Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

Elsherbiny, Doaa A.; Cohen, Karen; Jansson, Bjarne; Smith, Peter J.; McIlleron, Helen; Simonsson, Ulrika S. H.

doi:10.1007/s00228-008-0481-y

Cited by 28 publications

(24 citation statements)

References 36 publications

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“…It is suggested to perform nevirapine plasma concentration monitoring as methadone may influence the efficacy of treatment because it causes a decrease in nevirapine concentrations. Elevated AST levels, age, and weight are identified factors contributing to a high interindividual variance of nevirapine (12,14,(16)(17)(18)(19). In our study, univariate analysis showed that the AST and ALT levels were significantly associated with nevirapine concentrations and AUC 0-12 h. Furthermore, multivariate analyses confirmed that increased ALT levels significantly increased nevirapine concentrations and AUC 0-12 h. A recent study reported that hepatotoxicity was significantly associated with higher nevirapine trough concentrations (20).…”

Section: Discussionsupporting

confidence: 77%

Exploring CYP2B6 activity by measuring the presence ofnevirapine hydroxy metabolites in plasma

et al. 2016

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Background/aim: Nevirapine is a reverse-transcriptase inhibitor widely used in combination therapy to treat HIV infection. Nevirapine is extensively metabolized in the liver and CYP2B6 is mainly responsible for oxidation of 3-hydroxynevirapine (3-OH NVP). This study aims to explore CYP2B6 activity by measuring 2-hydroxynevirapine (2-OH NVP) and 3-OH NVP in plasma and to identify factors associated with nevirapine pharmacokinetic parameters. Materials and methods:A total of 112 patients were recruited and treated with nevirapine-based antiretroviral therapy. Plasma nevirapine and metabolite concentrations were assayed using high-performance liquid chromatography via liquid-liquid extraction.Results: Thirty-nine (34.8%) of the patients had no 3-OH NVP detected in their plasma while 2-OH NVP was detected in all patients. Metabolite concentrations were low compared to nevirapine. Positive correlations were observed between nevirapine and its metabolites, 2-OH NVP (P < 0.01) and 3-OH NVP (P = 0.012). Nevirapine concentration was decreased when concomitantly administered with methadone. Univariate analysis showed that ALT level, AST level, and detection of 3-OH NVP were associated with nevirapine pharmacokinetic parameters. Conclusion:The variability of nevirapine pharmacokinetic parameters was caused by liver enzymes and the presence of 3-OH NVP metabolites. The presence of 3-OH NVP can probably be used to distinguished CYP2B6 activity and efficacy of nevirapine in patients with HIV infection.

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Section: Discussionsupporting

confidence: 77%

Exploring CYP2B6 activity by measuring the presence ofnevirapine hydroxy metabolites in plasma

et al. 2016

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“…Modeling of data from South African patients indicates that increasing nevirapine doses by 50% to 300 mg twice daily would achieve therapeutic concentrations in the majority [21], but the safety of this strategy has not been adequately explored for recommendation as routine practice, and may result in increased hypersensitivity reactions [22]. …”

Section: Drug Interactionsmentioning

confidence: 99%

Management of individuals requiring antiretroviral therapy and TB treatment

Cohen¹,

Meintjes

2010

Current Opinion in HIV and AIDS

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Purpose of review-Globally, tuberculosis (TB) is the commonest opportunistic infection in people living with HIV. Many co-infected patients first present with advanced immunosuppression and require antiretroviral therapy (ART) initiation during TB treatment. The incidence of TB in patients established on ART remains high. Co-treatment presents several management challenges. Recent data on these management issues are reviewed.Recent findings-Efavirenz concentrations at standard doses are similar with and without concomitant rifampicin-based TB treatment. Nevirapine concentrations are frequently subtherapeutic during lead-in dosing at 200 mg daily in patients on rifampicin-based TB treatment, which may result in inferior virological outcomes. Hepatotoxicity occurred in 3 pharmacokinetic studies (conducted in healthy volunteers) of boosted protease inhibitors initiated in participants on rifampicin. Results of a clinical trial comparing efavirenz and nevirapine-based ART in patients on TB treatment, with no lead-in dosing of nevirapine, are awaited. Concurrent TB treatment increases the need for stavudine substitutions, mainly related to neuropathy. Consensus case definitions for TB immune reconstitution inflammatory syndrome (TB-IRIS) have been published. It is important to exclude TB drug resistance in patients with suspected TB-IRIS. A clinical trial demonstrated benefit of prednisone for treating TB-IRIS, reducing a combined endpoint of days hospitalised and outpatient therapeutic procedures. Starting ART during TB treatment improved survival in patients with CD4 < 500 cells/μL, but the optimal interval between starting TB treatment and starting ART remains to be determined in several ongoing trials.Summary-ART improves survival in co-infected TB patients, but is complicated by several management challenges that compromise programmatic implementation in resource-limited settings. Recent findings and the findings of ongoing studies will assist clinicians in dealing with these challenges.

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“…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.…”

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confidence: 99%

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

Nikanjam

Kabamba

Cressey

et al. 2012

Antimicrob Agents Chemother

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N evirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used worldwide as part of antiretroviral therapy. NVP in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) is recommended by the World Health Organization (WHO) for first-line therapy in infants Ͼ24 months of age and in infants Ͻ24 months of age who were not exposed to maternal or infant NVP or other NNRTIs used for maternal treatment or prevention of mother-to-child transmission of HIV (7). The chemical and pharmacokinetic properties of NVP are advantageous in these settings, particularly in sub-Saharan Africa, as it can be formulated as a heatstable liquid preparation and has fewer drug interactions than protease inhibitors, and its bioavailability is not affected by food intake (20).NVP is metabolized by a variety of cytochrome P450 (CYP) enzymes but predominantly by CYP2B6 and CYP3A. Prior studies have found an association between the CYP2B6 516 GT single nucleotide polymorphism and NVP pharmacokinetics in adults and children. Lower clearance and higher trough concentrations have previously been observed in patients with the CYP2B6 516 TT genotype (22,24).The weight-adjusted oral clearance of NVP is higher in younger children than in older children or adults. The initial FDA pediatric dosing of 7 mg/kg twice daily in children less than 8 years of age was thus reduced to 4 mg/kg for children 8 years of age or older. Subsequently, an alternative dosing recommendation of 150 mg/m 2 twice daily was approved by the FDA (25). In resourcelimited settings, dosing based on body surface area (BSA) is not ideal, as it requires obtaining an accurate height measurement and utilizing a mathematical calculation to obtain the appropriate dose. 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. The current evaluation combines PK data from eight studies of NVP in infants, children, and adolescents, generating a robust NVP PK data set of

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Population pharmacokinetics of nevirapine in combination with rifampicin-based short course chemotherapy in HIV- and tuberculosis-infected South African patients

Cited by 28 publications

References 36 publications

Exploring CYP2B6 activity by measuring the presence ofnevirapine hydroxy metabolites in plasma

Exploring CYP2B6 activity by measuring the presence ofnevirapine hydroxy metabolites in plasma

Management of individuals requiring antiretroviral therapy and TB treatment

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

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