Feiyan Liu1, Xuexin Ye1, Zeneng Cheng1, Feifan Xie1
1Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University
Objectives: Highly active antiretroviral therapy (ART) has significantly reduced HIV-related mortality and morbidity. However, tuberculosis (TB) remains a leading cause of death among HIV-infected individuals, particularly in resource-limited settings. Concomitant ART and antitubercular agents improve survival in HIV-TB co-infected patients, while managing drug-drug interactions (DDIs) remains challenging. Nevirapine, a first-line ART metabolized primarily by CYP2B6 and CYP3A4, exhibits enzyme auto-induction and significant ethnic variability in its pharmacokinetics (PK). These factors complicate its dosing in HIV-TB co-infected patients receiving rifampicin/isoniazid-based anti-tuberculosis therapies, as rifampicin (a strong CYP3A4 inducer and moderate CYP2B6 inducer) and isoniazid (a moderate CYP3A4 inhibitor) create intricate DDIs with nevirapine. Given that Physiologically-based pharmacokinetic (PBPK) modeling is a powerful tool for predicting DDIs and guiding clinical dosing, this study employed a PBPK modeling approach to investigate ethnic differences in nevirapine clearance and the combined effects of rifampicin and isoniazid on nevirapine PK, aiming to establish optimal nevirapine dosing regimens for HIV and HIV-TB co-infected patients across Caucasian, African and Asian populations. Methods: A nevirapine PBPK model incorporating CYP2B6 and CYP3A4 auto-induction was developed and verified in healthy and HIV-infected individuals across diverse ethnic populations. To ensure the accurate parameterization of CYP2B6 and CYP3A4 induction by nevirapine, the model was further verified by evaluating its ability to predict altered PK profiles of dolutegravir (a substrate of CYP3A4) and methadone (a substrate of both CYP3A4 and CYP2B6) when co-administered with nevirapine as the perpetrator. Upon successful verification, the model was expanded to evaluate DDIs with rifampicin and isoniazid, assessing their impact on nevirapine PK under clinical relevant conditions. The verified PBPK-DDI model was then applied to optimize nevirapine dosing regimens, with and without concomitant rifampicin-based antitubercular therapy, across different ethnic populations. Model development and simulations were performed using Simcyp Simulator (version V22, Certara, Sheffield, UK). Results: The nevirapine PBPK model, comprising first-order absorption, full PBPK distribution, and enzyme kinetics elimination, successfully captured the time-dependent PK of nevirapine across Caucasian, African, and Asian populations, with and without rifampicin/isoniazid co-administration. The model demonstrated robust prediction performance, with most observed concentration data fell within the 90% confidence interval of the simulated concentration-time profiles, and key PK parameters (AUC0-12h and Cmax) consistently within 0.5 to 2-fold of the published values. Simulations indicated that the standard nevirapine dose regimen could be sufficient for HIV patients across ethnic populations, while a lower dose (lead-in: 150 mg QD, maintenance: 150 mg BID) may be preferable for the Asian population due to the potential toxicity risks. For HIV-TB co-infected patients receiving rifampicin/isoniazid-based treatments, nevirapine co-administration may not be recommended for the Caucasian population regarding the insufficient exposure. In contrast, a similar reduced nevirapine dose may be appropriate for Asian patients, whereas African patients may require a higher dose (lead-in: 200 mg QD, maintenance: 300 mg BID), with careful consideration of toxicity risks. Conclusions: Our PBPK model effectively predicts the PK and DDIs of nevirapine in concomitant with rifampicin and isoniazid across diverse populations. The model simulations highlight the need for population-specific nevirapine dosing strategies, with distinct recommendations for patients receiving concomitant therapy. These findings underscore the importance of personalized medicine in the treatment of HIV and HIV-TB co-infection, and advocate for further clinical validation of the proposed dosing strategies to optimize therapeutic outcomes.
Reference: PAGE 33 (2025) Abstr 11546 [www.page-meeting.org/?abstract=11546]
Poster: Drug/Disease Modelling - Absorption & PBPK