The Drug–Drug Interaction Profile of Presatovir

Abstract

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5. This study enrolled 64 healthy subjects to evaluate the effect of cyclosporine, a P-gp, BCRP, and OATP1B1/1B3 inhibitor; rifampin, a strong CYP3A4 and P-gp inducer; efavirenz, a moderate CYP3A4 inducer; and cobicistat, a potent CYP3A inhibitor, on presatovir pharmacokinetics. Presatovir plasma exposures (maximum observed plasma concentration [C ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUC ]) were not affected by coadministration of cyclosporine, suggesting presatovir is not a sensitive substrate of P-gp, BCRP, or OATP1B1/1B3. As expected, based on the role of CYP3A in presatovir metabolism, presatovir exposure was increased by cobicistat (122% in AUC ), and decreased by rifampin (40.3% in C and 82.5% in AUC ) and efavirenz (55.7% in AUC ). These data support coadministration of presatovir with inhibitors of P-gp, BCRP, OATP1B1/1B3, or CYP3A, but not with moderate or strong CYP3A4 inducers. Presatovir was well-tolerated with the most common drug-related adverse events of dizziness (n = 12) and somnolence (n = 4) reported during efavirenz treatment.

Small molecule inhibits respiratory syncytial virus entry and infection by blocking the interaction of the viral fusion protein with the cell membrane

“…GS-5806 is the only RSV fusion inhibitor that has reached the late phase of clinical trials. It was efficacious in the treatment of healthy adults who were challenged with RSV (22,38,39). In vitro, GS-5806 exhibited a potent antiviral activity against RSV infection (EC 50 = 0.35 nM) and showed various levels of cytotoxicity in different cell lines (40).…”

Assessment of Drug Resistance during Phase 2b Clinical Trials of Presatovir in Adults Naturally Infected with Respiratory Syncytial Virus

“…Presatovir, an orally bioavailable RSV fusion inhibitor, has a favorable safety profile and significantly reduced viral load and symptoms relative to placebo in healthy adults experimentally challenged with RSV (10)(11)(12). In a phase 2a challenge study, the rate of treatment-emergent substitutions associated with presatovir resistance ranged from 7.7% to 35.3%, depending on the dosing regimen (13).…”

A Phase 2b, Randomized, Double-blind, Placebo-Controlled Multicenter Study Evaluating Antiviral Effects, Pharmacokinetics, Safety, and Tolerability of Presatovir in Hematopoietic Cell Transplant Recipients with Respiratory Syncytial Virus Infection of the Lower Respiratory Tract

“…Presatovir is a novel, orally available RSV fusion inhibitor under investigation for treatment of RSV [15]. Presatovir has a favorable safety profile in adult volunteers, and presatovir treatment reduced viral load and respiratory symptoms in healthy adults challenged with RSV [16][17][18]. Here the safety, tolerability, and efficacy of presatovir in naturally infected HCT recipients with RSV LRTI were evaluated.…”