PK disposition for some compounds differs between men and women, with women displaying distinct therapeutic and toxic responses. For example, PK and virological responses to saquinavir, a CYP3A4 substrate, were found to be linked to gender [16
]. These sex-based differences may be amplified during pregnancy. Previously, the impact of gender and pregnancy on NVP PK has undergone limited investigation. A population PK analysis of NVP indicated reduced clearance in non-pregnant females, but the impact of this effect was small (<15%) and may have been confounded by ethnic differences in the study populations [17
In contrast, pregnancy may have profound effects on drug disposition, including induction of cytochrome P450 isoenzymes such as CYP2D6 and CYP3A4 [18
]. This is supported by additional findings from P1026 including the reduced lopinavir exposure observed in 17 patients during pregnancy [6
]. Thus, the development of appropriatedosing regimens of ARVs specifically for pregnant women is critical to the health of both the mother and the foetus.
NVP CL/F found in this study is significantly greater than the level reported previously following single-dose administration to pregnant women in labour [12
]. This is expected because chronic NVP administration leads to auto-induction of its metabolism. The PK parameter estimates in this study compare favourably to those found in a large population PK study of chronic NVP use in adults [19
], with the estimate for apparent volume of distribution (Vd/F) in this study a bit smaller, while the estimates for CL/F were almost identical (3.3 L/h vs
. 3.4 L/h).
One previous report compared NVP PK levels in 16 pregnant women to those in men (n
= 13) and non-pregnant women (n
= 10) using a cross-sectional analysis [14
]. While NVP AUC and Cmax
were 29 and 32% lower, respectively, in pregnant women than in non-pregnant women, there was no difference in NVP Cmin
. 3.1) nor was there a difference between pregnant women and male patients. Patient selection and slower NVP absorption during pregnancy may have resulted in these observations.
The current study did not find a significant impact of pregnancy during the second or third trimester on NVP PK compared to values found postpartum in the same patients. NVP exposure was not affected by pregnancy using any comparative method including mixed-effects modelling, paired t-test or the ‘bioequivalence’ approach. Assessing the impact of pregnancy as a fixed effect on CL/F in the population model change did not improve the model fit. The median maximum a posteriori (MAP) Bayesian CL/F values were also similar during pregnancy (3.23 L/h) and postpartum (3.56 L/h). In addition, if one only compares the third trimester and postpartum AUCs, the values become nearly identical. If a minor pregnancy effect exists, one would have expected the maximal difference to occur during the third trimester.
Female gender and high CD4 cell count have been shown to increase the risk for hepatotoxicity with NVP [20
]. Hepatitis, including fatal hepatic failure, has been seen with NVP use during pregnancy [4
]. The lack of altered NVP PK during pregnancy suggests that elevated NVP exposure does not contribute to adverse effects that may be encountered in pregnant women.
While none of the patients with PK evaluations had Grade 2 AST elevations, 5/17 patients in P1022 experienced NVP-associated toxicity, including fulminant fatal hepatic failure. While toxicity has tempered enthusiasm for overall NVP use during pregnancy, the teratogenic effects of EFV and sometimes erratic absorption of PIs during pregnancy are concerns for the use of these agents. Given these considerations, NVP remains a recommended treatment option for women with low CD4 cell counts during pregnancy [21
]. The wide availability NVP formulations, including generics (some in combination with NRTIs), also make NVP a cost-effective option in resource-limited settings.
Placental transfer of ARVs is an important consideration for drug selection during pregnancy. High placental expression of p-glycoprotein and possibly other drug transporters limit foetal exposure to PIs [22
]. This characteristic reduces the potential for foetal ARV toxicity but may leave infants ‘under-protected’ against HIV infection in utero
and during birth. Our study indicates that NVP - unlike PIs - readily crosses the placenta, achieving therapeutic concentrations in foetal circulations to help protect against early transmission. The near unity between cord and maternal blood NVP concentrations is consistent with a prior evaluation of NVP cord blood concentrations in women undergoing Caesarean section [24
We used population PK and empiric Bayesian compartmental approaches to allow combination of PK data from two studies with different sampling designs to determine appropriate NVP dosing in pregnancy. CIs were used to assess the power of this PK study and the potential for pregnancy-induced changes in NVP disposition. This approach demonstrates that the 90% CI for NVP AUC during pregnancy falls entirely within 80-125% of reference AUC (postpartum). Therefore, this study had sufficient power to exclude any change in NVP exposure during pregnancy that would be considered clinically relevant and require a dose modification.
Although this analysis was well powered to address the impact of pregnancy on NVP AUC, only one of the two studies included in this analysis had frequent sampling to precisely determine Cmax. This translates into more limited precision in the Vd/F estimates. Also, we also did not assess patients for CYP 2B6 genotype. Genetic polymorphism for this enzyme has been linked with reduced metabolism of NVP. While patient genotypes were not determined in this study, alterations in activity would have been detected because each patient served as their own control.
In summary, NVP exposure (AUC) at steady state during the second or third trimester of pregnancy is similar to postpartum values. NVP readily crosses the placenta and provides ARV prophylaxis to the newborn at birth. Because pregnancy does not alter NVP clearance, no dose adjustment of NVP is required as a result of pregnancy. The PK properties of NVP make it a useful agent for continuous use in pregnant women with low CD4 cell counts.