Modelling the tail-phase pharmacokinetics of long-acting cabotegravir and rilpivirine from early pregnancy to postpartum at steady state.

Long-acting cabotegravir and rilpivirine combination (LA-CAB/RPV) is approved for HIV treatment whilst LA-CAB alone is approved for HIV prevention, both in adults. However, individuals who become pregnant might prefer to discontinue it due to lack of definitive data on safety. The aim of this study was to characterise the tail-phase maternal and fetal pharmacokinetics of LA-CAB/RPV following discontinuation at steady-state early in pregnancy using physiologically-based pharmacokinetic modelling. A virtual population of non-pregnant women (n = 100 per scenario) initiated intramuscular injections of LA-CAB/RPV at the approved dosage and continued maintenance dose (400/600 mg once monthly or 600/900 mg once every two months) until steady state. We simulated discontinuation at steady state after only one injection during pregnancy. Tail-phase pharmacokinetics of CAB and RPV from LA injections were characterised during gestation and until 64 weeks postmenstrual age. Pharmacokinetic tails of LA-CAB/RPV were driven by the residual drug in the muscle depot which stabilised at steady state and reduced steadily upon dosing discontinuation. Upon discontinuation of the monthly dosing, predicted median (IQR) maternal plasma concentrations for LA-CAB were 415 (386-448) ng/mL at delivery and 125 (115-139) ng/mL at 64 weeks postmenstrual age. For LA-RPV, these were 11.6 (11.0-12.6) ng/mL and 7.84 (7.30-8.49) ng/mL at delivery and at 64 weeks postmenstrual age, respectively. Pharmacokinetic tails of LA-CAB/RPV extend to several months postpartum, with levels falling below established minimum effective concentration in most women after gestation week 33. Potential strategies to minimise potential risks associated with LA-CAB/RPV discontinuation in this population are needed.