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Lenacapavir Exhibits Atropisomerism-Mechanistic Pharmacokinetics and Disposition Studies of Lenacapavir Reveal Intestinal Excretion as a Major Clearance Pathway.
Zheng, Jim; Lu, Bing; Carr, Gavin; Mwangi, Judy; Wang, Kelly; Hao, Jia; Staiger, Kelly McLennan; Kozon, Nathan; Murray, Bernard P; Bashir, Mohammad; Gohdes, Mark A; Tse, Winston C; Schroeder, Scott; Graupe, Michael; Link, John O; Yoon, Jungjoo; Chiu, Anna; Rowe, William; Smith, Bill J; Subramanian, Raju.
Afiliación
  • Zheng J; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Lu B; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Carr G; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Mwangi J; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Wang K; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Hao J; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Staiger KM; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Kozon N; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Murray BP; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Bashir M; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Gohdes MA; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Tse WC; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Schroeder S; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Graupe M; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Link JO; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Yoon J; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Chiu A; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Rowe W; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Smith BJ; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.).
  • Subramanian R; Gilead Sciences, Inc., Foster City, California (J.Z., B.L., G.C., J.M., K.W., J.H., K.M.S., N.K., B.P.M., W.C.T., S.S., M.G., J.O.L., J.Y., A.C., W.R., B.J.S., R.S.); and Labcorp Early Development Laboratories Inc., Madison, Wisconsin (M.B., M.A.G.) Raju.Subramanian@gilead.com.
J Pharmacol Exp Ther ; 391(1): 91-103, 2024 Sep 18.
Article en En | MEDLINE | ID: mdl-39117460
ABSTRACT
Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few Food and Drug Administration-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (half-life < 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 [14C]LEN in intravenously dosed bile duct-cannulated 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 cocultures and those observed in human. Our studies highlight the importance of IE for efflux substrates that are highly metabolically stable compounds with slow elimination rates. SIGNIFICANCE STATEMENT LEN is a long-acting injectable that exists as conformationally stable atropisomers. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ratas Sprague-Dawley Límite: Animals / Humans / Male Idioma: En Revista: J Pharmacol Exp Ther Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ratas Sprague-Dawley Límite: Animals / Humans / Male Idioma: En Revista: J Pharmacol Exp Ther Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos