Long acting injectable (LAI) cabotegravir (CAB) has recently been approved for the treatment of HIV in adults. However, there are currently no adequate data to inform its administration during pregnancy. The aim of this study was to apply physiologically-based pharmacokinetic (PBPK) modelling to predict the PK of LAI CAB in pregnancy.
An adult PBPK model was modified in SimBiology (MATLAB R2019a) to represent a pregnant population; pregnancy-induced anatomical, physiological, and metabolic changes (e.g., progesterone-mediated induction, organ blood-flow rates etc.) known to influence drug PK were incorporated. Prior to running simulations in pregnant patients, the non-pregnant model was qualified against clinical PK data in adults for single doses of 30 mg oral, 400 mg and 800 mg intramuscular (IM) CAB, and 400 mg oral raltegravir (RAL). Clinical PK data for probe substrate RAL in pregnant women was used to validate the activity of key enzyme UGT1A1 during pregnancy. The qualified pregnancy model was used to predict the PK of single doses of CAB (30 mg oral, LAI 400 mg & 600 mg IM) across different trimesters in pregnancy.
Absolute average fold errors (AAFE) of the mean PK parameters for oral RAL and CAB in adults were between 1.0-1.9 fold, and <1.5 fold, respectively. IM CAB simulations in non-pregnant adults successfully passed model qualification criteria with AAFEs between 1.0-1.9 fold. In the second and third trimester of pregnancy, AAFE values of oral RAL were within the 2-fold acceptance criteria, providing confidence in model simulations for CAB. Predicted elimination kinetics of CAB 400mg IM were closely related to observed data. The predicted geometric mean of plasma exposures in pregnant and non-pregnant patients were comparable for each of the single doses of CAB that were examined in this study (Table 1).
These data suggest dosage adjustments are not necessary for IM LA CAB to maintain therapeutic concentrations and clinical efficacy during pregnancy. This approach could be utilised to predict the risk related to altered PK during pregnancy for IM LA therapy and support the design of future clinical trials in pregnant women.