Pharmacokinetics Of Nevirapine Research Articles

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

The pharmacokinetics of 150 mg lamivudine, 300 mg zidovudine, and 200 mg nevirapine were assessed following single oral administration of a fixed-dose combination tablet and coadministration of the separate innovator products in healthy male subjects (n = 64) under fasting conditions in an open-label, randomized, 2-way crossover study. Multiple blood samples were collected up to 72 hours and plasma concentrations of antiretrovirals were assayed using liquid chromatography/tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods, and bioequivalence was assessed using an analysis of variance model. The ratio of the least squares mean (fixed-dose combination to individual products) and 90% confidence intervals of AUC(0-t), AUC(0-infinity), and C(max) for lamivudine, zidovudine, and nevirapine were all within 80.0% to 125.0%, suggesting a similar rate and extent of antiretroviral exposure in the bloodstream. Mean oral clearance (CL/F) values of lamivudine, zidovudine, and nevirapine for the fixed-dose combination were 23.7, 127, and 1.65 L/h, respectively. The fixed-dose combination and individual products were equally safe and well tolerated, with only a few subjects experiencing drug-related adverse events. The current fixed-dose combination of lamivudine, zidovudine, and nevirapine is expected to provide a similar efficacy/safety profile as coadministration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV.

CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children

Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited. In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases. NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01). The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

Steady-State Pharmacokinetics of Nevirapine in HIV-1 Infected Adults in India

A variety of demographic factors, sex, and degree of immunosuppression can influence antiretroviral drug concentrations. The authors studied the influence of immune status, sex, and body mass index (BMI) on the steady-state pharmacokinetics of nevirapine delivered as a fixed-dose combination in HIV-1-infected patients in India. Twenty-six HIV-1-infected adult patients undergoing treatment with nevirapine-based highly active antiretroviral therapy regimens participated in the study. Pharmacokinetic variables were compared between patients divided based on CD4 cell counts, sex, and BMI. Patients with higher BMI had lower peak and trough concentration and exposure of nevirapine than those with lower BMI; none of the differences in the pharmacokinetic variables of nevirapine between the various patient groups was statistically significant. Patients' immune status, sex, or BMI had no impact on the pharmacokinetics of nevirapine. Plasma nevirapine concentrations were maintained within the therapeutic range of the drug in the majority of the patients.

A liquid chromatography/atmospheric pressure ionization tandem mass spectrometry quantitation method for nevirapine and its two oxidative metabolites, 2‐hydroxynevirapine and nevirapine 4‐carboxylic acid, and pharmacokinetics in baboons

A rapid highly sensitive and specific electrospray ionization (ESI) liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantification of nevirapine (NVP) and its two metabolites, 2-hydroxynevirapine (2-OHNVP) and nevirapine 4-carboxylic acid (4-CANVP), in baboon serum was developed and validated. Nevirapine, 2-OHNVP, 4-CANVP, and the internal standard, hesperetin, were extracted from baboon serum with ethyl acetate. Components in the extract were separated on a 50 x 2.1 mm Aquasil C(18) 5 microm stainless steel column by isocratic elution with 40% acetonitrile/0.1% formic acid at a flow rate of 0.2 mL/min. The liquid flow was passed through a pre-source splitter and 5% of the eluant was introduced into the atmospheric pressure ionization (API) source. The components were analyzed in the multiple-reaction monitoring (MRM) mode as the precursor/product ion pair of m/z 267.2/226.2 for NVP, 283.0/161.2 for 2-OHNVP, 297.2/279.2 for 4-CANVP, and 303.2/177.2 for hesperetin. Linear calibration curves were obtained in the range of 1-1000 ng/mL for NVP and 2-OHNVP and 5-1000 ng/mL for 4-CANVP, using 0.2 mL baboon serum, respectively. The within-day and between-day precisions were <10% for NVP and 2-OHNVP, and <11.5% for 4-CANVP. Due to the similar structures and fragmentation patterns of 2-OHNVP and 3-OHNVP, it is not expected that the LC/MS/MS can differentiate 2-OHNVP and 3-OHNVP and they were assayed as a composite. The method was applied to a single-dose escalation study of NVP in non-pregnant baboons (Papio anubis) to characterize the pharmacokinetics of NVP, 2-OHNVP plus 3-OHNVP, and 4-CANVP, and to determine the appropriate dose necessary to achieve comparable peak serum concentration of NVP as reported in healthy human adults.

Safety Issues About Nevirapine Administration in HIV-Infected Pregnant Women

Nevirapine represents an effective and well-tolerated nonnucleoside reverse transcriptase inhibitor (NNRTI) that is broadly available to prevent vertical HIV transmission in resource-poor populations. Even after its removal from firstline antiretroviral drugs for drug-naive patients nevirapine is widely and safely used in simplification regimens. The latest guidelines for antiretroviral therapy (updated on October 10 20061) also state that nevirapine pharmacokinetics are not significantly affected by pregnancy such that no dosage change is indicated in this condition. Unfortunately although nevirapine has not been shown to cause fetal malformations some reports point out that women whose CD4+ counts are greater than 250 cells/mL when they first initiate therapy may face an increased risk of potentially fatal liver toxicity which is often associated with rash. A 2005 warning from the US Food and Drug Administration (FDA) recommended maximum attention on a possible increase of nevirapine liver toxicity among HIV-infected women with CD4+ counts >250 cells/mL especially during pregnancy. (excerpt)

Pharmacokinetic study of the interaction between itraconazole and nevirapine

To investigate the drug interaction potential between itraconazole and nevirapine. Our study was conducted in 12 healthy volunteers in two phases. In phase 1 (from days 1-28), all subjects were randomly assigned to a two-way crossover study of a nevirapine regimen (nevirapine 200 mg once daily for 7 days) and an itraconazole regimen (itraconazole 200 mg once daily for 7 days) with a 14-day wash-out period between. Phase 2 (from days 43-49) was performed 14 days after phase 1 ended, and all subjects received a combination regimen (nevirapine 200 mg combined with itraconazole 200 mg once daily for 7 days). Nevirapine pharmacokinetic studies were carried out starting with the seventh dose of nevirapine in the nevirapine regimen (on days 7-10 or 28-31) and the combination regimen (on days 49-52). Itraconazole pharmacokinetic studies were carried out starting with the seventh dose of itraconazole in the itraconazole regimen (on days 7-10 or 28-31) and the combination regimen (on days 49-52). There was no significant difference in nevirapine pharmacokinetic parameters between the nevirapine and combination regimens. Itraconazole plasma concentrations were lower when it was administered in the combination regimen than when it was administered in the itraconazole regimen. The mean C(max), AUC(0-96) and t (1/2) of itraconazole were significantly reduced by 38, 61 and 31%, respectively. Nevirapine had a strong inducing effect on the metabolism of itraconazole, but there was no significant effect of itraconazole on the pharmacokinetics of nevirapine. However, a higher daily dosage of itraconazole might have an inhibitory effect.

Increasing Nevirapine Dose Can Overcome Reduced Bioavailability Due to Rifampicin Coadministration

We studied the effect of rifampicin on steady-state pharmacokinetics of nevirapine and the impact of increasing the dose of nevirapine on its peak (Cmax) and trough (Cmin) levels in 13 HIV-infected patients on regular antiretroviral treatment with nevirapine-containing regimens (200 mg twice daily). A baseline pharmacokinetic study was conducted and repeated after 1 week of daily rifampicin (450/600 mg). The study was repeated in 7 of 8 patients who had subtherapeutic Cmin nevirapine levels after increasing nevirapine dose to 300 mg twice daily. Liver function was monitored. Rifampicin caused significant reductions in Cmax (42%), Cmin (53%), and exposure (46%) of nevirapine (P <.01). The Cmin of nevirapine fell below the therapeutic range of 3 microg/ml in 8 of 13 patients. An increase of nevirapine to 300 mg twice daily raised Cmin to therapeutic range in all 7 patients without exceeding the toxic level of 12 microg/mL. There were no clinical or laboratory adverse events. Our findings suggest that decreased bioavailability of nevirapine because of rifampicin coadministration could be overcome by increasing the dose of nevirapine from 200 to 300 mg twice daily without short-term adverse events. Further studies to evaluate the long-term safety of higher dose of nevirapine are required.

A comparison of the steady-state pharmacokinetics of nevirapine in men, nonpregnant women and women in late pregnancy.

To evaluate the pharmacokinetics of nevirapine and any possible influencing factors in pregnant women (n = 16), nonpregnant women (n = 13) and men (n = 14), who received nevirapine 200 mg twice daily together with nucleoside reverse transcriptase inhibitors. Blood samples were taken for 12 h at steady state. Nevirapine concentrations were measured by liquid chromatography-tandem mass spectrometry. The influence of gender, age, body weight and comedication on minimum and maximum concentrations (C(min), C(max)), area under the concentration-time curve (AUC), total clearance (CL(tot)), half-life (t(1/2)) and volume of distribution (V(d)) was analysed by multivariate techniques. Mean [95% confidence interval (CI)]C(max), AUC(ss) and clearance were 5221 ng ml(-1) (4267, 6175), 50 789 ng (-1)h ml(-1) (43 453, 58 125) and 69.9 ml min(-1) for men, 5871 ng ml(-1) (4848, 6895), 57 045 ng h(-1) ml(-1) (45 997, 68 093) and 65.6 ml min(-1) for nonpregnant women and 4505 ng ml(-1) (3644, 5366), 44 579 ng h(-1) ml(-1) (36 564, 52 594) and 82.1 ml min(-1) for pregnant women. The differences between pregnant and nonpregnant women (% difference, 95% CI) in C(max) (-30.3; -28.5, -33.0), AUC(ss) (-28.0; - 25.8, - 29.5) and clearance (20.2; 26.6, 15.6) reached statistical significance (P = 0.010, P = 0.028 and P = 0.028, respectively). The multivariate analysis underscored the influence of bodyweight on the plasma exposure to nevirapine. Pregnant women exhibited an increased nevirapine clearance and comparably low plasma concentrations, whereas women with a low bodyweight achieved high plasma nevirapine concentrations. The large variability in nevirapine concentrations in women may lead to loss of efficacy and viral resistance, or drug toxicity, and therefore these patients should be monitored frequently.

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

Objective: As part of the large international, randomized 2NN trial, the pharmacokinetics of nevirapine in once-daily 400 mg and twice-daily 200 mg dosing regimens were investigated. Method: Treatment-naive HIV-1-infected patients were randomized to receive nevirapine 400 mg once daily or 200 mg twice daily, in combination with lamivudine and stavudine. Blood samples were collected at several time-points (day 3, weeks 1, 2, 4, 24, and 48). Differences in pharmacokinetics between once- versus twice-daily dosing were investigated with nonlinear mixed effects modelling (NONMEM). Results: In total, 2,899 nevirapine plasma concentrations were available from 578 patients. Dosage and dosing frequency did not influence clearance or volume of distribution of nevirapine, indicating linear pharmacokinetic behavior of nevirapine whether given as a single daily dose or as divided doses over 24 hours. During steady state, the Cmin was lower (3.26 mg/L vs. 4.44 mg/L; p < .001) and the Cmax was higher (7.88 mg/L vs. 6.55 mg/L; p < .001) in the once-daily arm. However, compared to total variability in nevirapine levels for both treatments, these differences were minor. During steady state, total exposure, measured as AUC24h, was comparable for both regimens (133 mg/L*h vs. 133 mg/L*h; p = .084). Conclusion: The daily exposure to nevirapine (AUC24h) was similar for the 400 mg once-daily and the 200 mg twice-daily dosing regimens. The Cmin of nevirapine is lower and the Cmax of nevirapine is higher for the once-daily regimen as compared to the twice-daily regimen. As a result, 200 mg nevirapine dosed twice daily may be preferred over 400 mg nevirapine dosed once daily.

Pharmacokinetics of nevirapine in HIV-infected children receiving an adult fixed-dose combination of stavudine, lamivudine and nevirapine

To evaluate the steady state pharmacokinetics of nevirapine (NVP) in HIV-infected children receiving a fixed-dose combination of stavudine, lamivudine and NVP. This cross-sectional study enrolled 34 children (18 girls) who had received GPO-VIR S30 (30 mg stavudine, 150 mg lamivudine and 200 mg NVP) for at least 8 weeks. Tablets were divided into quarter fractions (1/4, 1/2, 3/4 or 1 tablet) to attain the NVP dosages of 120-200 mg/m every 12 h. Plasma NVP levels were measured at predose, and at 2 and 6 h after drug administration. The median age was 8.4 years (range, 3-15). Median CD4 lymphocyte count and percentage at study entry was 576 x 10 cells/l and 20.25%, respectively. The median pharmacokinetics parameters were area under the curve at 12 h, 78.4 h x mug/ml; minimum plasma drug concentration, 5.98 microg/ml; plasma half-life, 25.5 h; apparent oral clearance, 0.079 l/kg per h; and volume of distribution, 2.95 l/kg. Only one child had a minimum plasma drug concentration < 3.4 microg/ml (2.57 microg/ml). Of the 13 children who received GPO-VIR as their first-line regimen, 12 had plasma HIV-1 RNA < 400 copies/ml at 6-18 months, with a median CD4 lymphocyte increase of 216 and 433 x 10 cells/l at 6 and 12 months of treatment, respectively. The administration of GPO-VIR S30 fixed-dose combination tablets in fractions or as a whole tablet to children resulted in appropriate NVP exposure and satisfactory virological and immunological benefit. This finding confirms the effectiveness of using a fixed-dose combination as a "transitional option" while waiting for a paediatric fixed-dose combination drug formulation.

Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals

Plasma concentrations of nevirapine have been linked to human immunodeficiency virus (HIV) treatment outcome. However, because the site of action of nevirapine is within HIV-infected cells, intracellular concentrations may better relate to antiviral exposure. Investigation of factors that alter the intracellular pharmacokinetics of nevirapine may also aid in our understanding of therapeutic failure. Our objective was to determine intracellular (or cell-associated) nevirapine concentrations over the full dosing interval and to relate protein binding and P-glycoprotein (P-gp) expression to intracellular exposure. Plasma and peripheral blood mononuclear cells were isolated from blood samples taken from 10 HIV-infected patients at 0, 2, 4, 8, and 12 hours after dosing. Intracellular and plasma (total and unbound) concentrations were determined by liquid chromatography-tandem mass spectrometry, and the ratios of intracellular to total plasma exposure (area under the concentration-time curves) were calculated. P-gp expression was measured by flow cytometry. The median intracellular accumulation ratio was 0.005 (range, 0.001-0.054) and remained unchanged over the dosing interval. There was an association between higher plasma concentrations and lower cellular concentrations of nevirapine (total r(2) = 0.62, P = .007). There was no relationship between percent unbound nevirapine and intracellular nevirapine. There was a correlation between higher plasma nevirapine exposure and higher P-gp expression (r(2) = 0.77, P = .03), whereas intracellular nevirapine exposure decreased with higher P-gp expression (r(2) = 0.62, P = .01). The intracellular accumulation of nevirapine was low, did not change over the dosing interval, and was not related to protein binding. In this small study, cells with higher P-gp expression had lower cellular concentrations of nevirapine. Further studies are required to explore the influx and efflux transporter profile of this drug.

No pharmacokinetic drug???drug interaction between nevirapine and paclitaxel

We have investigated the pharmacokinetics of nevirapine and paclitaxel in a patient who used both drugs concomitantly, as there are strong theoretical indications for a potential pharmacokinetic drug-drug interaction. Plasma concentrations of nevirapine (dose: 200 mg twice daily orally) and paclitaxel (dose: 100 mg/m(2) 3-h i.v. infusion) were determined in a HIV-1-infected patient with Kaposi's sarcoma. Since both drugs are metabolized via the same cytochrome P450 isoenzymes, investigation of a drug-drug interaction was considered important. We found that the plasma concentrations of nevirapine given together with paclitaxel were similar to those given without paclitaxel. The exposures to paclitaxel (AUC(0-infinity) = 3787 h.ng/ml) and its hydroxy metabolites when co-administered with nevirapine were comparable to the mean exposure to paclitaxel and its metabolites from eight historical controls (AUC(0-infinity) = 3614 h.ng/ml) treated with the same dose. No pharmacokinetic drug-drug interaction between nevirapine and paclitaxel could be demonstrated in our HIV-1-infected patient.

Nevirapine and Efavirenz Pharmacokinetics and Covariate Analysis in the 2Nn Study

The aim of this 2NN pharmacokinetic substudy was to investigate the population pharmacokinetics of nevirapine and efavirenz. Treatment-naive, HIV-1-infected patients received nevirapine (once or twice daily), efavirenz or a combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Using non-linear mixed effects modelling, pharmacokinetics of nevirapine and efavirenz and factors involved in the inter-individual variability were investigated. Clearance of nevirapine in the induction phase (<14 days) and at steady state (>28 days) were 2.02 I/h and 2.81 I/h, respectively. Volume of distribution and absorption rate constant were 77.0 l and 1.66 h(-1), respectively. Clearance of nevirapine was lower in females (13.8%) and in patients with hepatitis B (19.5%). Patients from South America and Western countries had higher clearance of nevirapine compared with Thai and South African patients. The clearances of efavirenz in the induction phase and at steady state were 7.95 l/h and 8.82 l/h, respectively. The volume of distribution and absorption rate constant were 4181 and 0.287 h(-1), respectively. Concomitant use of nevirapine increased clearance of efavirenz (43%). Patients from Thailand had lower clearance than the rest of the population. The population pharmacokinetics of nevirapine and efavirenz were assessed in the 2NN trial. For both drugs, an induction phase was distinguished from the steady-state phase. Gender, hepatitis B and geographical region were involved in the variability of the pharmacokinetics of nevirapine. Region and concomitantly used nevirapine were determinants of the pharmacokinetics of efavirenz.

Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients

Efavirenz (EFV) and nevirapine (NVP) are metabolized by cytochrome P450 2B6 (CYP2B6). Allele 516 G>T (Gln172His) is associated with diminished activity of this isoenzyme, and may lead to differences in drug exposure. We evaluated this allele as a pharmacogenetic marker of EFV and NVP pharmacokinetics and EFV toxicity in 167 participants receiving EFV and 59 receiving NVP recruited within the genetics project of the Swiss HIV Cohort Study. Drug concentrations were measured in plasma and in peripheral blood mononuclear cells (PBMCs) from the same sample. Neuropsychological toxicity of EFV (sleep disorders, mood disorders, fatigue) was assessed using a standardized questionnaire. CYP2B6 516TT was associated with greater plasma and intracellular exposure to EFV, and greater plasma exposure to NVP. Intracellular drug concentration, and CYP2B6 genotype were predictors of EFV neuropsychological toxicity. CYP2B6 genotyping may be useful to complement an individualization strategy based on plasma drug determinations to increase the safety and tolerability of EFV.

No relationship between high nevirapine plasma concentration and hepatotoxicity in HIV-1-infected patients naive of antiretroviral treatment or switched from protease inhibitors.

A prospective population pharmacokinetic study of nevirapine (NVP) was performed to test the relationship between hepatotoxicity and NVP trough plasma concentration and to identify which covariates could influence NVP pharmacokinetics. All patients [77 HIV-1 (human immunodeficiency virus type 1)-infected patients (128 samples)] were either on first-line antiretroviral therapy or switched from successful therapy containing protease inhibitor. Population pharmacokinetic parameters were estimated by a non-linear mixed-effect modelling method. Hepatotoxicity was evaluated by ASAT (aspartate aminotransferase) plasma level. No correlation was found between high NVP trough plasma concentration and high ASAT level or the increase of ASAT level on NVP therapy. Age and Caucasian race were found to be significant covariates of NVP clearance (Cl/F). Population pharmacokinetic parameters (rate absorption constant=1.04 h(-1); Cl/F=3.31 h(-1); apparent volume of distribution=92 l) are consistent with previous studies. High NVP trough plasma concentrations are not correlated with hepatotoxicity in our population. NVP clearance is decreased in the elderly patients, suggesting a potential increase of NVP plasma level and the interest of therapeutic drug monitoring for this population.

Sex differences in nevirapine disposition in HIV-infected patients.

To evaluate the role of sex in nevirapine pharmacokinetics, we analysed the pharmacokinetic profile of nevirapine in 11 male and 11 female HIV-positive patients chronically treated with nevirapine 400 mg once a day. Statistically significant inter-group differences in the plasma concentration and fluctuations between that and the concentration just before the next dose, at steady-state, were observed. Variations in lean body mass and composition affecting nevirapine distribution might account for inter-sex discrepancies in nevirapine plasma levels.

Introduction

This supplement summarizes presentations made at the Spring Symposium sponsored by Boehringer Ingelheim International entitled Optimising HIV Treatment - Building on Experience. It took place at the Alcora Hotel, Seville, Spain, on 15 March 2002. The aim of the symposium was to provide an overview of the field of HIV/AIDS with a particular emphasis on the non-nucleoside reverse transcriptase inhibitor, nevirapine. The mechanism of action, resistance profile and pharmacokinetics of nevirapine were reviewed by Drs Wainberg and Back. Three presentations, by Drs Murphy, Mayers and Dieterich, focused on the safety profile of nevirapine, especially recently obtained hepatic safety data about the drug. Drs Lange and Harris discussed a number of clinical studies that have demonstrated the safety and efficacy of nevirapine in two very different patient populations: antiretroviral naïve and treatment experienced patients. Dr Rockstroh addressed the complex issues involved in managing hepatitis B and C infections in HIV co-infected patients. Single dose nevirapine has been shown to be effective in preventing mother-to-child transmission of HIV-1. Dr Sullivan presented these data and outlined the issues that need to be resolved in order to ensure that HIV-infected mothers can have healthy children, in both the developed and developing world, as well as the chance of improving their own health. Concerns have been growing about the potential risk of cardiovascular disease in HIV-infected patients taking antiretroviral drugs. Dr Carr put these into perspective by summarizing the current status of this area. Dr Clotet then described the effect of nevirapine on a number of lipid parameters, including high density lipoprotein (HDL) cholesterol and triglycerides, in both antiretroviral naïve and protease-inhibitor-experienced patients. The effects of antiretroviral therapy on mitochondrial function are another growing area of concern, reviewed by Dr Montaner. He also described a novel experimental assay that is currently under evaluation to further characterize and possibly monitor mitochondrial toxicity. The last two presentations focused on future treatment options for patients with HIV/AIDS. Dr Yeni presented preclinical and early clinical data on tipranavir, a novel non-peptidic protease inhibitor, and Dr Vella discussed future treatment perspectives in the field. The symposium was very stimulating and we trust that you find this supplement a useful and educational record of the event. Editors and Co-chairs of the Symposium: David Cooper (Australia) Joep Lange (The Netherlands) Julio Montaner (Canada)

Short communication: interactions between nevirapine plasma levels, chronic hepatitis C, and the development of liver toxicity in HIV-infected patients.

Both chronic hepatitis C and nevirapine (NVP) use are risk factors for transaminase elevation under highly active antiretroviral therapy. NVP is metabolized in the liver and its clearance could be altered in the presence of chronic hepatitis C virus (HCV) infection, enhancing the risk of liver toxicity. We examined NVP plasma levels in 70 HIV-infected subjects receiving NVP-containing triple combinations. The median (range) NVP plasma trough concentrations were similar in 32 HCV antibody-positive and 38 HCV antibody-negative patients (5.8 [0.7-29] vs. 6.1 [0.9-9.6] microg/ml). Thus, HCV coinfection itself does not seem to influence significantly the pharmacokinetics of NVP in HIV-infected subjects.

Drug Interaction of Fluvoxamine and Fluoxetine with Nevirapine in HIV-1-Infected Individuals

To evaluate the possible pharmacokinetic interactions between nevirapine and fluvoxamine or fluoxetine in patients with HIV-1 infection. Patients who were using fluvoxamine or fluoxetine concomitantly were chosen from an unselected cohort (n = 173) of HIV-1-infected individuals using a nevirapine-containing regimen (study group). HIV-1-infected patients using nevirapine without fluvoxamine or fluoxetine and non-HIV-infected individuals who were using fluvoxamine and fluoxetine were included as controls. The influence of fluvoxamine and fluoxetine on the pharmacokinetics of nevirapine was investigated with a previously developed population pharmacokinetic model. Concomitant use of fluvoxamine or fluoxetine was tested independently as covariate for apparent clearance (CL/F) of nevirapine using nonlinear mixed-effect modelling (NONMEM). Furthermore, to explore the influence of nevirapine on the pharmacokinetics of fluvoxamine and fluoxetine, dose-normalised concentrations of fluvoxamine and fluoxetine from the study group were compared with those of the controls. Of the 173 HIV-1-infected individuals, 14 were using fluoxetine (n = 7) or fluvoxamine (n = 7) simultaneously with nevirapine. In addition, 17 and 29 individuals were identified as controls for the fluoxetine- and fluvoxamine-group, respectively. Concomitant use of fluvoxamine resulted in a significant reduction of 33.7% in CL/F of nevirapine; this reduction in CL/F appeared to be dose-dependent. Concomitant use of fluoxetine had no influence on the pharmacokinetics of nevirapine. Conversely, nevirapine significantly lowered plasma levels of fluoxetine plus norfluoxetine (seproxetine). In contrast, no significant difference was observed in dose-normalised concentrations of fluvoxamine when the controls were compared with the study group. We advise that special attention is paid to HIV-1-infected indivi-duals using a nevirapine-containing regimen and fluvoxamine or fluoxetine con-comitantly, since pharmacokinetic interactions have been observed.

Population pharmacokinetics of nevirapine in an unselected cohort of HIV-1-infected individuals

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor that is frequently used as part of the currently recommended combination therapy in the treatment of HIV-1 infection. NVP has been proven to be safe and effective, but when administered in suboptimal regimens, highly drug-resistant virus emerges rapidly limiting future options for treatment. Patient characteristics (e.g. demographics, co-morbidity) may have a large impact on the pharmacokinetics of nevirapine. Therefore, we explored the population pharmacokinetics of NVP in an unselected cohort of HIV-1-infected individuals. Included patients were ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, The Netherlands. Data were retrospectively collected from January 1997 to April 2000. The pharmacokinetics of NVP were described with a one-compartment model with first-order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (clearance (CL/F), volume of distribution (V/F), absorption rate constant (Ka)) were estimated. Interindividual (IIV) and interoccasion variability (IOV) were estimated with a proportional error model. Furthermore, the influence of patient characteristics on the pharmacokinetics of NVP were determined. From a small fraction of patients, baseline liver function test results were not available. In order to avoid bias, a covariate was included in the model indicating missing data. From 173 outpatients a total number of 757 NVP plasma concentrations at a single random timepoint and full pharmacokinetic curves of 13 patients were available resulting in a database of 1329 NVP plasma concentrations. CL/F of NVP was 3.49 l h−1 with an IIV and IOV of 28 and 21%, respectively. V/F was 93.1 l (IOV=46%) and the Ka was 1.65 h−1 (IIV=60%). CL/F of NVP was correlated with weight (WT), chronic hepatitis C infection (HepC), ASAT>1.5×upper limit of normal (ULN) at baseline, and the black race (RACE). These correlations are described by the following equation: CL/F=(3.49+0.0205×[WT-70])×0.483HepC× 0.66ASAT×(1−MISS)×0.671MISS×0.731RACE, in which HepC is 1 for individuals with hepatitis C infection and 0 for all others, ASAT is 1 for patients with baseline ASAT>1.5×ULN and 0 for all others, MISS is 1 for patients with no baseline ASAT value and 0 for all others, and RACE is 1 for black patients and 0 for all others. Thus, HepC, ASAT>1.5×ULN, and the black race reduce CL/F of NVP by 52%, 34%, and 27%, respectively, whereas an increase in WT of 10 kg increases the CL/F by 0.21 l h−1. The pharmacokinetics of NVP were adequately described with the developed population pharmacokinetic model. Weight, chronic hepatitis C infection, baseline ASAT>1.5×ULN, and the black race were found to be significant covariates for CL/F of NVP. The described model including these significant covariates could be an aid in optimizing NVP-containing therapy.