Physiologically based pharmacokinetic modelling in pregnancy: Model reproducibility and external validation.

Area of Science:

• Pharmacometrics and Drug Development
• Translational Pharmacology
• Computational Biology

Background:

• Physiologically based pharmacokinetic (PBPK) models are crucial for predicting drug behavior during pregnancy.
• Previous PBPK models for betamethasone and buprenorphine exist for pregnant populations.

Purpose of the Study:

• To replicate and reassess existing PBPK models for betamethasone and buprenorphine using recent clinical data.
• To evaluate the reproducibility and external validation of these PBPK models in pregnant women.

Main Methods:

• PBPK models for betamethasone and buprenorphine were developed in Simcyp V19, based on prior publications.
• Model replication was verified by comparing Simcyp V19 predictions to published results.
• Reassessed models were compared against new observational data from pregnant women.

Main Results:

• The betamethasone PBPK model was successfully replicated and showed sufficient prediction of betamethasone exposure changes across gestation.
• The buprenorphine PBPK model was not reproducible, with Simcyp V19 predicting 70% of the previously reported intravenous clearance.

Conclusions:

• Model reproducibility and external validation are essential for advancing PBPK modeling.
• PBPK modeling publications require sufficient detail to ensure reproducibility.
• The betamethasone PBPK model adequately predicted exposure, while the buprenorphine model's reproducibility was a concern.