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Pharmacokinetics, Disposition, and Biotransformation of [14C]Lenacapavir, a Novel, First-in-Class, Selective Inhibitor of HIV-1 Capsid Function, in Healthy Participants Following a Single Intravenous Infusion

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Abstract

Background and 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 [14C]LEN in healthy participants.

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 [14C]LEN containing 200 µCi (n = 10; cohort 2). Blood, urine, and feces samples (when applicable) were collected after dosing, and radioactivity (cohort 2) was assessed using liquid scintillation counting in both plasma and excreta. LEN in plasma was quantified by liquid chromatography (LC) tandem mass spectroscopy (MS/MS) method bioanalysis. Metabolite profiling in plasma and excreta were performed using LC-fraction collect (FC)-high-resolution MS and LC-FC-accelerator mass spectrometry in plasma.

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 [14C]LEN (200 µCi), the mean cumulative recovery of [14C] radioactivity was 75.9% and 0.24% from feces and urine, respectively. The mean whole [14C] blood-to-plasma concentration ratio was 0.5–0.7, which showed a low distribution of LEN to red blood cells. Intact LEN was the predominant circulating species in plasma (representing 68.8% of circulating radioactivity), and no single metabolite contributed to > 10% of total radioactivity exposure through 1176 h postdose. Similarly, intact LEN was the most abundant component (32.9% of administered dose; 75.9% of recovered dose) measured in feces, with metabolites accounting for trace amounts. These results suggest metabolism of LEN is not a primary pathway of elimination. Of the metabolites observed in the feces, the three most abundant metabolites were direct phase 2 conjugates (glucuronide, hexose, and pentose conjugates), with additional metabolites formed to a lesser extent via other pathways. The administered LEN IV doses were generally safe and well-tolerated across participants in this study.

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.

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Acknowledgements

The authors thank all study participants, their families, and the clinical study team members. Funding was provided by Gilead Sciences, Inc. Authors thank internal Gilead Sciences, Inc. cross-functional member – Liping Meng. Additional thanks to the Labcorp clinical research unit, mass balance and metabolite profiling team – Irene Mirkin, Bonnie A. Jung, Sarah Mills, Mohammad Bashir, Mark Gohdes, Matthew Acheson, and Sara Leitz – and the Pharmaron AMS profiling team led by Stephen English.

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Authors and Affiliations

  1. Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA

    Elijah Weber, Raju Subramanian, William Rowe, Michael Graupe, John Ling, Gong Shen, Martin Rhee, Ramesh Palaparthy & Renu Singh

  2. Vir Biotechnology, Inc, San Francisco, CA, USA

    Jennifer Sager

  3. Terns Pharmaceuticals, San Mateo, CA, USA

    Rebecca Begley

  4. Ventyx Biosciences, Encinitas, CA, USA

    Scott Wolckenhauer

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Correspondence to Renu Singh.

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Funding

Funding for this project and involved analyses was provided by Gilead Sciences, Inc.

Conflict of interest

All authors are/were employees and/or shareholders of Gilead Sciences, Inc. at the time of this study.

Ethics approval

This study was conducted in accordance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice and was approved by the institutional review board.

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Each participant provided written informed consent before any study-related procedures were performed.

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All authors provided consent for publication.

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Author contributions

Conceptualization: EW, RS, WR, MG, JL, RB, JS, SW, MR. Formal analysis and investigation: EW, RS, WR, JL, GS, RB, JS, SW, MR, RP, RS. Writing: All authors read, commented, and approved the previous or final version of the manuscript.

Data sharing

Gilead Sciences shares anonymized individual patient data upon request or as required by law or regulation with qualified external researchers based on submitted curriculum vitae and reflecting no conflict of interest. The request proposal must also include a statistician. Approval of such requests is at Gilead Science's discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to datarequest@gilead.com.

Additional information

Authors participated in this work while employed at the Gilead Sciences: Rebecca Begley, Jennifer Sager, Scott Wolckenhauer.

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Weber, E., Subramanian, R., Rowe, W. et al. Pharmacokinetics, Disposition, and Biotransformation of [14C]Lenacapavir, a Novel, First-in-Class, Selective Inhibitor of HIV-1 Capsid Function, in Healthy Participants Following a Single Intravenous Infusion. Clin Pharmacokinet 63, 241–253 (2024). https://doi.org/10.1007/s40262-023-01328-1

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