Marco Siccardi

Aims Long‐acting cabotegravir and rilpivirine have been approved to manage HIV in adults, but data regarding safe use in pregnancy are limited. Physiologically‐based pharmacokinetic (PBPK) modelling was used to simulate the approved dosing regimens in pregnancy and explore if C trough was maintained above cabotegravir and rilpivirine target concentrations (664 and 50 ng/mL, respectively). Methods An adult PBPK model was validated using clinical data of cabotegravir and rilpivirine in nonpregnant adults. This was modified by incorporating pregnancy‐induced metabolic and physiological changes. The pregnancy PBPK model was validated with data on oral rilpivirine and raltegravir (UGT1A1 probe substrate) in pregnancy. Twelve weeks' disposition of monthly and bimonthly dosing of long‐acting cabotegravir and rilpivirine was simulated at different trimesters and foetal exposure was also estimated. Results Predicted C trough at week 12 for monthly long‐acting cabotegravir was above 664 ng/mL throughout pregnancy, but below the target in 0.5% of the pregnant population in the third trimester with bimonthly long‐acting cabotegravir. Predicted C trough at week 12 for monthly and bimonthly long‐acting rilpivirine was below 50 ng/mL in at least 40% and over 90% of the pregnant population, respectively, throughout pregnancy. Predicted medians (range) of cord‐to‐maternal blood ratios were 1.71 (range, 1.55‐1.79) for cabotegravir and 0.88 (0.78‐0.93) for rilpivirine between weeks 38 and 40. Conclusions Model predictions suggest that monthly long‐acting cabotegravir could maintain antiviral efficacy throughout pregnancy, but that bimonthly administration may require careful clinical evaluation. Both monthly and bimonthly long‐acting rilpivirine may not adequately maintain antiviral efficacy in pregnancy.