538. Clinical Evaluation of Drug-drug Interactions with Remdesivir
Authors: Peng Chi-Chi , Shelton Mark , Raut Anuja , Kwan Anna , Chhabra Kanika , Shen Gong , Xiao Deqing , Kim Aryun , Madera Sharline , Hyland Robert H , Winter Helen , Humeniuk Rita 
Published: November 2023

Abstract

Background
Remdesivir (RDV), a nucleotide prodrug approved for COVID-19, is a substrate and inhibitor of organic anion-transporter polyprotein (OATP) transporters and cytochrome P450 3A4 (CYP3A4) metabolizing enzyme based on in vitro data. Here, clinical studies of potential drug-drug interactions (DDIs) assessed RDV as a victim of OATP1B1/B3 inhibition and CYP3A induction and RDV as a perpetrator on OATP and CYP3A4.

Methods
Two Phase 1 open-label, fixed sequence studies were conducted in healthy participants (Table 1). Study 1 (n = 9) tested the effect of OATP1B1/1B3 inhibition (cyclosporin A, CsA) and CYP3A4 induction (carbamazepine, CBZ) on the pharmacokinetics (PK) of RDV. Study 2 (n = 19-22) tested the effect of RDV on the PK of substrates of OATP transporters (pitavastatin, PIT) and CYP3A4 (midazolam, MDZ). Plasma concentrations of RDV, its metabolites GS-704277 and GS-441524 (Study 1), and probe substrates (Study 2) were measured by validated mass spectrometry methods. PK parameters (AUCinf and Cmax) were estimated by noncompartmental analysis (Phoenix WinNonlin™). Treatments were compared with a parametric mixed-effects model with point estimates for geometric least-squares mean (GLSM) and 90% CI with pre-specified no-effect bounds. Safety was monitored throughout.

Results
In Study 1, coadministration of RDV with CsA resulted in 89%, 197%, and 3% increases in AUCinf for RDV, GS-704277, and GS-441524, respectively, whereas coadministration with CBZ did not impact AUCinf or Cmax for RDV or its metabolites. In Study 2, RDV did not impact AUCinf of PIT or MDZ, although mild increases in Cmax were observed for MDZ and 1’-OH-MDZ (29% and 25-39%, respectively). No deaths, serious adverse events (AEs), Grade 4 AEs, or AEs leading to discontinuation were reported. Most AEs were Grade 1 or 2 and consistent with known safety profiles.Table 1.Clinical RDV DDI Study Design CharacteristicsRDV, remdesivir; DDI, drug-drug interaction; CYP3A4, cytochrome P450 3A4; CBZ, carbamazepine; OATP, organic anion-transporter polyprotein; CsA, cyclosporin A; PIT, pitavastatin; MDZ, midazolam.

Conclusion
OATP 1B1/1B3 inhibition increased plasma PK exposures to RDV and GS-704277, but these increases remained within the range of exposures shown to be safe in Phase 3 studies and were not considered clinically relevant. CYP3A induction did not impact plasma PK exposures to RDV or metabolites. Low potential for RDV as a perpetrator of DDIs with CYP3A and OATP1B1/1B3 substrates was confirmed. For these DDIs, dose adjustments are not necessary with RDV.

Disclosures
Chi-Chi Peng, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Mark Shelton, PharmD, Certara, Inc.: Employee|Gilead Sciences, Inc.: Former Employee Anuja Raut, MS, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Anna Kwan, BS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Kanika Chhabra, MS, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Gong Shen, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Deqing Xiao, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Aryun Kim, PharmD, Gilead Sciences, Inc: Company employee|Gilead Sciences, Inc: Stocks/Bonds Sharline Madera, MD, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Robert H. Hyland, DPhil, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Helen Winter, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds Rita Humeniuk, PhD, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds