BACKGROUND: Lenacapavir (LEN) is currently approved for the treatment of multidrug-resistant HIV-1 in combination with other antiretrovirals for heavily treatment-experienced (HTE) individuals. In the ongoing pivotal Phase 2/3 study (CAPELLA), participants received oral LEN loading (600 mg on Days 1 and 2; 300 mg on Day 8) followed by 927 mg SC Q6M starting from Day 15 (Phase 2/3 regimen). Current data indicate that a mean trough LEN concentration of 15.5 ng/mL (inhibitory quotient-4 [IQ4]) is associated with high antiviral activity. Given the importance of oral loading doses in achieving and maintaining concentrations >IQ4, it is imperative to consider options to manage missed oral loading doses. We used a population-pharmacokinetic (PopPK) model to simulate various dosing scenarios to guide missed oral loading-dose recommendations for the HTE population.
METHODS: A previously developed 2-compartment PopPK model with 1st-order absorption and linear elimination was used to simulate plasma concentrations following missed oral LEN doses to provide recommendations for different scenarios of missed doses, and identify alternative dosing options.
RESULTS: Recommendations for missed oral loading dose scenarios in Phase 2/3 regimen are shown (Table 1). In all scenarios, the recommended alternative dosing option maintained LEN concentrations >IQ4. Figure 1 shows a scenario in which the Day 2 oral dose is missed by =6 days, with alternative dosing options on Days 8 and 15.

Table 1. Summary of Missed Dose Recommendations for Oral LEN Loading in Phase 2/3 Dosing Regimen
Loading Dose Day	Missed Dose Scenario	Recommendation
Day 2	Day 2 oral dose missed by <6 days	Participant should take 600 mg PO dose as soon as possible
	Day 2 oral dose missed by =6 days	Participant should take 600 mg instead of 300 mg on Day 8 and 300 mg on Day 15 (along with SC injection)
Day 8	Day 8 oral dose missed by <6 days	Participant should take 300 mg PO dose as soon as possible
	Day 8 oral dose missed by =6 days	Participant should take 300 mg on Day 15 (along with SC injection)

CONCLUSIONS: PopPK modeling was used to provide dosing recommendations for missed oral loading doses of LEN. The dosing window for oral LEN loading is wide and forgiving, while maintaining therapeutic concentrations.

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