Nonnucleoside Reverse Transcriptase Inhibitor Pharmacokinetics in a Large Unselected Cohort of HIV-Infected Women

Gandhi, Monica; Benet, Leslie Z.; Bacchetti, Peter; Kalinowski, Ann; Anastos, Kathryn; Wolfe, Alan R.; Young, Mary; Cohen, Mardge H.; Minkoff, Howard; Gange, Stephen J.; Greenblatt, Ruth M.

doi:10.1097/qai.0b013e31819c3376

Cited by 23 publications

(28 citation statements)

References 44 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: 81%

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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: 81%

“…Its pharmacokinetic characteristics include a long plasma half-life after single-dose administration which decreases with repeated doses due to autoinduction of its biotransformation (6,(9)(10)(11). Nevirapine is 60% bound to plasma proteins, and elimination occurs mainly through oxidative metabolism.…”

mentioning

confidence: 99%

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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“…A relationship between nevirapine clearance and creatinine clearance was unexpected as nevirapine is eliminated mostly by biotransformations. Such a relationship was noted by Gandhi et al (17) in a cohort of HIV-infected women, and they sug- gested that the effect of uremic toxins on relevant hepatic transporters and metabolizing enzymes may explain the influence of renal insufficiency on nevirapine clearance. However, the clinical relevance of this phenomenon is small as the major changes were less than 20% from the mean.…”

Section: Discussionmentioning

confidence: 80%

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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“…This could be a consequence of nevirapine toxicity and adherence [13]. Cost is an important factor in the choice of an efavirenzcontaining vs. a nevirapine-containing regimen [14].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of treatment outcomes for patients on first‐line regimens in US President's Emergency Plan for AIDS Relief (PEPFAR) clinics in Uganda: predictors of virological and immunological response from RV288 analyses

et al. 2014

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ObjectivesViral load (VL) monitoring is recommended, but seldom performed, in resource-constrained countries. RV288 is a US President's Emergency Plan for AIDS Relief (PEPFAR) basic programme evaluation to determine the proportion of patients on treatment who are virologically suppressed and to identify predictors of virological suppression and recovery of CD4 cell count. Analyses from Uganda are presented here. MethodsIn this cross-sectional, observational study, patients on first-line antiretroviral therapy (ART) (efavirenz or nevirapine + zidovudine/lamivudine) from Kayunga District Hospital and Kagulamira Health Center were randomly selected for a study visit that included determination of viral load (HIV-1 RNA), CD4 cell count and clinical chemistry tests. Subjects were recruited by time on treatment: 6-12, 13-24 or > 24 months. Logistic regression modelling identified predictors of virological suppression. Linear regression modelling identified predictors of CD4 cell count recovery on ART. ResultsWe found that 85.2% of 325 subjects were virologically suppressed (viral load < 47 HIV-1 RNA copies/ml). There was no difference in the proportion of virologically suppressed subjects by time on treatment, yet CD4 counts were higher in each successive stratum. Women had higher median CD4 counts than men overall (406 vs. 294 cells/μL, respectively; P < 0.0001) and in each time-on-treatment stratum. In a multivariate logistic regression model, predictors of virological suppression included efavirenz use [odds ratio (OR) 0.47; 95% confidence interval (CI) 0.22-1.02; P = 0.057], lower cost of clinic visits (OR 0.815; 95% CI 0.66-1.00; P = 0.05), improvement in CD4 percentage (OR 1.06; 95% CI 1.014-1.107; P = 0.009), and care at Kayunga vs. Kangulamira (OR 0.47; 95% CI 0.23-0.92; P = 0.035). In a multivariate linear regression model of covariates associated with CD4 count recovery, time on highly active antiretroviral therapy (ART) (P < 0.0001), patient satisfaction with care (P = 0.038), improvements in total lymphocyte count (P < 0.0001) and haemoglobin concentration (P = 0.05) were positively associated, whereas age at start of ART (P = 0.0045) was negatively associated with this outcome. ConclusionsHigh virological suppression rates are achievable on first-line ART in Uganda. The odds of virological suppression were positively associated with efavirenz use and improvements in CD4 cell percentage and total lymphocyte count and negatively associated with the cost of travel to The US President's Emergency Plan for AIDS Relief (PEPFAR), launched in 2002, has played a major role in the rapid scale-up of and expanded access to ART in resourcelimited countries, particularly in sub-Saharan Africa. In the opening session of the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013), Dr Thomas Frieden, Director of the Centers for Disease Control and Prevention (CDC), articulated the goals of interventions in the global HIV epidemic, stating, 'the proportion of patients with viral suppression should be the p...

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Nonnucleoside Reverse Transcriptase Inhibitor Pharmacokinetics in a Large Unselected Cohort of HIV-Infected Women

Cited by 23 publications

References 44 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

Evaluation of treatment outcomes for patients on first‐line regimens in US President's Emergency Plan for AIDS Relief (PEPFAR) clinics in Uganda: predictors of virological and immunological response from RV288 analyses

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