Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics

Abstract

ObjectivesTo determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population. MethodsTwenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante-and postpartum comparisons were made using paired t-tests and using a 'bioequivalence' approach to determine confidence interval (CI). ResultsThe average NVP Area Under the Curve (AUC) was 56 AE 13 mcg*h/mL antepartum and 61 AE 15 mcg*h/mL postpartum. The typical parameters AE standard error were apparent clearance (CL/F) 5 3.51 AE 0.18 L/h and apparent volume of distribution (Vd/F) 5 121 AE 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median ( AE standard deviation) cord blood to maternal NVP concentration ratio was 0.91 AE 0.90. ConclusionsPregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.Keywords: HIV, nevirapine, non-nucleoside reverse transcriptase, pharmacokinetics, pregnancy IntroductionMother-to-child transmission of HIV-1 can be greatly reduced if the maternal viral loads are below the limit of detection at delivery [1]. To achieve this target, combination antiretroviral (ARV) therapy, consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI), is recommended. Although efavirenz (EFV) is the preferred NNRTI in the general population, it has been found to cause severe central nervous system defects when given to primates during the Physiological and hormonal changes associated with pregnancy can have profound effects on drug disposition, including increased plasma volume and reduced plasma protein concentration, increased renal blood flow and modified metabolic enzyme activity. Several ARVs have been studied in pregnancy, with some exhibiting significant alterations in pharmacokinetics (PK), requiring drug dose modifications or avoidance [5,6].The antiviral effects of NVP are rapid, with significant reduction in plasma virus. However, development of viral resistance to NVP can occur with a single mutation in the HIV-1 reverse transcriptase gene [7]. NVP is metabolized primarily in the liver by the cytochrome P450 (CYP) 2B6 and 3A family enzymes [8,9]. Low NVP concentrations have been associated with inadequate viral suppression [10] and may also contribute to NNRTI resistance [11]. The PK of single-dose NVP to mothers at delivery have been described [12,13], but welldesigned PK studies of continuous NVP therapy in pregnancy have not been pub...

Quantitative Prediction of CYP2B6 Induction by Estradiol During Pregnancy: Potential Explanation for Increased Methadone Clearance During Pregnancy

“…The magnitude of change in sertraline concentrations varied from 29% decrease to 90% decrease (Freeman et al, 2008). In contrast to these observations, the oral clearance of nevirapine was not different during the third trimester of pregnancy and postpartum when evaluated in a population of unknown CYP2B6 genotypes (Capparelli et al, 2008). Because all of these drugs are eliminated by multiple cytochrome P450 enzymes, the effect of pregnancy on CYP2B6 activity cannot be conclusively evaluated from these studies.…”

Nevirapine Exposure with WHO Pediatric Weight Band Dosing: Enhanced Therapeutic Concentrations Predicted Based on Extensive International Pharmacokinetic Experience

“…An alternative approach is to dose NVP based on weight bands, which requires no calculations and is easy to implement in the developing world. The WHO selected weight bands rather than age for dosing in resource-poor countries, as obtaining an accurate age can be difficult due to poor record-keeping.NVP has been studied extensively in adults, and multiple population pharmacokinetics (PK) studies have been published (1,4,6,8,11,13,21,27). While many studies have looked at NVP in HIV-infected infants, children, and adolescents (12,15,17,23,26), no comprehensive population analyses have been performed to assess NVP across the pediatric age continuum.…”

Long-term efficacy and safety of treatment with nevirapine plus nucleoside reverse transcriptase inhibitors for HIV-1 infection: An eight-years follow-up

“…In collusion with other studies [1,18,19], we have observed that NVP-treatment causes more often the increase of ␥-GT than ALT and AST: after two years, ␥-GT levels reached a plateau in patients without hepatitis. This trend has been pointed out also by the Murphy et al meta-analysis [19].…”