Pharmacokinetics, Disposition, and Biotransformation of [
Journal
Clinical pharmacokinetics
ISSN: 1179-1926
Titre abrégé: Clin Pharmacokinet
Pays: Switzerland
ID NLM: 7606849
Informations de publication
Date de publication:
18 Jan 2024
18 Jan 2024
Historique:
accepted:
12
11
2023
medline:
18
1
2024
pubmed:
18
1
2024
entrez:
18
1
2024
Statut:
aheadofprint
Résumé
Lenacapavir (LEN) is a novel, first-in-class, multistage, selective inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function recently approved for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. The purpose of this multicohort study was to evaluate the pharmacokinetics, metabolism, excretion, safety, and tolerability of LEN following a single intravenous (IV) infusion of 10 mg LEN or 20 mg [ Twenty-one healthy adult participants were enrolled into the study and received either a single IV dose of 10 mg LEN (n = 8 active, n = 3 placebo; cohort 1) or a single IV dose of 20 mg [ Between the 10 mg and 20 mg doses of LEN, the observed plasma exposure of LEN doubled, while the elimination half-life was similar. Following administration of 20 mg [ The results of this mass balance study indicated that LEN was majorly eliminated as intact LEN via the feces. The renal pathway played a minor role in LEN elimination (0.24%). In addition, no major circulating metabolites in plasma or feces were found, indicating minimal metabolism of LEN.
Sections du résumé
BACKGROUND AND OBJECTIVE
OBJECTIVE
Lenacapavir (LEN) is a novel, first-in-class, multistage, selective inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function recently approved for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. The purpose of this multicohort study was to evaluate the pharmacokinetics, metabolism, excretion, safety, and tolerability of LEN following a single intravenous (IV) infusion of 10 mg LEN or 20 mg [
METHODS
METHODS
Twenty-one healthy adult participants were enrolled into the study and received either a single IV dose of 10 mg LEN (n = 8 active, n = 3 placebo; cohort 1) or a single IV dose of 20 mg [
RESULTS
RESULTS
Between the 10 mg and 20 mg doses of LEN, the observed plasma exposure of LEN doubled, while the elimination half-life was similar. Following administration of 20 mg [
CONCLUSIONS
CONCLUSIONS
The results of this mass balance study indicated that LEN was majorly eliminated as intact LEN via the feces. The renal pathway played a minor role in LEN elimination (0.24%). In addition, no major circulating metabolites in plasma or feces were found, indicating minimal metabolism of LEN.
Identifiants
pubmed: 38236562
doi: 10.1007/s40262-023-01328-1
pii: 10.1007/s40262-023-01328-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Références
UNAIDS. 2021 Global HIV Statistics. Fact Sheet—June, 2021. [cited 2022 March 11]. https://www.unaids.org/en/resources/fact-sheet .
HIV.gov. U. S. Statistics. [cited 2022 March 11]. https://www.hiv.gov/hiv-basics/overview/data-and-trends/statistics .
Board NL, Moskovljevic M, Wu F, Siliciano RF, Siliciano JD. Engaging innate immunity in HIV-1 cure strategies. Nat Rev Immunol. 2022;22(8):499–512.
doi: 10.1038/s41577-021-00649-1
pubmed: 34824401
Segal-Maurer S, DeJesus E, Stellbrink H-J, Castagna A, Richmond GJ, Sinclair GI, et al. Capsid inhibition with lenacapavir in multidrug-resistant HIV-1 infection. N Engl J Med. 2022;386(19):1793–803.
doi: 10.1056/NEJMoa2115542
pubmed: 35544387
Daar ES, McDonald C, Crofoot G, Ruane P, Sinclair G, Patel H, et al. Safety and antiviral activity over 10 days following a single dose of subcutaneous GS-6207, a first-in-class, long-acting HIV capsid inhibitor in people living with HIV. IAS; Abstract LBPEB13; 2019.
Yant SR, Mulato A, Stepan G, Villasenor AG, Jin D, Margot NA, et al. GS-6207, a potent and selective first-in-class long-acting HIV-1 capsid inhibitor. In: Conference on retroviruses and opportunistic infections; Seattle, Washington. Abstract 480; 2019.
Zheng J, Yant SR, Ahmadyar S, Chan TY, Chiu A, Cihlar T, et al. 539. GS-CA2: a novel, potent, and selective first-in-class inhibitor of HIV-1 capsid function displays nonclinical pharmacokinetics supporting long-acting potential in humans. Open Forum Infect Dis. 2018;5(Suppl 1):S199–S200.
Bester SM, Wei G, Zhao H, Adu-Ampratwum D, Iqbal N, Courouble VV, et al. Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science. 2020;370(6514):360–4.
doi: 10.1126/science.abb4808
pubmed: 33060363
pmcid: 7831379
Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020;584(7822):614–8.
doi: 10.1038/s41586-020-2443-1
pubmed: 32612233
pmcid: 8188729
Begley R, Lutz J, Rhee M, Dvory-Sobol H, Chiu A, West SK, et al. GS-6207 sustained delivery formulation supports 6-month dosing interval. In: AIDS; Virtual. Abstract 8533; Poster PEB0265; 2020.
Sager JE, Begley R, Rhee M, West SK, Ling J, Schroeder SD, et al. Safety and PK of subcutaneous GS-6207, a novel HIV-1 capsid inhibitor. In: Conference in retroviruses and opportunistic infections; Seattle, Washington. Abstract 141; 2019.
Gilead Sciences I. Sunlenca (lenacapavir) [package insert]. 2023.
Molina J-M, SoranaSegal-Maurer, Stellbrink H-J, Castagna A, MezgebeBerhe, Richmond G, et al. Efficacy and safety of long-acting subcutaneous lenacapavirin phase 2/3 in heavily treatment-experienced people with HIV: week 26 results (CAPELLA study). In: IAS conference on HIV science. 2021; Abstract 2605.
Ogbuagu O, Segal-Maurer S, Brinson C, Chetchotisakd P, Lichtenstein K, McGowan J, et al. Long-acting lenacapavir in people with multidrug resistant HIV-1: week 52 results. In: Conference on retroviruses and opportunistic infections; Virtual; Abstract 491; February 12–16; 2022.
ClinicalTrials.gov. A phase 2/3 study to evaluate the safety and efficacy of long acting capsid inhibitor GS-6207 in combination with an optimized background regimen in heavily treatment experienced people living with HIV-1 infection with multidrug resistance. [cited 2022 March 11]. https://clinicaltrials.gov/ct2/show/NCT04150068 .
New Clinical Data Support the Sustained Efficacy of Long-acting Lenacapavir, Gilead’s Investigational HIV-1 Capsid Inhibitor. [cited 2022 March 11]. https://www.gilead.com/news-and-press/press-room/press-releases/2022/2/new-clinical-data-support-the-sustained-efficacy-of-longacting-lenacapavir-gileads-investigational-hiv1-capsid-inhibitor .
Gilead Sciences I. Sunlenca (lenacapavir) Summary of Product Characteristics. 2023.
ClinicalTrials.gov. [NCT04143594] Study to evaluate the safety and efficacy of lenacapavir in combination with other antiretroviral agents in people living with HIV (CALIBRATE).
FDA. Clinical Pharmacology Considerations for Human Radiolabeled Mass Balance Studies Guidance for Industry. 2022.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for industry estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Rockville. 2005.
National Institute of Allergy and Infectious Diseases. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events. Corrected Version 2.1 July 2017. [cited 2022 March 11]. https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf .
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. 2021 [cited 2022 September 21]. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf .
Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009 Apr 10;58(Rr-4):1–207; quiz CE1–4.
Ramamoorthy A, Bende G, Chow ECY, Dimova H, Hartman N, Jean D, et al. Human radiolabeled mass balance studies supporting the FDA approval of new drugs. Clin Transl Sci. 2022;15(11):2567–75.
doi: 10.1111/cts.13403
pubmed: 36066467
pmcid: 9652429
Zheng J, Tse W, Lu B, Mwangi J, Rowe W, Schroeder S, et al. Intestinal excretion is a major disposition pathway of lenacapavir in rat and dog. FASEB J. 2021;35.
Subramanian R, Tang J, Zheng J, Lu B, Wang K, Yant SR, et al. Lenacapavir: a novel, potent and selective first-in-class inhibitor of HIV-1 capsid function exhibits optimal pharmacokinetic properties for a long-acting injectable antiretroviral agent. Mol Pharm. 2023. https://doi.org/10.1021/acs.molpharmaceut.3c00626 . Epub ahead of print. PMID: 37917742.
doi: 10.1021/acs.molpharmaceut.3c00626
pubmed: 37917742
pmcid: 10698746
Zheng J, Yant SR, Ahmadyar S, Chan TY, Chiu A, Cihlar T, et al. 539. GS-CA2: a novel, potent, and selective first-in-class inhibitor of HIV-1 capsid function displays nonclinical pharmacokinetics supporting long-acting potential in humans. Open Forum Infect Dis. 2018;5(Suppl 1):S199–200.
Jogiraju V, Begley R, Hindman J, West SK, Ho E, Ling J, German P. Pharmacokinetics of lenacapavir, an HIV-1 capsid inhibitor, in hepatic impairment. In: Conference on retroviruses and opportunistic infections; 2021.
FDA. Guidance for Industry—Pharmacokinetics in Patients with Impaired Renal Function—Study Design, Data Analysis, and Impact on Dosing and Labeling. 2010.
Weber EJ, Graham H, West SK, Ling J, Rhee M, Palaparthy R. Pharmacokinetics of lenacapavir in participants with severe renal impairment. In: Conference on retroviruses and opportunistic infections; 2022.