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

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.