Intestinal Excretion is a Major Disposition Pathway of Lenacapavir in Rat and Dog

Abstract

Lenacapavir (LEN), previously known as GS-6207 or GS-CA2, is a first-in-class HIV capsid inhibitor in clinical development as a long-acting agent. LEN displays three characteristics of an ideal long-acting agent: picomolar potency, low systemic clearance and a slow subcutaneous (SC) release. In Phase 1 clinical studies, a single SC administration of LEN was safe and well tolerated, showed sustained pharmacologically active plasma concentrations for > 6 months, and led to mean maximum reductions in HIV-1 RNA of 1.4-2.3 log10 over 9 days. Herein, we present the pharmacokinetics (PK) and mechanistic understanding of LEN disposition in rat and dog. PK was determined following intravenous (IV) administration of LEN alone or coadministration with either activated charcoal (AC) or elacridar, a Pgp inhibitor, in intact and bile-duct cannulated (BDC) rats or dogs. The disposition was assessed following a single IV administration of [14C]LEN to intact and BDC rats and dogs. LEN and [14C] concentrations were determined by LC-MS/MS and liquid scintillation counting, respectively. In vitro metabolic stability and metabolic profiles were assessed in hepatocytes using [3H]LEN and in Hµrel® hepatic co‑cultures using [14C]LEN. In intact rats, 94% of dose, including 64% unchanged LEN, was excreted in feces. In BDC rats, 42% and 35% of dose was excreted in bile and feces, respectively, with unchanged LEN accounting for 31% of dose in feces. In intact dogs, 86% of dose, including 65% unchanged LEN, was excreted in feces. In BDC dog, 32% and 63% of dose was excreted in bile and feces, respectively, with unchanged LEN accounting for 60% of dose in feces. Renal excretion was low (< 1% of dose) in both species. Almost all radioactivity was unchanged LEN in plasma. Metabolites were observed in excreta; these included conjugates formed with glutathione, pentose and glucuronic acid. LEN was stable in vitro; minor turnover was observed in Hµrel® hepatic co‑cultures, and the observed metabolites were consistent with those formed in vivo. Excretion of radioactivity in feces after IV administration in BDC rats and dogs confirmed significant intestinal excretion (IE) of parent LEN. Oral coadministration of AC had minimum effect on LEN systemic exposure and the amount excreted in feces following LEN IV administration in intact and BDC dogs. Oral coadministration of elacridar increased LEN systemic exposure, half-life and decreased LEN amount in feces following IV dosing in intact and BDC rats, but changes in clearance were less than 2-fold. IE was a major (>25% of dose and > 25% of LEN) disposition pathway for LEN in rat and dog in addition to biliary excretion. The lack of impact with AC coadministration was attributed to the lack of binding interactions and/or the poor permeability which limited charcoal's ability to “pull” intact LEN out of systemic circulation. Coadministration of a Pgp inhibitor resulted in a modest decrease in LEN clearance. Overall, LEN is mainly cleared intact via biliary and IE pathways; metabolic clearance played a lesser role. Few drugs have described clearance by IE and our studies highlight the importance of IE for highly metabolically stable compounds with slow elimination.