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.