In Vitro Lipolysis Model to Predict Food Effect of Poorly Water-Soluble Drugs Itraconazole, Rivaroxaban, and Ritonavir

Roshni P Patel; Rodrigo Cristofoletti; Fang Wu; Abdullah Al Shoyaib; James E Polli

doi:10.1016/j.xphs.2024.04.007

In Vitro Lipolysis Model to Predict Food Effect of Poorly Water-Soluble Drugs Itraconazole, Rivaroxaban, and Ritonavir

J Pharm Sci. 2024 Apr 16:S0022-3549(24)00132-1. doi: 10.1016/j.xphs.2024.04.007. Online ahead of print.

Authors

Roshni P Patel¹, Rodrigo Cristofoletti², Fang Wu³, Abdullah Al Shoyaib³, James E Polli⁴

Affiliations

¹ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.
² Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
³ Office of Generic Drugs, Food and Drug Administration, White Oak, MD, USA.
⁴ Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA. Electronic address: jpolli@rx.umaryland.edu.

PMID: 38614321
DOI: 10.1016/j.xphs.2024.04.007

Abstract

It is desirable to predict positive food effect of oral formulations due to food mediated dissolution enhancement of lipophilic drugs. The objective was to assess the ability of in vitro lipolysis to anticipate a positive food effect. Tested formulations included rivaroxaban and itraconazole, where some formulations, but not all, exhibit a positive food effect in vivo in humans. Amorphous solid dispersion formulations of ritonavir, which exhibit a negative food effect in vivo in humans, were also studied. Fe-lipolysis and Fa-lipolysis media representing fed and fasted intestinal conditions were used. Results show frequent agreement between in vitro lipolysis predictions and in vivo human outcomes. For rivaroxaban, food effect of unformulated active pharmaceutical ingredient (API) and products were correctly predicted where 2.5 mg and 10 mg strengths did not show any food effect; however, 20 mg did show a positive food effect. For itraconazole, all four products were correctly predicted, with Sporanox, Sempera, and generic capsules having a food effect, but Tolsura not having a positive food effect. For ritonavir, lipolysis predicted a positive food effect for API and Norvir tablet and powder, but Norvir products have negative food effect in vivo in humans. Overall, the lipolysis model showed favorable predictability and merits additional evaluation.

Keywords: Bioequivalence; Dissolution; Dose dependent; Fa-lipolysis; Fe-lipolysis; Formulation dependent; Free fatty acid; Lipolysis; Poorly soluble drugs; Positive food effect.