Pharmacokinetics of Nevirapine: Once-Daily Versus Twice-Daily Dosing in the 2NN Study

Kappelhoff, Bregt S; Huitema, Alwin D. R.; Leth, Frank van; Robinson, Patrick; MacGregor, Thomas R.; Lange, Joep M. A.; Beijnen, Jos H.

doi:10.1310/b5vu-fu5f-qnwc-udck

Cited by 28 publications

(31 citation statements)

References 19 publications

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“…Weight, hepatitis C virus (HCV) infection status and baseline aspartate aminotransferase (AST) levels were identified as significant covariates in one out-patient cohort study [7]. Gender, geographical region, and hepatitis B virus (HBV) status were identified in the 2NN study [8]. Both analyses utilized a nonlinear mixed-effects, one-compartment model with first-order absorption and elimination.…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Both analyses utilized a nonlinear mixed-effects, one-compartment model with first-order absorption and elimination. The factors identified to be related to nevirapine clearance in at least two independent studies included gender (reduced clearance in women [8,9]) and race (reduced clearance in Asian and Negroid races [10,11]). A trend towards a similar race effect on nevirapine clearance was noted in an additional analysis [7].…”

Section: Pharmacokineticsmentioning

confidence: 99%

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Once‐daily nevirapine dosing: a pharmacokinetics, efficacy and safety review

Cooper

Heeswijk

2007

HIV Medicine

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In the context of attempts to simplify treatment regimens and enhance adherence, there is great interest in once-daily dosing regimens for the treatment of HIV-1 infection. Nevirapine has a long half-life and achieves high steady-state plasma concentrations relative to the concentration required to inhibit 50% viral replication in vitro (IC 50 ) in patients. For this reason, it has been considered as a once-daily antiretroviral. Pharmacokinetic and efficacy data support the use of this dosing approach, but excess rash and lingering concerns over liver toxicity preclude use of once-daily dosed nevirapine at this time. Tolerance to high nevirapine concentrations may develop when dose escalation is used during initiation of therapy. It is theoretically possible that the benefits of oncedaily dosing may be achieved without excess toxicity by switching to once-daily nevirapine following several months of twice-daily administration. This dosing strategy is currently under evaluation.

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Section: Pharmacokineticsmentioning

confidence: 99%

Section: Pharmacokineticsmentioning

confidence: 99%

Once‐daily nevirapine dosing: a pharmacokinetics, efficacy and safety review

Cooper

Heeswijk

2007

HIV Medicine

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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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“…Because the phase II trials will be conducted in HIV-infected male and female patients, a larger intersubject variability than those observed in this study is expected. A 40 to 50% intersubject variability in trough levels was reported for nevirapine (14), an NNRTI structurally similar to BILR 355, suggesting that a variability of 48 to 50% for the C min,ss for BILR 355 in HIV-infected patients is a reasonable assumption in projecting phase II doses. Apparently, when phase II data become available, it will be necessary to refine the PK model by incorporating the demographic data and patient disease characteristics, as well as pharmacodynamic data, to simulate the phase III doses in aiding the design of the pivotal trials.…”

Section: Discussionmentioning

confidence: 96%

Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir

Huang

Drda

MacGregor

et al. 2009

Antimicrob Agents Chemother

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The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID. Following oral dosing, BILR 355 was rapidly absorbed, with the mean time to maximum concentration of drug in serum reached within 1.3 to 5 h and a mean half-life of 16 to 20 h. BILR 355 exhibited an approximately linear pharmacokinetics for doses of 5 to 50 mg when given as a solution; in contrast, when given as tablets, BILR 355 displayed a doseproportional pharmacokinetics, with a dose range of 50 to 100 mg; from 100 to 150 mg, a slightly downward nonlinear pharmacokinetics occurred. The exposure to BILR 355 was maximized at 150 mg and higher due to a saturated dissolution/absorption process. After oral dosing of BILR 355/r, 150/100 mg BID, the values for the maximum concentration of drug in plasma at steady state, the area under the concentration-time curve from 0 to the dose interval at steady state, and the minimum concentration of drug in serum at steady state were 1,500 ng/ml, 12,500 h ⅐ ng/ml, and 570 ng/ml, respectively, providing sufficient suppressive concentration toward human immunodeficiency virus type 1. Based on pharmacokinetic modeling along with the in vitro virologic data, several BILR 355 doses were selected for phase II trials using Monte Carlo simulations. Throughout the study, BILR 355 was safe and well tolerated.Nonnucleoside reverse transcriptase inhibitors (NNRTIs) include a diverse group of compounds that bind to a hydrophobic pocket in the p66 subunit of human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT). Unlike nucleoside reverse transcriptase inhibitors (NRTIs), which exert antiretroviral activity on the active site of HIV-1 RT following initial activation through intracellular phosphorylation, NNRTIs exert their antiviral activity by disrupting the conformation of the active site of HIV-1 RT through noncompetitive binding to a hydrophobic pocket distant from the active site (7). Because of their distinct mechanism of antiretroviral activity and relatively better tolerability profiles, as well as convenient dosing regimens, NNRTI-based regimens are recommended by expert panels as preferred regimens for treatment-naïve and treatment-experienced HIV-infected patients (6). Despite better tolerability and convenient dosing, the clinical utility of the current licensed NNRTIs is somewhat limited by their low genetic barrier (5, 9, 19). Compared to that in other antiretroviral agents, the selection of resistance mutations occurs relatively rapidly in NNRTIs, and mutant HIV viruses are often cross-resistant to the whole class of NNRTIs. As a result, patients failing on a current NN...

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Pharmacokinetics of Nevirapine: Once-Daily Versus Twice-Daily Dosing in the 2NN Study

Cited by 28 publications

References 19 publications

Once‐daily nevirapine dosing: a pharmacokinetics, efficacy and safety review

Once‐daily nevirapine dosing: a pharmacokinetics, efficacy and safety review

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

Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir

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