Lenacapavir Exhibits Atropisomerism—Mechanistic Pharmacokinetics and Disposition Studies of Lenacapavir Reveal Intestinal Excretion as a Major Clearance Pathway

作者：Jim Zheng, Bing Lu, Gavin Carr, Judy Mwangi, Kelly Wang, Jia Hao, Kelly McLennan Staiger, Nathan Kozon, Bernard P. Murray, Mohammad Bashir, Mark Gohdes, Winston C. Tse, Scott D. Schroeder, Michael Graupe, John O. Link, Jung-Joo Yoon, Anna Chiu, William Rowe, Bill J. Smith, Raju Subramanian · 发表于：Journal of Pharmacology and Experimental Therapeutics · 年份：2024 · DOI：10.1124/jpet.124.002302 · 被引用次数：13 · 研究领域：Axial and Atropisomeric Chirality Synthesis、Molecular spectroscopy and chirality、Alkaloids: synthesis and pharmacology

Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few FDA-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (t 1/2 <2 hours) with a ratio that is stable over time and unaffected by enzymes or binding to proteins in plasma. LEN exhibits low systemic clearance (CL) in nonclinical species and humans; however, in all species the observed CL was higher than the in vitro predicted CL. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole body autoradiography in rats. LEN does not distribute to brain, consistent with being a P-glycoprotein (P-gp) substrate. Mechanistic drug disposition studies with [ 14 C]LEN in IV-dosed BDC rats and dogs showed a substantial amount of unchanged LEN (31 - 60% of dose) excreted in feces, indicating that intestinal excretion (IE) was a major clearance pathway for LEN in both species. Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Renal excretion was <1% of dose in both species. In plasma, almost all radioactivity was unchanged LEN. Low levels of metabolites in excreta included LEN-conjugates with glutathione, pentose, and glucuronic acid, which were consistent with metabolites formed in vitro in Hµrel® hepatocyte co‑cultures and those observed in human. Our studies highligh...