Strategies to Manage Dosing Deviations and Interruptions of Cabotegravir Long‐Acting Intramuscular Injections

TL;DR

This study provides strategies to manage dosing issues with cabotegravir, a long-acting HIV treatment, to ensure effective and safe drug exposure.

Contribution

The study introduces simulation-based strategies for managing dosing deviations and interruptions of cabotegravir injections.

Findings

Doubled doses resulted in a median Cmax of ≤6.35 µg/mL, within safe limits.

Oral bridging with 30 mg daily maintained adequate exposure during injection delays.

Delays >1 month require reinitiating the loading dose to mitigate efficacy loss and resistance risks.

Abstract

Long‐acting cabotegravir is approved for HIV treatment and prevention. To guide management of dosing deviations and interruptions, concentration‐time profiles for monthly and every 2 months regimens were simulated using a population pharmacokinetic (PPK) model. Adequate exposure was defined as trough concentration (Ctau) >0.45 µg/mL (observed 5th percentile of first Ctau in pivotal studies) in >95% of subjects and maximum concentration (Cmax) <13.1 µg/mL (highest observed median steady‐state Cmax in previous studies) in >50% of subjects. Simulations showed: (1) median Cmax remained ≤6.35 µg/mL after doubled doses; (2) Ctau was suboptimal after half dose at first injection but recovered with a corrective dose; (3) injection delays ≤7 days maintained adequate Ctau, while longer delays caused extended low‐exposure periods (≤23 days for 1‐month delay, ≤83 days for 3‐month delay); (4) reinitiating loading dose after delays >1 month led to higher exposure than continuing injections and may mitigate efficacy loss and resistance risks; and (5) oral bridging (30 mg daily) maintained adequate exposure during delays. Recommended strategies include no action for higher‐than‐planned doses, corrective dosing for lower‐than‐planned doses, strict adherence to schedule, reinitiating the loading dose after delays >1 month, and oral bridging. These findings were incorporated into product labeling and can inform next‐generation cabotegravir and other long‐acting agent development.

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