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

Abstract

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.

Keywords: HIV-1 capsid inhibitor; PK modeling; combination antiretroviral therapy; human PK; long-acting injectable; nonclinical pharmacokinetics.

Scheme 1. Lenacapavir (LEN) Structure and Considerations for a Long-Acting Injectable Drug Product

Link et al.

Scheme 2. Compartmental Analysis Model-Informed Input and Exit Rates

A two-compartment model with parallel first-order slow and fast-release absorption and first-order elimination was sufficient to describe LEN SC suspension and solution PK. The slow-release component was sufficiently described with a lag time (T_lag) for the aqueous suspension PK and with transit compartments for the PEG/water SC PK. Legend: Dose (mg/kg); Frac_direct, fraction of dose released via a direct process; Frac_indirect, 1-Frac_direct; fraction of dose released via an indirect process; F_SC, total fraction of dose released following subcutaneous administration; IV, intravenous; k_direct, direct release absorption rate constant (1/h); k_indirect, indirect release absorption rate constant (1/h); k_tr, transit rate constant between compartments (1/h); MTT, mean transit time (h); T_lag, lag time (h); Q, intercompartmental CL (L/h/kg); SC, subcutaneous; V_c, volume of central compartment (L/kg); V_p, volume of peripheral compartment (L/kg).

Figure 1

Plasma concentration–time profiles of LEN following intravenous infusion administration of LEN to rats at 3 mg/kg and dogs at 1 mg/kg (n = 3; mean ± SD).

Figure 2

Plasma concentration–time profiles of LEN following subcutaneous administration of an aqueous suspension formulation at 100 mg/mL to male rats (n = 3; mean ± SD).

Figure 3

Plasma concentration–time profiles of LEN following subcutaneous administration of an aqueous suspension formulation to male dogs (n = 3; mean ± SD). (A) 3–100 mg/kg of a 100 mg/mL formulation; (B) 6 mg/kg of a 100 or 200 mg/mL formulation; (C) 6 mg/kg of a 100 mg/mL formulation as one or two equal-volume injections.

Figure 4

Plasma concentration–time profiles of LEN following subcutaneous administration of a PEG/water solution formulation at 309 mg/mL to male rats (n = 3; mean ± SD).

Figure 5

Plasma concentration–time profiles of LEN following subcutaneous administration of a PEG/water solution formulation at 309 mg/mL to male dogs (n = 3; mean ± SD).

Figure 6

Cumulative extent of dose release following SC administration of aqueous suspension (A) and PEG/water solution formulations (B) to rat, dog, and human (mean ± SD; n = 3 for rat and dog, n = 8 for human).

Figure 7

Observed and model-predicted plasma concentration–time profiles of LEN following subcutaneous administration of a LEN aqueous suspension formulation to rat (10 mg/kg; A), dog (6 mg/kg; B), and human (30–450 mg; C). Observed concentration values are mean ± SD; n = 3 for rat and dog; n = 8 for human. LEN: 1 nM = 0.968 ng/mL.

Figure 8

Observed and model-predicted plasma concentration–time profiles following subcutaneous administration of a LEN PEG/water solution formulation to rat (50 mg/kg, A) and dog (12 mg/kg, B). Observed concentration values are mean ± SD; n = 3 for rat and dog. Insets show expanded (0–14 day) views.