Nifedipine pharmacokinetics and pregnancy: Studies on clearance, absorption, and transport.

摘要

Nifedipine is one of the first-line therapies currently recommended by ACOG for treatment of preterm labor. However, large variability in nifedipine pharmacokinetics and tocolytic effects prevents it from being effective in all cases of preterm labor. We conducted a number of studies to evaluate factors contributing to variability in nifedipine pharmacokinetics that could ultimately be used to design approaches to reduce such variability. This overall goal was approached using three different research studies. First, we used compartmental population and physiologically-based models to evaluate the effects of pregnancy and CYP3A genotypes on nifedipine oral clearance. Second, we conducted a series of in vitro dissolution studies followed by a two-phase pharmacokinetic study to determine the effect of fluid volume on nifedipine dissolution and pharmacokinetics. Finally, we performed a number of in vitro cellular transport and uptake studies to examine the possible role of drug transporters in nifedipine permeability across the placenta.;The results of our first aim showed that nifedipine clearance is increased at least two-fold during pregnancy as compared to reported values in healthy volunteers. In addition, CYP3A5 expression significantly increased nifedipine clearance by 2-3-fold in pregnant women. Investigation of nifedipine dissolution in vitro demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution for doses of 10 mg IR capsules. Further exploration of such effect in humans using a crossover clinical trial did not show a significant effect of gastric fluid volume on nifedipine pharmacokinetic parameters. However, administration of larger fluid volumes resulted in lower variability in observed nifedipine Cmax. In vitro drug transport studies in B30 cells showed that nifedipine permeability across placental B30 cell lines is similar to that of the passive diffusion marker, fluorescein, and is not directional. In addition, cellular uptake studies to investigate the role of active transport processes in nifedipine permeability into B30 cells showed that nifedipine uptake is not mediated through active transport processes and relies mainly on passive diffusion.;Based on the present results, future consideration of CYP3A5 genotype during dosing of nifedipine may be recommended to ensure adequate exposure to the drug. With genotyping of patients for genes coding for metabolizing enzymes becoming easier and more accessible, dosing of preterm labor patients based on their already available CYP3A5 genotype may be a feasible approach. The increase in nifedipine oral clearance during pregnancy should be taken into consideration if nifedipine were to be continued after delivery (e.g. in pregnancy-induced hypertension) since dose reduction may be needed to avoid overdosing and dose-related side effects (e.g. hypotension, dizziness, and palpitations). Nifedipine absorption is associated with high inter-individual variability even after administration of the same fluid volume. Administration of large fluid volumes with nifedipine IR capsules is warranted in order to reduce inter-individual variability in nifedipine exposure. The knowledge gained from the studies we conducted provides a good chance for improvement of clinical outcomes in treatment of preterm labor. Consideration of CYP3A5 genotype, changes in enzyme activity, and effects of gastric fluid volume will indeed result in less variable and more predictable pharmacokinetic profiles and hence better patient outcomes. In the absence of a single ideal first-line therapy for treatment of preterm labor, improvement of tocolytic therapy with nifedipine may provide a significant health benefit to pregnant women with preterm labor.