Does pregnancy affect the pharmacokinetics of efavirenz?

The latest WHO guidelines recommend efavirenz treatment throughout pregnancy, including during the first trimester [1,2]. Despite evidence for teratogencity in animal models [3], a meta-analysis found no evidence of an increased risk of overall or central nervous system congenital anomalies associated with first-trimester exposure to efavirenz [4]. Therapeutic levels of antiretrovirals must be maintained throughout pregnancy to ensure maximal viral suppression to prevent vertical transmission. During pregnancy, temporal changes in hepatic drug-metabolizing enzymes and other physiological changes might affect the metabolism of efavirenz. [5]. Trans-placental passage of antiretrovirals has also been evaluated to assess foetal drug exposure. Efavirenz is primarily metabolized by the hepatic cytochrome 2B6 isoenzyme (CYP2B6); single nucleotide polymorphisms in the CYP2B6 gene significantly efavirenz clearance [6] and have been associated with early efavirenz treatment discontinuation [7]. In nonrandomized cohort studies, low efavirenz plasma concentrations have not only been associated with higher virological failure rates but may also have been linked to poor adherence [8,9]. By contrast, the randomized ENCORE-1 study showed equivalent virological efficacy of a lower 400 mg once-daily dose for first-line treatment, than the standard 600 mg dose [10]. The Phase 2 DMP-005 trial also showed similar levels of efficacy for efavirenz at doses of 200, 400 and 600 mg daily [11]. We searched Medline and EMBASE from 2000 to 2013 for studies of efavirenz pharmacokinetics in pregnancy. Table 1 summarizes the results from the five studies identified, which included 235 pregnant women treated with efavirenz 600 mg once daily [12–17].Table 1: Summary of pharmacokinetic studies of efavirenz in pregnant women.In the IMPAACT P1026s study [12], intensive steady-state 24-h blood sampling was performed during the third trimester and 6–12 weeks postpartum. Antepartum assessment of efavirenz pharmacokinetics was performed at a median (range) gestational age of 33 (30–39) weeks. During pregnancy, the mean efavirenz C24h was 1.6 mg/l [95% confidence interval (95% CI) 0.23–8.13], with 12% of mothers having C24h below the recommended efficacy threshold of 1.0 mg/l; 6–12 weeks postpartum, the mean efavirenz C24h was 2.05 mg/l (95% CI 0.31–8.43), with 8% of mothers having C24h below 1.0 mg/l. There was no significant difference in efavirenz AUC or Cmax between the women during pregnancy and postpartum. However, efavirenz C24h was significantly lower in the third trimester versus 6–12 weeks postpartum (P = 0.01). One of the 25 infants was vertically infected with HIV. The efavirenz C24h level in the mother was 1.6 mg/l at 32 weeks gestational age, maternal viral load was 238 copies/ml at delivery and efavirenz was detectable in the cord blood. Efavirenz was able to cross the placenta: at the time of delivery, the median concentration of efavirenz in cord blood was 1.05 mg/l, compared with 2.24 mg/l in maternal blood. The median ratio of cord blood to maternal delivery efavirenz concentration was 0.49 (0.37–0.74). In the TSHEPISO study [13], at week 37 of pregnancy, the estimated efavirenz Cmin was 1.4 mg/l (95% CI 0.99–1.89), with 25.4% of mothers having a Cmin below 1.0 mg/l. Six weeks postpartum, the estimated efavirenz Cmin was 1.68 mg/l (95% CI 1.22–2.78), with 20% of mothers having a Cmin below 1.0 mg/l. There was no significant difference in efavirenz Cmin between women during pregnancy and postpartum; maternal body weight and CYP2B6 genotype were the most significant predictors of efavirenz plasma concentrations. In the PROMOTE study [14], efavirenz pharmacokinetics were evaluated from dried blood spot samples taken during pregnancy and postpartum. Estimates of pharmacokinetics parameters were made using a nonlinear mixed effects pharmacokinetics model. There was no effect of pregnancy on the clearance of efavirenz. In a subsequent study, efavirenz was found to transfer from the mother to the infant in utero, and also during breastfeeding [15]. In the AMATA study [16], 13 women received two nucleoside analogues along with efavirenz, starting from week 28 of gestation. Blood samples were collected 3–4 h after the last drug intake. The mean (range) efavirenz concentration in maternal plasma was 6.55 (1.62–14.43) mg/l. In a French study [17], seven women received efavirenz for the entire duration of pregnancy, seven only during the first trimester, one during the first two and one during the last two trimesters. The median Cmin was 2.25 mg/l (range undetectable to 12 mg/l). No difference in efavirenz Cmin was observed between trimesters. Of the 25 efavirenz Cmin levels measured, 21 were in the predefined therapeutic range of 1–4 mg/l, one was above 4 mg/l and three were undetectable, suggesting adherence difficulties. In conclusion, these five studies of 235 women treated with efavirenz during pregnancy reported that efavirenz drug concentrations were not significantly affected and high rates of HIV RNA suppression in the mothers at the time of delivery. The overall results suggest that pregnancy has limited, if any clinically important effects, on efavirenz pharmacokinetics. Acknowledgements Conflicts of interest There are no conflicts of interest.