Predicting drug–drug interactions between ainuovirine and rifampicin plus isoniazid using PBPK modelling

Abstract

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Predicting drug–drug interactions between ainuovirine and rifampicin plus isoniazid using PBPK modelling

Lu Hongzhou¹, Meng Xianmin¹ and Qin Hong²

¹The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology; ²Jiangsu Aidea Pharmaceutical Co., Ltd

Objectives: Ainuovirine (ANV) is a newly developed next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) metabolized by CYP2C19. The primary objective of this study was to simulate and predict drug–drug interaction (DDI) between ainuovirine and rifampicin (RIF) combined with isoniazid (INH) using physiologically based pharmacokinetic (PBPK) modelling. Additionally, we aimed to recommend suitable dose adjustments for ANV for the treatment of people living with HIV (PLWH) coinfected with tuberculosis.

Methods: A comprehensive whole-body PBPK model for DDI was developed using PK-SIM® (version 11.2, Open Systems Pharmacology, USA). This model was validated against phase 1 DDI study of ANV with RIF and reported clinical data for all drugs administered alone and ANV-RIF/ANV-INH dual- and triple-drug concomitantly. The model contained the potent induction and concentration-dependent inhibition mechanisms of RIF and INH on CYP2C19. The model was considered verified if the predicted pharmacokinetic values vs. observed were within 0.5–2-fold. Alternative dosing regimens for ANV were simulated to ensure that the C_trough exceeded the clinical reference interval's lower limit of 153.04 ± 59.22 ng/mL, while the C_max remained below the upper limit of 526.45 ± 143.52 ng/mL.

Results: The PBPK model was successfully verified according to the criteria. Simulation of different dose adjustments predicted that a change in regimen to 225 mg ANV (75 + 150 mg, while 75 mg co-administered with RIF plus INH, 150 mg after 12 h) may alleviate the inhibition effect of INH on ANV C_max and induction effect of RIF on ANV C_trough at steady state, which were within the clinical reference intervals.

Conclusions: The developed PBPK model characterized the opposite effect-mediated DDI between RIF and INH on ANV, accurately predicting a narrowed therapeutic window when 150 mg daily of ANV co-administered with RIF plus INH. A change in the ANV dosing regimen from 150 to 225 mg was predicted to mitigate the effect of the DDI on the C_max and C_trough of ANV, maintaining plasma concentration levels above the therapeutic threshold while not too high.

Keywords: ainuovirine, drug–drug interactions, isoniazid, pharmacokinetics, rifampicin