Persistence of nevirapine in breast milk and plasma of mothers and their children after single-dose administration

Kunz, Andrea; Frank, Monika; Mugenyi, Kizito; Kabasinguzi, Rose; Weidenhammer, Astrid; Kurowski, Michael; Kloft, Charlotte; Harms, Gundel

doi:10.1093/jac/dkn441

Cited by 35 publications

(29 citation statements)

References 45 publications

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“…Interestingly, the effect of nevirapine induction on CYP2B6 activity leads to an increased concentration of 3-hydroxynevirapine and a lower concentration of the 2-hydroxynevirapine metabolite formed through the CYP3A pathway. The pharmacokinetic characteristics of parent nevirapine in the present study agree with those of previous studies conducted in patients or volunteers after a single dose or at steady state, a finding which clearly demonstrates the autoinducing properties of nevirapine (10,(19)(20)(21)(22)(23)(24)(25)(26)(27). Indeed, the two populations studied herein differ by their ethnicity, demographics, and HIV infection status; the CYP2B6 *1*6 genetic polymorphism frequency is very close, but the significant difference remains when clearances are weight normalized (0.83 ml/ min/kg versus 0.29 ml/min/kg).…”

Section: Discussionsupporting

confidence: 91%

Pharmacokinetics of Phase I Nevirapine Metabolites following a Single Dose and at Steady State

Fan-Havard

Liu

Chou

et al. 2013

Antimicrob Agents Chemother

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g Nevirapine is one of the most extensively prescribed antiretrovirals worldwide. The present analyses used data and specimens from two prior studies to characterize and compare plasma nevirapine phase I metabolite profiles following a single 200-mg oral dose of nevirapine in 10 HIV-negative African Americans and a steady-state 200-mg twice-daily dose in 10 HIV-infected Cambodians. Nevirapine was assayed by high-performance liquid chromatography (HPLC). The 2-, 3-, 8-and 12-hydroxy and 4-carboxy metabolites of nevirapine were assayed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). Pharmacokinetic parameters were calculated by noncompartmental analysis. The metabolic index for each metabolite was defined as the ratio of the metabolite area under the concentration-time curve (AUC) to the nevirapine AUC. Every metabolite concentration was much less than the corresponding nevirapine concentration. The predominant metabolite after single dose and at steady state was 12-hydroxynevirapine. From single dose to steady state, the metabolic index increased for 3-hydroxynevirapine (P < 0.01) but decreased for 2-hydroxynevirapine (P < 0.001). The 3-hydroxynevirapine metabolic index was correlated with nevirapine apparent clearance (P < 0.001). These findings are consistent with induction of CYP2B6 (3-hydroxy metabolite) and a possible inhibition of CYP3A (2-hydroxy metabolite), although these are preliminary data. There were no such changes in metabolic indexes for 12-hydroxynevirapine or 4-carboxynevirapine. Two subjects with the CYP2B6 *6*6 genetic polymorphism had metabolic indexes in the same range as other subjects. These results suggest that nevirapine metabolite profiles change over time under the influence of enzyme induction, enzyme inhibition, and host genetics. Further work is warranted to elucidate nevirapine biotransformation pathways and implications for drug efficacy and toxicity.

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Section: Discussionsupporting

confidence: 91%

Pharmacokinetics of Phase I Nevirapine Metabolites following a Single Dose and at Steady State

Fan-Havard

Liu

Chou

et al. 2013

Antimicrob Agents Chemother

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“…19 The majority of methods were either LC-MS or HPLC with ultraviolet detection based; one study employed GC-MS. Two studies described the use of drug-free milk for use in assay optimization. 20,21 Fourteen studies described assay validation or referenced validated methods. Fourteen studies specified the assay sensitivity in terms of the lower limit of quantification and eight studies specified the internal standard used (Table S2).…”

Section: Resultsmentioning

confidence: 99%

Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies

Waitt

Garner

Bonnett

et al. 2015

Journal of Antimicrobial Chemotherapy

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ObjectivesThe objectives of this study were to summarize antiretroviral drug concentrations in breast milk (BM) and exposure of breast-fed infants.MethodsThis was a systematic review of pharmacokinetic studies of HIV-positive women taking antiretrovirals that measured drugs in BM. The quality of pharmacokinetic and laboratory methods was assessed using pre-defined criteria. Pooled ratios and 95% CIs were calculated using the generalized inverse variance method and heterogeneity was estimated by the I2 statistic. PubMed Central, SCOPUS and LactMed databases were searched. No date or language restrictions were applied. Searches were conducted up to 10 November 2014. Clinical relevance was estimated by comparing ingested dose with the recommended therapeutic dose for each drug.ResultsTwenty-four studies were included. There was substantial variability in the clinical and laboratory methods used and in reported results. Relative to maternal plasma (MP), NRTIs accumulate in BM, with BM : MP ratios (95% CI estimates) from 0.89 to 1.21 (14 studies, 1159 paired BM and MP samples). NNRTI estimates were from 0.71 to 0.94 (17 studies, 965 paired samples) and PI estimates were from 0.17 to 0.21 (8 studies, 477 paired samples). Relative to the recommended paediatric doses, a breast-fed infant may ingest 8.4% (95% CI 1.9–15.0), 12.5% (95% CI 2.6–22.3) and 1.1% (95% CI 0–3.6) of lamivudine, nevirapine and efavirenz, respectively, via BM.ConclusionsTransfer to untreated infants appears quantitatively important for some NRTIs and NNRTIs. The pharmacokinetic methods varied widely and we propose standards for the design, analysis and reporting of future pharmacokinetic studies of drug transfer during breastfeeding.

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“…22) exhibited NVP-resistant virus in high proportions at week 4–6 which was selected most likely by the maternal NVP dose. NVP rapidly crosses the placenta, resulting in high NVP concentrations in the infant's blood at birth [59], [60]. Postnatal NVP dosing of the infant only slightly elevated the NVP levels in infants [61].…”

Section: Discussionmentioning

confidence: 99%

Emergence of Minor Drug-Resistant HIV-1 Variants after Triple Antiretroviral Prophylaxis for Prevention of Vertical HIV-1 Transmission

et al. 2012

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Background WHO-guidelines for prevention of mother-to-child transmission of HIV-1 in resource-limited settings recommend complex maternal antiretroviral prophylaxis comprising antenatal zidovudine (AZT), nevirapine single-dose (NVP-SD) at labor onset and AZT/lamivudine (3TC) during labor and one week postpartum. Data on resistance development selected by this regimen is not available. We therefore analyzed the emergence of minor drug-resistant HIV-1 variants in Tanzanian women following complex prophylaxis. Method 1395 pregnant women were tested for HIV-1 at Kyela District Hospital, Tanzania. 87/202 HIV-positive women started complex prophylaxis. Blood samples were collected before start of prophylaxis, at birth and 1–2, 4–6 and 12–16 weeks postpartum. Allele-specific real-time PCR assays specific for HIV-1 subtypes A, C and D were developed and applied on samples of mothers and their vertically infected infants to quantify key resistance mutations of AZT (K70R/T215Y/T215F), NVP (K103N/Y181C) and 3TC (M184V) at detection limits of <1%. Results 50/87 HIV-infected women having started complex prophylaxis were eligible for the study. All women took AZT with a median duration of 53 days (IQR 39–64); all women ingested NVP-SD, 86% took 3TC. HIV-1 resistance mutations were detected in 20/50 (40%) women, of which 70% displayed minority species. Variants with AZT-resistance mutations were found in 11/50 (22%), NVP-resistant variants in 9/50 (18%) and 3TC-resistant variants in 4/50 women (8%). Three women harbored resistant HIV-1 against more than one drug. 49/50 infants, including the seven vertically HIV-infected were breastfed, 3/7 infants exhibited drug-resistant virus. Conclusion Complex prophylaxis resulted in lower levels of NVP-selected resistance as compared to NVP-SD, but AZT-resistant HIV-1 emerged in a substantial proportion of women. Starting AZT in pregnancy week 14 instead of 28 as recommended by the current WHO-guidelines may further increase the frequency of AZT-resistance mutations. Given its impact on HIV-transmission rate and drug-resistance development, HAART for all HIV-positive pregnant women should be considered.

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Persistence of nevirapine in breast milk and plasma of mothers and their children after single-dose administration

Cited by 35 publications

References 45 publications

Pharmacokinetics of Phase I Nevirapine Metabolites following a Single Dose and at Steady State

Pharmacokinetics of Phase I Nevirapine Metabolites following a Single Dose and at Steady State

Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies

Emergence of Minor Drug-Resistant HIV-1 Variants after Triple Antiretroviral Prophylaxis for Prevention of Vertical HIV-1 Transmission

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