奈非那韦和M8在孕期及产后的药代动力学。

The pharmacokinetics of nelfinavir and M8 during pregnancy and post partum.

作者信息

van Heeswijk Rolf P G, Khaliq Yasmin, Gallicano Keith D, Bourbeau Marc, Seguin Isabelle, Phillips Elizabeth J, Cameron D William

机构信息

Division of Incectious Diseases and Department of Pharmacy, The Ottawa Hospital, Ottawa, ON K1H 8L6, Canada.

出版信息

Clin Pharmacol Ther. 2004 Dec;76(6):588-97. doi: 10.1016/j.clpt.2004.08.011.

DOI:10.1016/j.clpt.2004.08.011

PMID:15592330

Abstract

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.

摘要

目的

本研究的目的是探讨奈非那韦及其活性代谢产物羟基叔丁酰胺奈非那韦（M8）在孕期及产后的药代动力学。

方法

纳入11名接受奈非那韦每日两次、每次1250mg治疗的1型人类免疫缺陷病毒感染孕妇。在孕期（中位孕周32周；范围31 - 36周）和产后（中位产后8周；范围6 - 15周）的12小时期间评估奈非那韦和M8的药代动力学。通过高效液相色谱-串联质谱分析法分析药物浓度，并使用非房室方法计算药代动力学参数。

结果

产后奈非那韦的0至12小时血浆浓度-时间曲线下面积（AUC0 - 12）中位数、最大血浆浓度（Cmax）和给药间隔结束时的浓度（C12）分别为33.5 h·μg/mL、5.80μg/mL和1.40μg/mL。奈非那韦AUC0 - 12、Cmax和C12的几何平均比值（GMR）（孕晚期/产后）分别为0.76（90%置信区间[CI]，0.54 - 1.06）、0.81（90%CI，0.57 - 1.15）和0.43（90%CI，0.25 - 0.76）。M8的AUC0 - 12、Cmax和C12的GMR值分别为0.32（90%CI，0.18 - 0.55）、0.31（90%CI，0.19 - 0.51）和0.30（90%CI，0.14 - 0.64）。孕晚期和产后M8与奈非那韦的AUC0 - 12中位数比值分别为11%和27%（GMR，0.42[90%CI，0.33 - 0.53]）。