The effect of P-glycoprotein, breast cancer resistance protein and CYP3A4 modulators on the pharmacokinetics of the TLR-7 agonist vesatolimod in people living with HIV

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The effect of P-glycoprotein, breast cancer resistance protein and CYP3A4 modulators on the pharmacokinetics of the TLR-7 agonist vesatolimod in people living with HIV

Yanan Zheng¹, Mary Wire¹, Buyun Chen¹, Christiaan de Vries¹, Olayemi Oisyemi², Kimberly Cruz³, Howard Hassman⁴, Juan Rondon⁵, Daina Lim¹, Steve West¹, Jia Hao¹, Yiding Hu¹, Yurong Lai¹ and Ramesh Palaparthy¹

¹Gilead Sciences, Inc.; ²Triple Research Institute; ³Advanced Pharma CR, LLC; ⁴CenExel HRI; ⁵Clinical Pharmacology of Miami, LLC

Background: Vesatolimod (VES) is a Toll-like receptor 7 (TLR-7) agonist being evaluated as an immunomodulator to enhance antiviral responses in the clear-and-control HIV cure strategy. Per nonclinical data, VES is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and CYP3A. Cobicistat (COBI; a P-gp, BCRP, and strong CYP3A inhibitor), voriconazole (VOR; a strong CYP3A inhibitor) and rifabutin (RFB; a moderate CYP3A inducer) have the potential to alter VES plasma concentrations, and these medications may be administered to people living with HIV (PLWH) as part of antiretroviral therapy (ART) or to treat fungal or bacterial infections.

Materials and methods: NCT05458102 was an open-label study to evaluate the effect of P-gp/BCRP/CYP3A4 modulators on VES pharmacokinetics (PK) in virologically suppressed PLWH on stable ART. In cohort 1, the following study drugs were administered orally in three periods sequentially: period 1, VES 2 mg; period 2, COBI 150 mg once daily for 5 days with VES 2 mg co-administered on day 2; period 3, VOR 400 mg twice daily on day 1 and 200 mg twice daily on days 2–6 with VES 2 mg co-administered on day 3. In cohort 2, the following study drugs were administered orally in two periods sequentially: period 1, VES 6 mg; period 2, RFB 300 mg once daily for 9 days with VES 2 mg co-administered on day 6. VES PK samples were collected over 96 h after each dose of VES. VES PK parameters were estimated using noncompartmental analysis and compared between treatments using an analysis of variance.

Results: In cohort 1 (N = 15), when VES was co-administered with COBI, median T_max occurred 1.5 h earlier and the geometric least squares mean (GLSM) VES AUC, C_max, and t1/2 increased 4.3-, 7.5- and 1.2-fold, respectively. When VES was co-administered with VOR, there was no change in median Tmax or in GLSM VES AUC_inf, C_max, and t1/2.

In cohort 2 (N = 2), when VES was co-administered with RFB, median VES T_max occurred 3.85 h earlier and individual increases in VES AUC and C_max were 26- and 98-fold and 2.6- and 10-fold, respectively. In one participant with evaluable VES t1/2 for both periods, t1/2 decreased from 23.9 h for VES alone to 14.3 h when VES was co-administered with RFB. Non-clinical investigations identified RFB as a P-gp and BCRP inhibitor and as a potent inhibitor of VES efflux in Caco-2 cells.

Eight participants (47.1%) experienced drug-related treatment-emergent adverse events (TEAEs), which were mainly grade 1. One participant (5.9%) experienced TEAEs greater than grade 1 which were considered related to VES + RFB. There were no serious TEAEs or deaths.

Conclusions: The larger magnitude of PK interaction between VES and COBI compared with VES and VOR suggests that transporters (P-gp and/or BCRP) play a greater role than drug-metabolizing enzymes (CYP3A) and that the interaction is predominantly pre-systemic. The increase in VES PK exposure when co-administered with RFB and the subsequent nonclinical results that identified RFB as a P-gp and BCRP inhibitor suggest that RFB inhibits these efflux transporters involved in VES absorption.