PBPK Absorption Modeling of Food Effect and Bioequivalence in Fed State for Two Formulations with Crystalline and Amorphous Forms of BCS 2 Class Drug in Generic Drug Development
- 149 Downloads
Prediction of the effect of food on drug’s pharmacokinetics using modeling and simulation could cause difficulties due to complex in vivo processes. A generic formulation with amorphous form of BCS 2 class drug substance was developed and compared in vitro and in vivo to the reference drug product with drug substance in crystalline form. In order to approve generic formulation, some regulatory agencies are requesting to perform bioequivalence (BE) studies also in fed state. Food can have various effects on drug dissolution and absorption, depending also on drug’s properties. A physiologically based pharmacokinetic (PBPK) absorption model was built in GastroPlus™ to predict the food effect on generic and reference formulation and to predict the fed BE study outcome. During model development, we were searching for model inputs that impact and describe in vivo behavior of amorphous and crystalline forms of active pharmaceutical ingredient (API) in fast and fed conditions. The developed model was able to predict the food effect with up to 10% prediction error (PE). Performed virtual BE trials confirmed the BE of drug products in fed state. Our model was able to capture the difference between the two drug products containing different forms of API (amorphous and crystalline) and predict the food effect on both formulations.
Keywordsphysiologically based pharmacokinetic (PBPK) modeling food effect BCS bioequivalence amorphous formulation
The authors would like to acknowledge coworkers in Sandoz for conducting experiments, sharing data, and valuable consultations regarding modeling.
Compliance with Ethical Standards
BE studies were performed for regulatory submission and were conducted in full accordance with the principles stated in the International Conference on Harmonization, Good Clinical Practice guidelines, and the Declaration of Helsinki.
Conflict of Interest
The authors declare that they have no conflicts of interest.
- 7.Food and Drug Administration. Guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a Biopharmaceutics Classification System [Internet]. 2017. Available from: http://www.fda.gov/downloads/Drugs/Guidances/ucm070246.pdf. Accessed 27 June 2018.
- 8.Xia B, Heimbach T, Lin T, Li S, Zhang H, Sheng J, et al. Utility of physiologically based modeling and preclinical in vitro/in vivo data to mitigate positive food effect in a BCS class 2 compound. AAPS PharmSciTech. 2013;14(3):1255–66. https://doi.org/10.1208/s12249-013-0018-2.CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Food and Drug Administration. Guidance for industry: bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA [Internet]. 2013. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM377465.pdf. Accessed 27 June 2018.
- 11.Simulations Plus. Manual GastroPlus™. California: EUA; 2010.Google Scholar
- 12.Takano R, Sugano K, Higashida A, Hayashi Y, Machida M, Aso Y, et al. Oral absorption of poorly water-soluble drugs: computer simulation of fraction absorbed in humans from a miniscale dissolution test. Pharm Res. 2006;23(6):1144–56. https://doi.org/10.1007/s11095-006-0162-4.CrossRefPubMedGoogle Scholar
- 13.Pepin XJ, Flanagan TR, Holt DJ, Eidelman A, Treacy D, Rowlingy CE. Justification of drug product dissolution rate and drug substance particle size specifications based on absorption PBPK modeling for Lesinurad immediate release tablets. Mol Pharm. 2016;13(9):3256–56. https://doi.org/10.1021/acs.molpharmaceut.6b00497.CrossRefGoogle Scholar
- 15.Food and Drug Administration. Guidance for industry: extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations [Internet]. 1997. Available from: https://www.fda.gov/downloads/drugs/guidances/ucm070239.pdf. Accessed 27 June 2018.Google Scholar
- 16.Food and Drug Administration. Guidance for industry: food-effect bioavailability and fed bioequivalence studies [Internet]. 2002. Available from: https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070241.pdf. Accessed 27 June 2018.
- 22.Purohit SH, Trasi NS, Sun DD, Chow ECY, Wen H, Zhang X, et al. Investigating the impact of drug crystallinity in amorphous tacrolimus capsules on pharmacokinetics and bioequivalence using discriminatory in vitro dissolution testing and physiologically based pharmacokinetic modeling and simulation. J Pharm Sci. 2018;107(5):1330–41. https://doi.org/10.1016/j.xphs.2017.12.024.CrossRefPubMedGoogle Scholar
- 25.Food and Drug Administration. Guidance for industry: physiologically based pharmacokinetic analyses – format and content [Internet]. 2016. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM531207.pdf. Accessed 27 June 2018.
- 26.European Medicines Agency. Guideline on the qualification and reporting of physiologically based pharmacokinetic (PBPK) modelling and simulation [Internet]. 2016. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500211315.pdf. Accessed 27 June 2018.