The Drug-Drug Interaction Profile of Presatovir
Yan Xin1, Winnie Weng1, Bernard P Murray1
1Gilead Sciences, Inc., Foster City, CA, USA.
Insights
Presatovir, an oral RSV fusion inhibitor, can be safely co-administered with certain drug interaction inhibitors, but not with strong CYP3A4 inducers. This finding is crucial for managing respiratory syncytial virus (RSV) infections in children.
Area of Science:
- Pharmacology and Drug Metabolism
- Virology and Infectious Diseases
Background:
- Respiratory syncytial virus (RSV) is a significant pathogen causing severe lower respiratory tract infections in young children.
- Presatovir (GS-5806) is an investigational oral fusion inhibitor demonstrating antiviral activity against RSV.
- Understanding presatovir's drug-drug interaction potential is critical for its clinical application.
Purpose of the Study:
- To evaluate the pharmacokinetic impact of co-administering presatovir with various drug interaction modulators.
- To assess presatovir's sensitivity to transporter proteins (P-gp, BCRP, OATP1B1/1B3) and metabolic enzymes (CYP3A4/5).
Main Methods:
- A clinical study involving 64 healthy subjects.
- Subjects received presatovir with cyclosporine (inhibitor of P-gp, BCRP, OATP1B1/1B3), rifampin (CYP3A4/P-gp inducer), efavirenz (CYP3A4 inducer), or cobicistat (CYP3A inhibitor).
- Presatovir plasma concentrations (Cmax, AUCinf) were measured to determine pharmacokinetic changes.
Main Results:
- Coadministration with cyclosporine did not affect presatovir exposure, indicating it's not a sensitive substrate for P-gp, BCRP, or OATP1B1/1B3.
- Presatovir exposure increased with cobicistat (potent CYP3A inhibitor) and decreased with rifampin and efavirenz (CYP3A4 inducers).
- Presatovir was generally well-tolerated; dizziness and somnolence were the most common adverse events during efavirenz treatment.
Conclusions:
- Presatovir can be co-administered with inhibitors of P-gp, BCRP, OATP1B1/1B3, and CYP3A.
- Coadministration with moderate or strong CYP3A4 inducers should be avoided due to significant alterations in presatovir pharmacokinetics.
- These findings support the potential clinical use of presatovir in combination therapies, with careful consideration of concomitant medications.
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 [Cmax ] and area under the plasma concentration-time curve from time 0 extrapolated to infinity [AUCinf ]) 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 AUCinf ), and decreased by rifampin (40.3% in Cmax and 82.5% in AUCinf ) and efavirenz (55.7% in AUCinf ). 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.
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