Pharmacokinetics of long‐acting cabotegravir and rilpivirine in seminal plasma throughout the dosing interval

14 Despite the suppression of HIV RNA in blood, HIV persistence in anatomical compartments is a major barrier to a cure. The male genital tract (MGT) is an important immune-privileged site. HIV curative strategies rely on the ability of antiretrovirals (ARVs) to adequately penetrate the MGT, which contains anatomical (e.g., blood-testis barrier) and physiological (e.g., drug efflux transporters) barriers that protect spermatozoa from potentially harmful xenobiotics. Adequate and suppressive ARV concentrations are necessary to decrease HIV replication in genital secretions; these have important implications for transmission. However, the extent to which long-acting ARVs penetrate the MGT across the extended dosing interval is unknown. This study aims to characterize the pharmacokinetics of long-acting cabotegravir (CAB) and rilpivirine (RPV) in blood plasma (BP) and seminal plasma (SP) throughout the dosing interval. Adult cisgender males continuing CAB±RPV intramuscular injection bimonthly were included. Participants provided time-matched blood and semen samples prior to injection, at predetermined timepoints throughout the dosing interval, and immediately before the next injection. Quantification of total CAB±RPV concentrations in BP and SP was completed using validated ultra-performance liquid chromatography–tandem mass spectrometry methods (lower limit of quantification: 0.1 ng/mL). The protein-unbound fractions in both matrices were determined using rapid equilibrium dialysis and multiplied by total concentrations to estimate protein-unbound concentrations. Protein-unbound concentrations were compared to half-maximal effective concentrations (EC₅₀). Total and protein-unbound SP-to-BP ratios (SP:BP) were calculated across the dosing interval. Pooled non-compartmental analysis was performed using Phoenix WinNonlin to obtain pharmacokinetic parameters to calculate AUCtau SP:BP. Data are reported as median (range). Actual times were used in pharmacokinetic analyses. Five participants provided 16 time-matched BP and SP samples. Three participants received CAB alone and two participants received CAB/RPV. Total CAB SP concentrations were 21.0 ng/mL (3.7–89.8), and total RPV SP concentrations were 5.6 ng/mL (4.0–13.5). Total SP:BP were 0.01 (0.002–0.01) and 0.07 (0.06–0.1) for CAB and RPV, respectively. This remained consistent throughout the dosing interval. CAB protein-unbound fractions were 0.1% (0.07%–0.5%) in BP and 43.9% (31.2%–56.1%) in SP. RPV protein-unbound fractions were 0.4% (0.2%–1.4%) in BP and 20.7% (7.5–27.4%) in SP. Protein-unbound CAB concentrations were 2.5 ng/mL (1.4–8.2) in BP and 9.3 ng/mL (1.6–36.2) in SP, yielding a protein-unbound SP:BP of 4.1 (0.2–11.5), which remained consistent throughout the dosing interval. Protein-unbound RPV concentrations were 1.0 ng/mL (0.6–2.2) in BP and 6.5 ng/mL (2.8–33.5) in SP, yielding a protein-unbound SP:BP of 2.7 (1.1–7.3). CAB and RPV protein-unbound SP concentrations were 43.4-fold (12.2–361) and 2.9-fold (1.0–36.2) above their respective EC₅₀ values across the dosing interval. Total AUCtau SP:BP were 0.01 (0.01–0.02) and 0.07 (0.06–0.08) for CAB and RPV, respectively. Protein-unbound AUCtau SP:BP were 3.8 (2.3–10.6) for CAB and 3.0 (2.4–3.6) for RPV. Although total SP concentrations were <10% of concentrations in BP for both ARVs, protein-unbound concentrations were >2.5-fold in SP. These patterns remained consistent throughout the dosing interval. Total and protein-unbound AUCtau SP:BP followed similar trends, suggesting adequate exposure. Importantly, protein-unbound CAB and RPV concentrations exceeded EC₅₀ values throughout the dosing interval in SP. Additional longitudinal studies are warranted to confirm these findings.