(T1430-05-27) Physiologically Based Pharmacokinetic Modeling to Inform Lenacapavir Dose Regimen when Co-Administered with Rifamycins in Participants with Tuberculosis

Purpose: 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 are 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 six months thereafter) that could maintain plasma concentrations above the inhibitory quotient-4 (4-fold 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.

Results: With the LEN PBPK model, the simulated maximum concentration (C_max) and area under the plasma concentration versus time curve extrapolated to infinity (AUC_0-inf) values for LEN alone administered SC and orally were within 1.5-fold of the observed data. The prediction errors on C_max and AUC_inf for oral LEN with perpetrators were mostly within the Guest criteria framework proposed for evaluation of quality of drug-drug interaction predictions. Based on model simulations of LEN co-administered with rifampin (or strong CYP3A inducer) or rifabutin (or moderate CYP3A inducer), the following dose adjustments of LEN are recommended to maintain adequate LEN concentrations throughout the duration of treatment: A) on day of initiation of a strong CYP3A inducer ( >2 days after LEN is first initiated), administer supplemental dosage of 927 mg LEN SC (2 x 1.5 mL injections) and 600 mg of LEN orally (2 x 300 mg tablets), and on day following initiation, administer 600 mg of LEN orally (2 x 300 mg tablets); B) on day of initiation of a moderate CYP3A inducer, administer supplemental dosage of 463.5 mg LEN SC (1 x 1.5 mL injection).

Conclusion: With supplemental dosage, LEN can be co-administered with strong or moderate CYP3A inducers including rifampin and rifabutin for tuberculosis treatment.

Acknowledgements: Viera Lukacova: employee and shareholder of Simulations Plus, Inc; Simulations Plus, Inc, received funding from Gilead Sciences, Inc., for these analyses. Ana Ruiz, Ramesh Palaparthy, Renu Singh and Sara Salerno: all employees and shareholders of Gilead Sciences, Inc. This research was funded by Gilead Sciences, Inc., Foster City, California, US. Editorial support was provided by Ashfield Medcomms (Macclesfield, UK), an Inizio company, and funded by Gilead Sciences, Inc.