The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum

Objective: The objective of this study was to explore the pharmacokinetics of nelfinavir and its active metabolite hydroxy-t-butylamidenelfinavir (M8) during pregnancy and post partum. Methods. Eleven human immunodeficiency virus type 1-infected Pregnant women receiving 1250 mg nelfinavir twice. daily were enrolled. Pharmacokinetics of nelfinavir and M8 were assessed over a 12-hour period during pregnancy (median, 32 weeks' gestation; range, 31-36 weeks) and post partum (median, 8 weeks post partum; range, 6-15 weeks). Drug concentrations were analyzed by HPLC coupled to tandem mass spectroscopy,, and pharmacokinetic parameters were calculated by use of noncompartmental methods. Results: The-median area under the plasma concentration-time curve from 0 to 12 hours (AUC(0-12)), the maximal plasma concentration (C-max), and the concentration at the end of the dosing interval (C-12) for nelfinavir postpartum were 33.5 h . mug/mL, 5.80 mug/mL, and 1.40 mug/mL, respectively. The values for the geometric mean ratio (GMR) (third trimester/post partum) for the nelfinavir AUC(0-12), C-max, and C-12 were 0.76 (90% confidence interval [CI], 0.54-1.06), 0.81 (90% CI, 0.57-1.15), and 0.43 (90% CI, 0.25-0.76), respectively. The GMR values for the M8 AUC(0-12), C-max, and C-12 were 0.32 (90% CI, 0.18-0.55), 0.31 (90% CI, 0.19-0.51), and 0.30 (90% CI, 0.14-0.64), respectively. The median ratio values of the AUC(0-12) of M8 and nelfinavir (M8/nelfinavir) during the third trimester and post partum were 11% and 27%, respectively (GMR, 0.42 [90% CI, 0.33-0.53]). Conclusions: Nelfinavir exposure was reduced during pregnancy, and the reduction was statistically significant for C-12. M8 concentrations were about 70% lower during pregnancy compared with post partum, suggesting either induction of hepatic cytochrome P450 (CYP) 3A4 or inhibition of CYP2C19, or both, during pregnancy. Because 8 of 11 women had subtherapeutic nelfinavir trough concentrations during pregnancy, the safety and efficacy of therapeutic drug monitoring should be investigated.