Tiered approach to evaluate the CYP3A victim and perpetrator drug–drug interaction potential for vonoprazan using PBPK modeling and clinical data to inform labeling

Abstract

Vonoprazan is metabolized extensively through CYP3A and is an in vitro timedependent inhibitor of CYP3A. A tiered approach was applied to understand the CYP3A victim and perpetrator drug-drug interaction (DDI) potential for vonoprazan. Mechanistic static modeling suggested vonoprazan is a potential clinically relevant CYP3A inhibitor. Thus, a clinical study was conducted to evaluate the impact of vonoprazan on the exposure of oral midazolam, an index substrate for CYP3A. A physiologically-based pharmacokinetic (PBPK) model for vonoprazan was also developed using in vitro data, drug-and system-specific parameters, and clinical data and observations from a [ 14 C] human absorption, distribution, metabolism, and excretion study. The PBPK model was refined and verified using data from a clinical DDI study with the strong CYP3A inhibitor, clarithromycin, to confirm the fraction metabolized by CYP3A, and the oral midazolam clinical DDI data assessing vonoprazan as a time-dependent inhibitor of CYP3A. The verified PBPK model was applied to simulate the anticipated changes in vonoprazan exposure due to moderate and strong CYP3A inducers (efavirenz and rifampin, respectively). The clinical midazolam DDI study indicated weak inhibition of CYP3A, with a less than twofold increase in midazolam exposure. PBPK simulations projected a 50% to 80% reduction in vonoprazan exposure when administered concomitantly with moderate or strong CYP3A inducers. Based on these results, the vonoprazan label was revised and states that lower doses of sensitive CYP3A substrates with a narrow therapeutic index should be used when administered concomitantly with vonoprazan, and co-administration with moderate and strong CYP3A inducers should be avoided.How to cite this article: Mulford DJ, Ramsden D, Zhang L, et al. Tiered approach to evaluate the CYP3A victim and perpetrator drug-drug interaction potential for vonoprazan using PBPK modeling and clinical data to inform labeling. CPT

Utility of PBPK Modeling in Predicting and Characterizing Clinical Drug Interactions

“…For example, a full PBPK model adequately predicted changes in half-life, C max , AUC and Cl tot /F for common CYP3A substrates such as midazolam, triazolam, alprazolam and simvastatin when co-dosed with common CYP3A inhibitors such as itraconazole, saquinavir or grapefruit juice (Fenneteau et al, 2010). In the case of vonoprazan, a CYP3A substrate and time-dependent inhibitor, PBPK modeling was used as part of the strategy to inform labeling requirements around potential dose reductions for concomitantly administered oral CYP3A sensitive substrates as well as avoiding co-administration of moderate and strong CYP3A inducers with vonoprazan (Mulford et al, 2023). Interestingly, a recent study comparing the effects of pharmacogenetics and concomitantly administered CYP3A or OATP1B1 inhibitors on oral simvastatin and simvastatin lactone pharmacokinetics, suggested that while model structure and inputs may significantly differ, the ultimate output of the PBPK models with regard to DDI predictions were similar (Prieto Garcia et al, 2022).…”

Clinical Study on the Eradication of Helicobacter pylori by Vonoprazan Combined with Amoxicillin for 10‐Day Dual Therapy

“…16 When co-administered with vonoprazan, lower doses of sensitive CYP3A substrates are advised and coadministrated with strong CYP3A inducers should be avoided. 17 There are no reports of neuroendocrine tumors or severe liver toxicity associated with vonoprazan treatment. 18 Potassium-competitive acid blockers such as vonoprazan hold promise in enhancing the management of acid peptic disorders.…”

“…TAK‐438, vonoprazan fumarate, showcases multiple metabolic pathways, reducing the impact of co‐administrated CYP inducers or inhibitors on TAK‐438 pharmacokinetics 16 . When co‐administered with vonoprazan, lower doses of sensitive CYP3A substrates are advised and co‐administrated with strong CYP3A inducers should be avoided 17 . There are no reports of neuroendocrine tumors or severe liver toxicity associated with vonoprazan treatment 18 .…”