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 post partum were 33.5 h . microg/mL, 5.80 microg/mL, and 1.40 microg/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.
van Heeswijk
Rolf P G
RP
Division of Incectious Diseases and Department of Pharmacy, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada. rvanheeswijk@ohri.ca
Khaliq
Yasmin
Y
Gallicano
Keith D
KD
Bourbeau
Marc
M
Seguin
Isabelle
I
Phillips
Elizabeth J
EJ
Cameron
D William
DW
D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008137:Longitudinal Studies; D013058:Mass Spectrometry; D019888:Nelfinavir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D049590:Postpartum Period / Q000378:metabolism*; D011247:Pregnancy / Q000378:metabolism*
D019380:Anti-HIV Agents; C495123:hydroxy-t-butylamidenelfinavir; D019888:Nelfinavir