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Efavirenz pharmacokinetics during pregnancy and infant washout.

ABSTRACT: BACKGROUND:Limited data exist on efavirenz pharmacokinetics in HIV-positive pregnant women and neonatal washout. METHODS:HIV-infected pregnant women receiving 600 mg efavirenz once daily had intensive steady-state 24-h pharmacokinetics profiles during the second trimester (2T), third trimester (3T) and 6-12 weeks postpartum (PP). Maternal and umbilical cord blood samples were drawn at delivery and neonatal washout pharmacokinetics were determined. Therapeutic targets were the estimated 10th percentile efavirenz area under the concentration-time curve (AUC) in non-pregnant historical controls (40.0 ?g•h/ml) and a trough concentration (C24 h) of 1 ?g/ml. Data were prospectively collected within two trials: IMPAACT P1026s (United States) and PANNA (Europe). RESULTS:Among 42 women studied, 15, 42 and 40 had efavirenz pharmacokinetic data available in 2T, 3T and PP, respectively. Median (range) 3T age 33 (20.7-43.5) years, weight 74 (50-132) kg and gestational age 33.4 (28.4-37.9 weeks). Efavirenz AUC during the 3T (60 ?g•h/ml) was similar to that reported in non-pregnant adults (58 ?g•h/ml). Exposure in the 2T was lower, but within the 0.80-1.25 range. C24 concentrations during pregnancy were lower compared to historical controls on 600 mg efavirenz, however, they were similar to the C24 concentrations after equally potent dose of 400 mg efavirenz. Cord blood/maternal plasma concentration ratio (range) was 0.67 (0.36-0.95). Among 23 infants with washout data available, median (interquartile range) elimination half-life was 65.6 h (40.6-129). HIV RNA viral loads at delivery were <400 and <50 copies/ml for 96.7% and 86.7% of women, respectively. In 3T and PP, respectively, 8/41 (19%) and 6/40 (15%) had AUC below target; 7/41 (17%) and 3/39 (8%) had C24 below target. CONCLUSIONS:Efavirenz exposure was similar during pregnancy compared with PP, C24 was in line with C24 after 400 mg equipotent efavirenz dosing. Efavirenz readily crossed the placenta and infant elimination half-life was over twice that of maternal participants. Clincaltrials.gov identifiers: NCT00825929 and NCT00042289.

SUBMITTER: Kreitchmann R

PROVIDER: S-EPMC6642905 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe impact of pregnancy on efavirenz (EFV) pharmacokinetics is unknown.MethodsInternational Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is an on-going, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg EFV once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6-12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile EFV area under the curve (AUC) in nonpregnant historical controls (40.0 mcg·hr(-1)·mL(-1)) and a trough concentration of 1 mcg/mL.ResultsTwenty-five women were enrolled during the third trimester: median (range) age was 29.3 (18.9-42.9) years, weight 69.0 (40-130) kg, and gestational age 32.9 (30.1-38.7) weeks. Median (range) EFV AUC(0-24), C(max), and C(24 hours) were 55.4 mcg·hr(-1)·mL(-1) (13.5-220.3), 5.4 mcg/mL (1.9-12.2), and 1.6 mcg/mL (0.23-8.13), respectively. EFV AUC and C(max) did not differ during pregnancy and postpartum but C(24 hours) was lower during the third trimester (1.6 vs. 2.1 mcg/mL, P = 0.01). During the third trimester, 5 of 25 (20%) women had an EFV AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. EFV cord blood/maternal concentration ratio was 0.49 (0.37-0.74). All women had a HIV-1 RNA viral load less than 400 copies per milliliter at delivery and 19 (76%) had a viral load below 50 copies per milliliter. One child was perinatally HIV infected. Three women were exposed to EFV throughout the first 6 weeks of pregnancy. EFV was well tolerated, and among the 25 infants, no congenital anomalies or newborn complications were reported.ConclusionsChanges in EFV pharmacokinetics during pregnancy compared with postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.

Project description:BackgroundFew data are available describing atazanavir exposure during pregnancy, especially when used in combination with tenofovir, whose coadministration with atazanavir results in decreased atazanavir exposure.DesignInternational Maternal Pediatric Adolescent AIDS Clinical Trials 1026 s is an ongoing, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included 2 cohorts receiving atazanavir/ritonavir 300 mg/100 mg once daily, either with or without tenofovir.MethodsIntensive steady-state 24-hour pharmacokinetic profiles were performed during the third trimester and at 6-12 weeks postpartum. Atazanavir was measured by reverse-phase high-performance liquid chromatography (detection limit 0.047 mcg/mL). Pharmacokinetic targets were the estimated 10th percentile atazanavir area under the concentration versus time curve [(AUC): 29.4 mcg · hr · mL-1] in nonpregnant historical controls (mean AUC = 57 mcg · hr · mL-1) and a trough concentration of 0.15 mcg/mL, the concentration target used in therapeutic drug monitoring programs.ResultsMedian atazanavir AUC was reduced during the third trimester compared with postpartum for subjects not receiving tenofovir (41.9 vs. 57.9 mcg · hr · mL-1, P = 0.02) and for subjects receiving tenofovir (28.8 vs. 39.6 mcg · hr · mL-1, P = 0.04). During the third trimester, AUC was below the target in 33% (6 of 18) of women not receiving tenofovir and 55% (11 of 20) of women receiving tenofovir. Trough concentration was below the target in 6% (1 of 18) of women not receiving tenofovir and 15% (3 of 20) of women receiving tenofovir. The median (range) ratio of cord blood/maternal atazanavir concentration in 29-paired samples was 0.18 (0-0.45).ConclusionsAtazanavir exposure is reduced by pregnancy and by concomitant tenofovir use. A dose increase of atazanavir/ritonavir to 400 mg/100 mg may be necessary in pregnant women to ensure atazanavir exposure equivalent to that seen in nonpregnant adults.

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Efavirenz pharmacokinetics during pregnancy and infant washout.

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