Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.

There is an unmet need for safe and efficacious oral therapies for COVID‐19 with low potential for drug–drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS‐CoV‐2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS‐443902), which acts as an inhibitor of the SARS‐CoV‐2 RNA‐dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first‐in‐human, randomized, placebo‐controlled, phase I study following oral administration of obeldesivir and a phase I, open‐label absorption, distribution, metabolism, and excretion study following oral administration of [¹⁴C]‐obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT‐concentration analysis. The exposures to GS‐441524 increased dose proportionally in the 100–900‐mg dose range. GS‐441524 accumulated by 35% after twice‐daily and 12% after once‐daily dosing for 5 days. Dose‐proportional increases in the intracellular concentration of GS‐443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS‐441524 was not significantly altered by food intake. Following oral administration of [¹⁴C]‐obeldesivir (500 mg; 100 μCi), the mean cumulative [¹⁴C]‐dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS‐441524 was the predominant plasma component (90% of ¹⁴C‐area under the concentration–time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice‐daily dosing regimen for further evaluation in phase III studies for COVID‐19.

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 [¹⁴C]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 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.

1. Bictegravir (BIC) is a potent small-molecule integrase strand-transfer inhibitor (INSTI) and a component of Biktarvy®, a single-tablet combination regimen that is currently approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, metabolism, distribution, and elimination (ADME) characteristics of BIC were determined through in vivo nonclinical and clinical studies (IND 121318). 2. [¹⁴C]BIC was rapidly absorbed orally in mice, rats, monkeys and human. The cumulative dose recovery was high in nonclinical species (> 80%) and humans (95.3%), with most of the excreted dose recovered in faeces. Quantifiable radioactivity with declining concentration was observed in rat tissues suggesting reversible binding. Unchanged BIC was the most abundant circulating component in all species along with two notable metabolites M20 (a sulfate conjugate of hydroxylated BIC) and M15 (a glucuronide conjugate of BIC). BIC was primarily eliminated by hepatic metabolism followed by excretion of the biotransformed products into faeces. In vitro drug-drug interaction (DDI) studies with M15 and M20 demonstrated that no clinically relevant interactions were expected. 3. Overall, BIC is a novel and potent INSTI with a favourable resistance, PK, and ADME profile that provides important improvements over other currently available INSTIs for the treatment of HIV-1.