Pharmacokinetics of Lamivudine, Zidovudine, and Nevirapine Administered as a Fixed‐Dose Combination Formulation Versus Coadministration of the Individual Products

Marier, Jean‐François; DiMarco, Marika; Guilbaud, Rudolf; Dodard, C.; Morelli, Gaetano; Tippabhotla, Sudhakar Koundinya; Singla, Anand; Thudi, Nageshwar Rao; Monif, Tausif

doi:10.1177/0091270007307572

Cited by 19 publications

(23 citation statements)

References 19 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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“…Interestingly, Manosuthi et al (30) recently reported that interpatient variability in the efavirenz group was 2.3-fold greater than in the nevirapine group, although these patients received concomitant use of rifampin, which could alter variability. The estimation of nevirapine CL/F calculated at steady state in our population is in the range, albeit somewhat lower, of values in previous studies including different populations (2.95 to 3.35 liters/h) (11-13, 17, 33, 42, 50) and is roughly twice the apparent clearance reported after single-dose administration (21,31), which clearly shows the importance of the autoinducing effect on either first-pass effect and bioavailability or total clearance. The 95% confidence interval for the apparent volume of distribution is large (111 to 446 liter), as the estimation error of this parameter is high.…”

Section: Discussioncontrasting

confidence: 54%

“…The 95% confidence interval for the apparent volume of distribution is large (111 to 446 liter), as the estimation error of this parameter is high. Therefore, comparison with other studies reporting somewhat lower values is difficult (21,31). Interpatient variability in V/F and k a could also not be estimated.…”

Section: Discussionmentioning

confidence: 91%

Population Pharmacokinetic-Pharmacogenetic Study of Nevirapine in HIV-Infected Cambodian Patients

Chou

Bertrand

Ségéral

et al. 2010

Antimicrob Agents Chemother

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The aims of this ANRS12154 open-label, single-center, multiple-dose pharmacokinetic study were to characterize nevirapine pharmacokinetics in a Cambodian population of HIV-infected patients and to identify environmental and genetic factors of variability, focusing on the CYP2B6, CYP3A5, and ABCB1 (MDR1) genes. A total of 170 Cambodian HIV-infected patients were included. Nevirapine trough concentrations were measured after 18 and 36 months of starting antiretroviral treatment and in samples drawn during a dosing interval in a subset of 10 patients. All data were analyzed by nonlinear mixed-effects modeling. The effect of covariates was investigated using the population pharmacokinetic model. Patients carrying homozygous lossof-function alleles CYP3A5 6986A>G, CYP2B6 516G>T, CYP2B6 1459C>T, and ABCB1 3435C>T represent 42.4%, 9.2%, 0%, and 18% of the population, respectively. The median nevirapine trough concentrations did not differ after 18 and 36 months of treatment (5,705 ng/ml [range, <50 to 13,871] and 5,709 ng/ml [range, <50 to 15,422], respectively). Interpatient and intrapatient variabilities of nevirapine apparent clearance were 28% and 17%, respectively. CYP2B6 516G>T and creatinine clearance were found to significantly affect nevirapine apparent clearance. The estimated nevirapine apparent clearances were 2.95 liters/h, 2.62 liters/h, and 1.86 liters/h for CYP2B6 516GG, CYP2B6 516GT, and CYP2B6 516TT genotypes, respectively. The impact of creatinine clearance was small. This study demonstrates that 95% of the patients had sustained nevirapine exposure well above the 3,000-ng/ml threshold. Nevirapine clearance was shown to be affected by CYP2B6 516G>T genetic polymorphism and creatinine clearance, although this explained only part of the interpatient variability, which remains low compared to that for other antiretroviral drugs.In resource-limited settings, nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTI) are the WHO-recommended backbone of first-line antiretroviral therapy. At the time of the study, nevirapine in combination with two nucleoside analog inhibitors of reverse transcriptase such as stavudine and zidovudine, in addition to lamivudine, was the recommended antiretroviral regimen in treatment-naïve patients, mainly because of the availability of WHO-prequalified low-cost generic fixed-dose combinations (7, 27). In Cambodia, the prevalence of HIV infection among the general population aged between 15 and 49 years peaked at 2% in 1998 and declined to 0.9% in 2006. This decrease has been attributed to many deaths among people infected during the early years of the epidemic before implementation of the continuum of care and the scaling-up of HIV prevention, care, and treatment programs. At the end of 2009, it is estimated that about 37,000 patients were on antiretroviral drug regimens and 69.5% were on a nevirapine backbone regimen (National Center for HIV/AIDS, Dermatology and STD [NCHADS]; http://www.nchads.org/). Therefore, worldwide, most patients living with AIDS who need antiretr...

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“…The total number of PBMCs is the sum of the CD4 + and CD4 − cells. The former are available for the different studies (Barry et al, 1996;Aweeka et al, 2007;Flynn et al, 2007;Marier et al, 2007), while the latter has been set to 800 [10 6 cells/L] (based on an average total PBMC count of 1600 in healthy subjects, with a CD4 − fraction of ∼ 50%) (Bisset et al, 2004).…”

Section: Detailed Physiologically Based Pharmacokinetic Model Of Zidomentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic relationship of NRTIs and its connection to viral escape: An example based on zidovudine

Kleist¹,

Huisinga²

2009

European Journal of Pharmaceutical Sciences

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In HIV disease, the mechanisms of drug-resistance are only poorly understood. Incomplete suppression of HIV by antiretroviral agents is suspected to be a main reason. The objective of this in silico study is to elucidate the pharmacokinetic origins of incomplete viral suppression, exemplified for zidovudine (AZT) as a representative of the key class of nucleoside reverse transcriptase inhibitors (NRTIs). AZT, like other NRTIs, exerts its main action through its intracellular triphoshate (AZT-TP) by competition with natural thymidine triphosphate. We developed a physiologically based pharmacokinetic (PBPK) model describing the intracellular pharmacokinetics of AZT anabolites and subsequently established the pharmacokinetic-pharmacodynamic relationship. The PBPK model has been validated against clinical data of different dosing schemes. We reduced the PBPK model to derive a simple threecompartment model for AZT and AZT-TP that can readily be used in population analysis of clinical trials. A novel machanistic, and for NRTIs generic effect model has been developed that incorporates the primary effect of AZT-TP and potential secondary effect of zidovudine monophosphate. The proposed models were used to analyze the efficacy and potential toxicity of different dosing schemes for AZT. Based on the mechanism of action of NRTIs, we found that drug heterogeneities due to temporal fluctuations can create a major window of unsuppressed viral replication. For AZT, this window was most pronounced for a 600mg/once daily dosing scheme, in which insufficient viral suppression was observed for almost half the dosing period.

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Pharmacokinetics of Lamivudine, Zidovudine, and Nevirapine Administered as a Fixed‐Dose Combination Formulation Versus Coadministration of the Individual Products

Cited by 19 publications

References 19 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

Population Pharmacokinetic-Pharmacogenetic Study of Nevirapine in HIV-Infected Cambodian Patients

Pharmacokinetic–pharmacodynamic relationship of NRTIs and its connection to viral escape: An example based on zidovudine

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