BACKGROUND: Lenacapavir (LEN) is currently approved for multidrug-resistant HIV-1 infection in combination with other antiretrovirals for heavily treatment-experienced individuals. In ongoing Phase 2/3 studies (CAPELLA and CALIBRATE), participants receive oral LEN loading (600 mg on Days 1 and 2; 300 mg on Day 8) followed by 927 mg SC given every 6-months (Q6M) starting from Day 15. In these studies, mean trough concentrations >15.5 ng/mL, which is inhibitory quotient-4 (IQ4; ie, 4-fold in-vitro protein binding-adjusted 95% effective concentration), are associated with high rates of virologic suppression. In participants temporarily unable to receive SC LEN during its clinical hold, oral bridging (300 mg QW) was used until SC dosing was resumed. Our objective was to evaluate the pharmacokinetics (PK) of LEN during oral bridging (OB) period to assess the adequacy of 300-mg oral QW LEN for maintaining therapeutic concentrations between missed SC LEN doses.
METHODS: During OB period, sparse PK samples were collected at the start (of OB period) and every ~10-12 weeks (without regard to a prespecified time since dose) until SC LEN was resumed. LEN plasma concentrations were summarized during OB period in the CAPELLA (N=57) and CALIBRATE (N=82) studies.
RESULTS: In both studies, mean LEN concentration and the lower-bound 90% confidence interval (CI) were maintained above the efficacy target of IQ4 at all OB period visits (Table 1). At the time of SC LEN resumption, mean (lower-bound 90% CI) predose concentrations in CAPELLA (74.4 ng/mL [56.2 ng/mL]) and CALIBRATE (50.7 [43.6]) exceeded IQ4.

Table 1. Plasma LEN Concentrations During OB Period With LEN 300 mg QW
StudyConcentrationOB Day 1OB Week 10OB Week 20OB Week 30
CAPELLAMean, ng/mL46.1
90% CI40.3, 51.966.1, 86.350.4, 99.329.9, 53.5
CALIBRATEMean, ng/mL27.8
90% CI 25.3, 30.447.1, 62.843.7, 61.424.4, 75.7

CONCLUSIONS: Mean LEN concentrations and the lower-bound 90% CIs were maintained above IQ4 from the first oral LEN bridging visits until SC LEN was resumed in both studies. These results indicate that LEN 300 mg oral QW provides adequate concentrations to bridge LEN dosing in participants who may miss their Q6M SC injection.