Physiologically based pharmacokinetic modelling to inform lenacapavir dose regimen when co‐administered with rifamycins in participants with tuberculosis

9 Introduction: There is a global need to provide rifamycin-based tuberculosis treatments in people who may be receiving lenacapavir (LEN), a potent capsid inhibitor approved for the treatment of multidrug-resistant HIV-1 and with high efficacy as HIV-1 pre-exposure prophylaxis (PrEP). LEN is eliminated by CYP3A, UGT1A1 and P-glycoprotein (P-gp) efflux, which are induced by rifamycins. We developed a physiologically based pharmacokinetic (PBPK) model to propose dosing recommendations for LEN when rifampin (or strong CYP3A inducer) or rifabutin (or moderate CYP3A inducer) is co-administered with subcutaneous (SC) LEN. Methods: A full-body LEN PBPK model was developed in GastroPlus® (version 9.8.3). Systemic distribution was captured with a perfusion-limited model for all tissues. Pathways for LEN elimination include efflux via direct intestinal secretion and liver uptake leading to biliary secretion and potential recirculation via P-gp, in addition to hepatic and intestinal metabolism by CYP3A4, UGT1A1 and minor contribution from non-specific clearance in liver. Kinetic parameters for LEN interactions with enzymes and P-gp were fitted against in vivo human data. The contribution of different pathways to LEN elimination were validated by comparing simulations to observed data from Phase 1 study participants receiving oral LEN in combination with voriconazole (strong CYP3A inhibitor), cobicistat (strong CYP3A and P-gp inhibitor), efavirenz (moderate CYP3A and P-gp inducer) and rifampin (strong CYP3A4, UGT1A1 and P-gp inducer, and P-gp inhibitor). We simulated different scenarios of a LEN dosing regimen (oral LEN 600 mg on Days 1 and 2 plus SC LEN administered on Day 1 and every 6 months thereafter) that could maintain plasma concentrations above the inhibitory quotient-4 (fourfold greater than the in vitro protein-adjusted 95% effective concentrations derived from MT-4 cells; 15.5 ng/mL) throughout the every-six-months interval, regardless of when rifampin/rifabutin (moderate CYP3A/P-gp inducer) treatment was initiated. Conclusions: With supplemental dosage, LEN can be co-administered with strong or moderate CYP3A inducers including rifampin and rifabutin for tuberculosis treatment.