Physiologically Based Pharmacokinetic Modeling to Assess Antiretroviral-BTK Inhibitor Interactions and Provide...

Objectives: The co-administration of Bruton's tyrosine kinase (BTK) inhibitors with antiretroviral drugs is challenging due to potential drug-drug interactions (DDIs). However, clinical trials specifically assessing such DDIs are lacking. We aimed to evaluate DDIs between the BTK inhibitors ibrutinib, zanubrutinib and acalabrutinib with representative antiretroviral drugs and to provide dose adjustment strategies using physiologically based pharmacokinetic (PBPK) models. Methods: PBPK models were developed in PK-Sim software. Model performance was verified by comparing simulated pharmacokinetic parameters and DDI magnitudes with probe drugs (midazolam or maraviroc) with reported clinical data. The validated models were subsequently applied to assess DDIs and explore dose adjustment strategies. Results: The developed PBPK model accurately describes the pharmacokinetics of each drug. Darunavir/ritonavir substantially increased the maximum plasma concentration (C_max) of ibrutinib, zanubrutinib, and acalabrutinib by 496%, 312%, and 160%, respectively. In contrast, efavirenz reduced C_max by 43%, 33%, and 37%, respectively, while etravirine caused smaller decreases of 5%, 0%, and 10%. Based on these predictions, recommended dose adjustment strategies include ibrutinib 105 mg once daily, zanubrutinib 40 mg twice daily, and acalabrutinib 50 mg twice daily when co-administered with darunavir/ritonavir or ibrutinib 980 mg once daily, zanubrutinib 240 mg twice daily, and acalabrutinib 150 mg twice daily when co-administered with efavirenz. No dose adjustment is required with etravirine. Conclusions: The PBPK models accurately predicted the in vivo pharmacokinetics of ibrutinib, zanubrutinib, acalabrutinib, and those of the antiretrovirals darunavir/ritonavir, efavirenz, and etravirine, and the DDIs between them. The dose adjustment strategies provided information valuable to the optimization of antineoplastic therapy in HIV-related lymphoma (HRL) patients.