Pharmacokinetics, metabolism and excretion of radiolabeled fostemsavir administered with or without ritonavir in healthy male subjects

Abstract

1. The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR.

2. Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%–36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix.

3. Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%.

4. The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged.

5. CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV.

Keywords:

• Fostemsavir
• temsavir
• glycoprotein 120 (gp120) attachment inhibitor
• cytochrome P450
• hydrolysis
• absorption-distribution-metabolism-excretion (ADME)
• biotransformation
• enzyme phenotyping

Acknowledgements

We thank all study participants and their families. Bristol-Myers Squibb was the study sponsor and we thank all the scientists for their contributions. ViiV Healthcare acquired fostemsavir. We also thank Cyril Llamoso, MD for his contribution when employed at Bristol-Myers Squibb and ViiV Healthcare and the editorial assistance provided by Joshua Wooten and Dr. Brandon Burch of Nuventra, funded by ViiV Healthcare.

Disclosure statement

The authors report no conflict of interest beyond the following: PG, MM, and XM and employees of and own stock in GlaxoSmithKline, which owns a stake in ViiV Healthcare, the owner of the asset of interest in this article. KM and PA are former employees of ViiV Healthcare and owners of GSK stock.

Additional information

Funding

This work was funded by Bristol-Myers Squibb.