiology. (1993) (Suppl. 1), 39.
  2. Kostewicz E, Sansom L, Fishlock R, Morella A and Kuchel T.  Bioavailability of Two Sustained Release Nifedipine Preparations in Humans and in Pigs. Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists. (1995) Vol 2, 47.
  3. Kostewicz E, Sansom L, Fishlock R, Morella A and Kuchel T. The Effect of   Nizatidine and Cisapride on the Bioavailability of an Experimental Sustained Release Nifedipine Formulation. Australian Journal of Hospital Pharmacy. (1996), 26(5): 605.
  4. Kostewicz E, Sansom L, Fishlock R, Morella A and Kuchel T. Pharmacokinetic Evaluation of Adalat-20® in the Pig. Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists. (1996), Vol 3, 152.
  5. Sansom L, Singh S, Kostewicz E, Kuchel T and Morella A. Biopharmaceutic Evaluation of Nifedipine Controlled Release (CR) Products in the Pig. European Journal of Pharmaceutical Sciences. (1997) 5(Suppl. 2), S65.
  6. Lu M, Fishlock R, Kostewicz E, Sansom L, Kuchel T. Biopharmaceutic Evaluation of a Diclofenac Product in the Pig. Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists. (1998). Vol 5.
  7. Kostewicz E, Becker R, Brauns U, Dressman J. In vitro model to predict the precipitation of a poorly soluble weak base following its transition out of the stomach and into the intestine. (1999) AAPS PharmSci Suppl. vol 1, Number 4.
  8. Kostewicz E, Becker R, Brauns U, Dressman J. Predicting the Precipitation of a poorly soluble base following transition out of the stomach into the intestine. Third World Meeting of Biopharmaceutics. APV/APGI, Berlin, 2000.
  9. Kein S, Kostewicz E, Reppas C, Dressman J. Characterization of the physicochemical properties of standard breakfast meals, whole milk and Ensure® with the aim of creating a new generation of dissolution media. Controlled Release Society, Paris, 2000.
  10. Kostewicz ES, Butler JM, Dressman JB. The use of an in vitro model to examine the precipitation characteristics of a poorly soluble weak base. EUFEPS meeting in Copenhagen June 2001.
  11. Scholz A, Kostewicz E, Polentarutti B, Abrahamsson B, Dressman JB. Solubility of felodipine in canine chyme and simulated intestinal fluids. Archive der Pharmazie. 334 (suppl 1) 2001.
  12. Scholz, B Abrahamsson, S Diebold, E Kostewicz, B Polentarutti, A Ungell, Dressman J. The influence of GI hydrodynamics and particle size on felodipine absorption. (2001) AAPS PharmSci Suppl
  13. Kostewicz E, Polentarutti B, Albery T, Lindqvist J, Ungell A-L, Björklund L, Abrahamsson B. The use of the Yucatan micropig as an animal model for human drug absorption studies. 4th World Meeting on Pharmaceutics, Biopharmaceutics, Pharmaceutical Technology, April 2002, Florence, Italy.
  14. Wunderlich M, Bock T, Kostewicz E, Dressman J. Predicting the precipitation of a poorly soluble weak base following transition out of the stomach into the intestine. 4th World Meeting on Pharmaceutics, Biopharmaceutics, Pharmaceutical Technology, April 2002, Florence, Italy.
  15. Kostewicz E, Carlsson A, Hanisch G, Nilsson R, Löfgren L & Abrahamsson B. Comparison of dog and human intestinal fluid and its impact on solubility estimations. European Journal of Pharmaceutical Sciences, 2002, EUFEPS suppl. 17S, S111.
  16. Hanisch G, Kostewicz E, Carlsson A & Abrahamsson B. The importance of using physiologically relevant solubility values for predicting the in vivo absorption behaviour for poorly soluble drugs. European Journal of Pharmaceutical Sciences, 2002, EUFEPS suppl. 17S, 105.
  17. Kostewicz E, Davie A, Giavannetti M, Smolic A, Fida R, Gill G, Grobelny D, Flynn B, Charman W. Plasma stability and pharmacokinetics of Combretastatin A4 Phosphate in the rat. Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists. (2004)
  18. Wagner C, Thelin K, Willmann S, Kostewicz E & Dressman JB. Predicting plasma profiles of a BCS class II compound using physiologically based pharmacokinetic modeling. GPEN (Chapel Hill, USA) 2010.
  19. Wagner C, Selen A, Thelen K, Willmann S, Kostewicz E, Gordon S, Müllertz A & Dressman JB. Plasma profiles of nifedipine, a BCS class II compound, can be simulated exactly using Physiologically Based Pharmacokinetic Modeling in conjunction with detailed drug metabolism data. AAPS (Washington) 2011
  20. Kambayashi A, Kostewicz E, Dressman JB. An in vitro-in silico-in vivo approach to predicting the oral pharmacokinetic profile of Dantrolene. AAPS (Washington) 2011
  21. Kostewicz E, Albery T, Polentarutti B, Björklund L & Abrahamsson B. Characterization of the in vivo transit and release characteristics of a felodipine hydrophilic matrix gel tablet in Yucatan mini-pigs under fasting and fed conditions. AAPS (Washington) 2011
  22. Y. Fei, E. Kostewicz, J. Dressman. Solubility and dissolution study of lipid-based formulation of fenofibrate in fasted state compendial and updated biorelevant media. APV (Istanbul) 2012
  23. Aaron Ruff, Jennifer Dressman, Edmund Kostewicz. Optimization of the transfer model to predict supersaturation and precipitation kinetics. AAPS (San Antonio), 2013
  24. Edmund S. Kostewicz, Tamsin Albery, Britta Polentarutti, Lars Björklund and Bertil Abrahamson. Simulation of oral felodipine plasma concentrations in the Yucatan mini-pig. FIP Conference (Melbourne) 2014