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AimsTo study the population pharmacokinetics of nevirapine and to identify relationships between patient characteristics and pharmacokinetics in an unselected population of patients attending our outpatient clinic. Methods Ambulatory HIV-1-infected patients from the outpatient clinic of the Slotervaart Hospital who were being treated with a nevirapine-containing regimen were included. During each visit, blood samples were collected for the determination of nevirapine plasma concentrations and clinical chemistry parameters. Variables that were collected at baseline were serology for hepatitis B (HBV) and C (HCV) viruses, liver enzymes, and total bilirubin (TBR). In addition, information about concomitant use of St John's wort and patient demographics were included. The pharmacokinetics of nevirapine were described by first-order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (apparent clearance (CL/ F ), volume of distribution ( V / F ), absorption rate constant ( k a )) were estimated, as were interindividual, interoccasion, and residual variability in the pharmacokinetics. The influence of patient characteristics on the pharmacokinetics of nevirapine was determined.Results From 173 outpatients a total number of 757 nevirapine plasma concentrations at a single random time point and full pharmacokinetic curves for 13 patients were available resulting in a database of 1329 nevirapine plasma concentrations. Mean CL/ F , V / F , and k a were 3.27 l h -1 , 106 l, and 01.66 h -1 , respectively. CL/ F of nevirapine was correlated with weight, chronic HCV infection, and baseline aspartate aminotransferase (ASAT). Chronic HCV and baseline ASAT > 1.5 ¥ upper limit of normal (ULN) decreased CL/ F by 27.4% and 13.2%, respectively, whereas an increase in body weight of 10 kg increased CL/ F by 0.14 l h -1 . A trend towards a lower CL/ F in patients of the Negroid race was observed. No significant covariates were found for V / F . Conclusions The pharmacokinetics of nevirapine were adequately described by our population pharmacokinetic model. Weight, chronic HCV infection, and baseline ASAT were found to be significant covariates for CL/ F of nevirapine. The model incorporating these significant covariates may be an important aid in further optimizing nevirapine-containing therapy.

Several relationships have been reported between antiretroviral drug concentrations and the efficacy of treatment, and toxicity. Therefore, therapeutic drug monitoring (TDM) may be a valuable tool in improving the treatment of HIV-1-infected patients in daily practice. In this regard, several measures of exposure have been studied, e.g. trough and maximum concentrations, concentration ratios and the inhibitory quotient. However, it has not been unambiguously established which pharmacokinetic parameter should be monitored to maintain optimal viral suppression. Each pharmacokinetic parameter has its pros and cons. Many factors can affect the pharmacokinetics of antiretroviral agents, resulting in variability in plasma concentrations between and within patients. Therefore, plasma concentrations should be considered on several occasions. In addition, the interpretation of the drug concentration of a patient should be performed on an individual basis, taking into account the clinical condition of the patient. Important factors herewith are viral load, immunology, occurrence of adverse events, resistance pattern and comedication. In spite of the described constraints, the aim of this review is to provide a practical guide for TDM of antiretroviral agents. This article outlines pharmacokinetic target values for the HIV protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir, and the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine. Detailed advice is provided on how to interpret the results of TDM of these drugs.

Objective: To determine the incidence of rash in HIV-1 infected individuals starting a nevirapine-containing regimen in an unselected outpatient clinic population. Possible risk factors including plasma concentrations of nevirapine were evaluated for their relationship with the occurrence of a rash. Methods: The occurrence of rash was extracted from the outpatient medical records or based on a prescription of the antihistaminic cetirizine as documented by the community pharmacy within the first 90 days of nevirapine use. During regular visits to the clinic blood samples were collected for the determination of nevirapine plasma concentrations. Possible risk factors such as demographics, immunology, virology, clinical chemistry and antiretroviral pretreatment were collected at baseline for each patient. In addition, concomitantly used drugs during the nevirapine-based regimen were recorded. The association between these factors and the occurrence of rash was studied. Primary outcome was the onset of rash within the first 90 days after initiation of a nevirapinecontaining regimen. Results: Data from 216 HIV-1-infected patients were used in this study. Thirty-eight patients (17.6%) developed a rash of some grade that led to discontinuation of nevirapine in seven patients (3.2% of the included patients). The median time to occurrence of rash was 26 days (interquartile range 17-46 days). The multivariate analysis showed that patients pretreated with antiretroviral drugs less than 12 months before the initiation of a nevirapinecontaining regimen had a more than 2.5-fold increased risk of developing rash. Furthermore, nevirapine plasma concentrations were also significantly related to the occurrence of rash. A more than twofold increased risk for developing rash was observed for patients with nevirapine plasma concentrations above 5.3 mg/l. Conclusions: This is the first study demonstrating that patients with antiretroviral pretreatment less than 12 months and with nevirapine plasma concentrations above 5.3 mg/l during the first 90 days of treatment are at a higher risk for the development of rash. It is therefore advised to monitor this group of patients carefully when initiating nevirapine-containing therapy.

Objective: To evaluate the usefulness of intervention in drug interactions of antiretroviral drugs with coadministered agents by a clinical pharmacist in outpatient HIV-treatment. Methods: The study design included two intervention arms (A and B), which were both preceded by a control observation period. In arm A, a complete list of the currently used drugs, extracted from pharmacy records was provided to the treating physician. In arm B the same list was provided but with a notification when a drug interaction was present and an advice how to handle this. The infectious disease specialist obtained the information before the patient's visit to the outpatient clinic (time point 0). Three months prior (time point )3) and 3 months after (time point +3) the intervention, pharmacy records were also screened for drug interactions. The number of drug interactions (total and per patient) was determined at the three different time points ()3, 0, +3). In addition, drug interactions encountered at time points )3 and 0 were checked for their presence at time points 0 and +3, respectively, for both intervention arms. Results: Arms A and B included 115 and 105 patients, respectively. Patient characteristics of both intervention arms were similar at time point 0. The number of interactions and the number of patients with interactions were similar in both intervention arms at time point 0. There were 42 and 40 potential drug interactions in 30 and 24 patients in arms A and B, respectively. The reduction in the number of interactions per patient over time and after intervention was small but significant, and was equal in both intervention arms. The advice of the clinical pharmacist had thus no additional value. Conclusion: Both interventions were effective in reducing the number of drug interactions per patient. The advice of a clinical pharmacist was, however, redundant in the studied setting.