2.7 Model Modifications to develop a pregnancy PBPK model
Following successful validation of the non-pregnant adult model, the adult PBPK model was feminised by limiting the values for gender-specific parameters (e.g. organ weights) to female only [27]. The adult female PBPK model was later modified to represent a pregnant population. Pregnancy-induced anatomical, physiological, and metabolic changes, known to influence PK, were incorporated into the adult female model to generate a pregnancy PBPK model [17, 50]. Blood-flow rates to different organs and tissues during pregnancy were computed as fractions of the cardiac output and were obtained from literature [50]. Key pregnancy-related biological changes that were implemented in the model have been listed in Table 2.
The varying levels of plasma proteins was also modelled using previously established equations [23, 39] to capture the effect on the unbound fraction of drug in plasma. The clinical PK data of oral 400 mg RAL [51, 52] and oral 25 mg RPV [21, 41] in pregnancy were used to validate the pregnancy PBPK model. By extension, the activity of UGT1A1 and CYP3A4 respectively, during pregnancy as represented within the pregnancy PBPK model, were also validated in the process.