Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum

Abstract

Background: The impact of pregnancy on efavirenz (EFV) pharmacokinetics is unknown.

Methods: International 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.

Results: Twenty-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.

Conclusions: Changes in EFV pharmacokinetics during pregnancy compared with postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.

Figure 1

Median (± interquartile range) concentration versus time curves for HIV-infected pregnant women using 600 mg, once daily, during the third trimester and postpartum. Dashed line represents the typical 50^th percentile concentrations in non-pregnant historical patients.

Figure 2

Individual efavirenz (a) AUC and (b) C_{24 hour} for HIV-infected pregnant women using 600 mg, once daily, during the third trimester and postpartum. Note: Dashed line represents (a) the 10^th percentile AUC (40 mcg.hr/mL) in non-pregnant historical patients and (b) suggested minimum target trough concentration (1 mcg/mL).

Figure 3

(a) Maternal delivery and cord blood efavirenz concentrations plotted against the interval between maternal dosing and delivery. Filled circles represent maternal plasma efavirenz concentration at delivery and open triangles represent cord blood efavirenz concentrations; (b) Maternal/cord blood efavirenz concentrations ratio plotted against the interval between maternal dosing and delivery. Filled circles represent the ratio of cord blood to maternal delivery efavirenz concentration.