PT-025 - DEVELOPMENT AND VERIFICATION OF A NIFEDIPINE CONTROLLED RELEASE PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL IN PREGNANCY

S. Zaidi¹, L. Da Silva², S. Quinney³; ¹Indiana University, Indianapolis, IN, USA, ²Indiana University School of Medicine, ³Indiana School of Medicine.

Background: Nifedipine is a first-line agent for the treatment of hypertension in pregnancy. However, there is little data to inform the dosing of controlled release (CR) nifedipine in pregnancy. We developed a physiologically based pharmacokinetic (PBPK) model to predict steady-state plasma concentration of nifedipine CR in pregnancy to compare the pharmacokinetics of 30mg CR twice daily (BID) and 60mg CR once daily (QD).

Methods: We constructed a PBPK model for the CR nifedipine using Simcyp V22. The default Sim-Nifedipine compound file was modified to employ the ADAM model drug dissolution and absorption and a full PBPK model for distribution. Model validation was performed by comparing simulated data with clinical studies in healthy volunteers, considering factors such as ethnicity, gender distribution, age, and dose regimen. Following successful validation in healthy populations, we utilized the model to simulate steady-state plasma concentrations in pregnant patients.

Results: Predicted pharmacokinetic parameters for nifedipine CR were consistent with published data from clinical studies in healthy volunteers. The ratios of predicted versus area under the curve (AUC), maximum plasma concentration (Cmax), and time to reach maximum concentration (Tmax) of nifedipine, were from 0.96-1.56 of the observed values. Cmax, AUC, and concentration at steady-state of 30mg BID and 60mg QD CR nifedipine pregnant populations was ~50% lower than in nonpregnant, which is consistent with a 2-fold increase in CYP3A4 activity during pregnancy. Steady-state plasma concentrations in both dosing regimens are similar i.e., 13 ng/ml. However, the 60 mg QD peak-to-trough ratio is substantially larger.

Conclusion: This model holds promise for enhancing our understanding of nifedipine CR pharmacokinetics in pregnancy, ultimately contributing to more informed and effective management of hypertensive disorders during pregnancy. It is unclear whether the pronounced peak-tot-rough ratio with 60 mg QD will result in a subtherapeutic effect. Data from clinical studies is needed to verify the pregnancy predictions.