Abstract
Background: Food-induced changes in gastric emptying time, gastric pH and/or intestinal fluid composition may have an impact on the pharmacokinetics of drugs. The aim of this work was to use mathematical models describing physiology in fed and fasted states together with biorelevant solubility and degradation data to simulate food effects for six compounds from recent Roche projects.
Methods: The solubility of each compound was measured in different biorelevant media: simulated human gastric fluid for the fasted and fed state, simulated human intestinal fluid for the fasted, fed and high-fat state, and simulated human colonic fluid for the upper and the lower colon. A physiologically based absorption model was developed in GastroPlus™ for each compound using permeability, solubility, metabolism and distribution data. By incorporating the appropriate physiological parameters and solubility data into the model, the oral pharmacokinetics of each drug was simulated under fasted, fed and/or high-fat conditions. Predicted and observed plasma concentration-time profiles and food effects were compared for a range of doses to assess the accuracy of the simulations.
Results: The models were able to distinguish between minor and significant food effects. The simulation captured well the magnitude of the food effects and for the six compounds correctly predicted the observed plasma exposure in fasted, fed and high-fat conditions.
Conclusion: Biorelevant solubility tests can be used together with physiologically based absorption models to predict clinical food effects caused by solubility and/or dissolution rate limitations.
Similar content being viewed by others
Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
References
Welling PG. Effects of food on drag absorption. Annu Rev Nutr 1996; 16: 383–415
Singh BN. Effects of food on clinical pharmacokinetics. Clin Pharmacokinet 1999; 37: 213–55
Charman WN, Porter CJH, Mithani A, et al. Physicochemical and physiological mechanisms for the effects of food on drag absorption: the role of lipids and pH. J Pharm Sci 1997; 86(3): 269–82
Dressman JB, Amidon GL, Reppas C, et al. Dissolution testing as a prognostic tool for oral drag absorption: immediate release dosage forms. Pharm Res 1998; 15(1): 11–22
Pargal A, Kelkar MG, Nayak PJ. The effect of food on the bioavailability of ibuprofen and flurbiprofen from sustained release formulations. Biopharm Drag Dispos 1996; 17(6): 511–9
Fleisher D, Li C, Zhou Y, et al. Drug, meal and formulation interactions influencing drug absorption after oral administration, clinical implications. Clin Pharmacokinet 1999; 36(3): 233–54
Martinez MN, Amidon GL. A mechanistic approach to understanding the factors affecting drag absorption: a review of fundamentals. J Clin Pharmacol 2002; 42: 620–43
Carver PL, Fleisher D, Zhou SY, et al. Meal composition effects on the oral bioavailability of indinavir in HIV-infected patients. Pharm Res 1999; 16(5): 718–24
Fausa O. Duodenal bile acids after a test meal. Scand J Gastroenterol 1974; 9: 567–70
Tangerman A, van Schaik A, van der Hoek EW. Analysis of conjugated and unconjugated bile acids in serum and jejunal fluid of normal subjects. Clin Chim Acta 1986; 159: 123–32
MacKay J, Mackie AE, Palmer JL, et al. Investigation into the mechanism for the improved oral systemic bioavailability of cefuroxime from cefuroxime axetil when taken after food. Br J Clin Pharmacol 1992; 33: 326P–7P
Zimmermann T, Yeates RA, Laufen H, et al. Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole. Eur J Clin Pharmacol 1994; 46: 147–50
Barnwell SG, Laudanski T, Dwyer M, et al. Reduced bioavailability of atenolol in man: the role of bile acids. Int J Pharm 1993; 89: 245–50
Grosvenor MP, Lofroth JE. Interaction between bile salts and beta-adrenergic receptor antagonists. Pharm Res 1995; 12: 682–6
Welty DF, Siedlick PH, Posvar EL, et al. The temporal effect of food on tacrine bioavailability. J Clin Pharmacol 1994; 34: 985–8
McLean AJ, Isbister C, Bobik A, et al. Reduction of first-pass hepatic clearance of Propranolol by food. Clin Pharmacol Ther 1981; 30(1): 31–4
Dressman JB. Comparison of canine and human gastrointestinal physiology. Pharm Res 1986; 3(3): 123–31
Carlsson AS, Kostewicz ES, Hanisch G, et al. Is the dog a suitable model for bioavailability studies of poorly soluble drugs? [abstract] AAPS Pharm Sci 2002; 4(4): T2161
Humberstone AJ, Porter CJH, Charman WN. A physicochemical basis for the effect of food on the absolute bioavailability of halofantrine. J Pharm Sci 1996; 85(5): 525–9
Paulson SK, Vaughn MB, Jessen SM, et al. Pharmacokinetics of celecoxib after oral administration in dogs and humans: effect of food and site of absorption. J Pharmacol Exp Ther 2001; 297(2): 638–45
Wu Y, Loper A, Landis E, et al. The role of biopharmaceutics in the development of a clinical nanoparticle formulation of MK-0869: a beagle dog model predicts improved bioavailability and diminished food effect on absorption in human. Int J Pharm. 2004; 285: 135–46
Galia E, Nicolaides E, Horter D, et al. Evaluation of various dissolution media fro predicting in vivo performance of class I and II drags. Pharm Res 1998; 15(5): 698–705
Lomstein Perdersen B, Mullertz A, Brondsted H, et al. A comparison of the solubility of danazol in human and simulated gastrointestinal fluids. Pharm Res 2000; 17(7): 891–4
Vertzoni M, Dressmann J, Butler J, et al. Simulation of fasting gastric conditions and its importance for the in vivo dissolution of lipophilic compounds. Eur J Pharm Biopharm 2005; 60: 413–7
Nicolaides E, Galia E, Efthymiopoulos C, et al. Forecasting the in vivo performance of four low solubility drags from their in vitro dissolution data. Pharm Res 1999; 16(12): 1876–82
Kostewicz ES, Brauns U, Becker R, et al. Forecasting the oral absorption behaviour of poorly soluble weak bases using solubility and dissolution studies in biorelevant media. Pharm Res 2002; 19(3): 345–9
Dressman JB, Reppas C. In vitro-in vivo correlations for lipophillic, poorly water-soluble drugs. Eur J Pharm Sci 2000; 11 Suppl. 2: S73–80
Lobenberg R, Kramer J, Shah VP, et al. Dissolution testing as a prognostic tool for oral drug absorption dissolution behaviour of glibenclamide. Pharm Res 2000; 17(4): 439–44
Nicolaides E, Symillides M, Dressman JB, et al. Biorelevant dissolution testing to predict the plasma profile of lipophillic drugs after oral administration. Pharm Res 2001; 18(3): 380–8
Agoram B, Woltosz WS, Bolger MB. Predicting the impact of physiological and biochemical processes on oral drug bioavailability. Adv Drug Deliv Rev 2001; 50 Suppl. 1: S41–67
Grass GM, Sinko PJ. Physiologically-based pharmacokinetic simulation modelling. Adv Drug Deliv Rev 2002; 54(3): 433–51
Willmann S, Schmitt W, Keldenich J, et al. A physiological model for the estimation of the fraction dose absorbed in humans. J Med Chem 2004; 47(16): 4022–31
Yu LX, Amidon GL. A compartmental absorption and transit model for estimating oral drug absorption. Int J Pharm 1999; 186: 119–25
Hasselbalch KA. Die Berechnung der Wasserstoffzahl des Blutes aus der freien und gebunden Kohlensaure desselben, und die Sauerstoffbindung des Blutes als Funktion der Wassertoffzahl. Die Biochem 1916; 78: 112–934
Noyes AS, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc 1897; 19: 930–4
Parrott N, Lavé T. Prediction of intestinal absorption: comparative assessment of GASTROPLUS and IDEA. Eur J Pharm Sci 2002; 17(1–2): 51–61
Lindahl A, Ungell A-L, Knutson L, et al. Characterisation of fluids from the stomach and proximal jejunum in men and women. Pharm Res 1997; 14: 497–502
Hofmann A, Borgström B. The intraluminal phase of fat digestion in man: the lipid content of the micellar and oil phases of intestinal content obtained during fat digestion and absorption. J Clin Invest 1964; 43(2): 247–57
Armand M, Borel P, Pasquier B, et al. Physiological characteristics of emulsions during fat digestion in human stomach and duodenum. Am J Physiol Gastrointest Liver Physiol 1996; 271(34): G172–83
Sellin JH. SCFAs: the enigma of weak electrolyte transport in the colon. News Physiological Sciences 1999; 14: 58–64
Lewis SJ, Heaton KW. Increasing butyrate concentration in the distal colon by accelerating intestinal transit. Gut 1997; 41: 245–51
Jones HM, Parrott NJ, Jorga K, et al. A novel strategy for physiologically based predictions of human pharmacokinetics. Clin Pharmacokinet 2006; 45(5): 511–42
Akaike H. A new look at the statistical model identification. IEEE Transactions on Automatic Control 1974; 19: 716–23
Bates TR, Gibaldi M, Kanig JL. Rate of dissolution of griseofulvin and hexoestrol in bile salt solutions. Nature 1966; 210(43): 1331–3
Milton KA, Edwards G, Ward SA, et al. Pharmacokinetics of halofantrine in man: effects of food and dose size. Br J Clin Pharmacol 1989; 28: 71–7
Van der Meer JWM, Keuning JJ, Scheijgrond HW, et al. Influence of gastric acidity on the bioavailability of ketoconazole. J Antimicrob 1980; 6: 520–4
Daneshmend TK, Warnock DW, Ene MD, et al. Influence of food on the pharmacokinetics of ketoconazole. Antimicrob Agents Chemother 1984; 25: 1–3
Lindholm A, Henricsson S, Dahlqvist R. The effect of food and bile acid administration on the relative bioavailability of cyclosporin. Br J Clin Pharm 1990; 29: 541–8
Evans DF, Pye G, Bramley R, et al. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 1988; 29: 1035–41
Fiese EF, Steffen SH. Comparison of the acid stability of azithromycin and erythromycin A. J Antimicrob Chemother 1990; 25 Suppl. A: 39–47
Sommers DEK, Van Wyk M, Moncrieff J, et al. Influence of food and reduced gastric acidity on the bioavailability of bacampicillin and cefuroxime axetil. Br J Clin Pharmacol 1984; 18: 535–9
Meyer JH, Dressman J, Fink A, et al. Effect of size and density on canine gastric emptying of nondigestible solids. Gastroenterology 1985; 89: 805–13
Acknowledgements
Drs Parrott, Ohlenbusch and Lavé are employees of Hoffmann-La Roche Ltd. Dr Hannah Jones was an employee of Hoffmann-La Roche Ltd at the time the study was undertaken, and is now an employee of Pfizer Ltd. No funding was used to assist in the preparation of this study.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jones, H.M., Parrott, N., Ohlenbusch, G. et al. Predicting Pharmacokinetic Food Effects Using Biorelevant Solubility Media and Physiologically Based Modelling. Clin Pharmacokinet 45, 1213–1226 (2006). https://doi.org/10.2165/00003088-200645120-00006
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-200645120-00006