Pharmacokinetics of nelfinavir in HIV‐1‐infected pregnant and nonpregnant women

Abstract

AimsTo compare steady-state nelfinavir (NFV) pharmacokinetics in pregnant and nonpregnant HIV-infected women. MethodsTwenty-five pregnant HIV-infected women were selected from an ongoing observational study evaluating the pharmacokinetics of antiretroviral agents during pregnancy. Twenty of them were in the third and five in the second trimester. Data for the control group of 21 HIV-infected nonpregnant women were taken from a previous multicentre pharmacokinetic trial. All the participating women achieved steady-state plasma concentrations while on a highly active antiretroviral therapy (HA ART) regimen including NFV (1250 mg bid) and two nucleoside reverse transcriptase inhibitors (N RTIs). Blood samples for NFV measurement were collected predose ( C trough ) and at 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 h post dose. ResultsDuring the third trimester of pregnancy NFV AUC 0 − 12 h median (range) values were 25.76 (12.61-42.74) µ g h − 1 ml − 1 , and were 32. 49 (19.16-63.81) µ g h − 1 ml − 1 in the control group [mean difference − 9.30 µ g h − 1 ml − 1 ; 95% confidence interval (CI) − 15.76, − 2.83; P < 0.05). Median oral clearance (CL/F) was significantly higher in pregnant women than in the control group (48.5 l h − 1 , range 29.3-99.1 l h − 1 vs. 38.5 l h − 1 , range 19.6-65.2 l h − 1 ; mean difference 12.6 l h − 1 ; 95% CI 3.3, 21.9) but the difference disappeared when CL/F was adjusted for body weight. C trough was significantly ( P < 0.01) lower in pregnant compared with nonpregnant women (median 0.8 µ g ml − 1 , range 0-2.6 µ g ml − 1 vs. 1.5 µ g ml − 1 , range 0.5-4.9 µ g ml − 1 ; mean difference − 1.0 µ g ml − 1 ; 95% CI − 1.7, − 0.31). The median elimination half-life of NFV observed during pregnancy was 3.7 h (range 1.4-6.6 h), compared with 5.2 (range 3.1-10.1 h) in the control group (mean difference − 1.7; 95% CI − 2.8, − 0.51). ConclusionsOur results indicate that women in the later stages of pregnancy may be exposed to subtherapeutic concentrations of NFV. Thus, adjustments in drug dosage or frequency of administration may be required. P. Villani et al. 31062 :3 Br J Clin Pharmacol

Genital Tract, Cord Blood, and Amniotic Fluid Exposures of Seven Antiretroviral Drugs during and after Pregnancy in Human Immunodeficiency Virus Type 1-Infected Women

“…Significant decreases in the area under the concentration-time curve from 0 h to time (time between dosing intervals) have been demonstrated for ZDV (59), TNF (8), LPV (50), and NFV (7,43,56), while decreased trough concentrations have been noted for TNF (8), LPV (50), and NFV (55,56). ARV blood plasma concentrations observed in the present study were similar to those described in previous reports (8,23,36,38,50,56,59).…”

“…Paired maternal and cord blood plasma samples were obtained a median of 15.5 hours (range, 11.7 to 54.7) after the last dose. Table 2 summarizes drug concentrations in maternal blood plasma, cord blood plasma, and amniotic fluid and corresponding (17,33,56). N, number of paired BP and GT samples by period (second trimester, third trimester, postpartum, and nonpregnant historical controls, respectively).…”

“…Previous studies using intensive pharmacokinetic sampling of ARVs in pregnancy have noted significantly decreased third trimester systemic exposure to NRTIs (ZDV and TNF) (8,59) and PIs (LPV and NFV) (7,43,50,55,56) compared to postpartum levels. Significant decreases in the area under the concentration-time curve from 0 h to time (time between dosing intervals) have been demonstrated for ZDV (59), TNF (8), LPV (50), and NFV (7,43,56), while decreased trough concentrations have been noted for TNF (8), LPV (50), and NFV (55,56).…”

Steady‐state nevirapine plasma concentrations are influenced by pregnancy

“…Pregnancy is accompanied by a variety of physiological changes that affect pharmacokinetics [6], resulting in lower plasma concentrations for several protease inhibitors (PI) [7][8][9][10]. NVP is metabolized through the cytochrome P450 isoenzymes CYP 3A4 (56%) and CYP 2B6 (32%) [11].…”

Implications of gender and pregnancy for antiretroviral drug dosing

“…Within-subject comparisons between pregnancy and postpartum showed significant postpartum increases in maximum concentration and AUC, and decreases in oral clearance and the ratio of its active metabolite to the parent drug concentration [66,67]. Two recent studies of 25 and 27 pregnant women taking nelfinavir 1250 mg twice daily showed significantly lower troughs, peaks and AUC and higher oral clearance in the third trimester compared with the same women 6-12 weeks postpartum [68 • ] or nonpregnant controls [69]. Doses of 750 mg three times daily should be avoided in pregnancy.…”