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Clinical pharmacological investigations of antiretroviral drugs

By B.S. Kappelhoff


The major aim of all studies described in this thesis is to contribute to the optimisation of antiretroviral drug treatment in HIV-infected patients by the assessment and interpretation of pharmacokinetic characteristics of antiretroviral drugs. In the first chapter the current knowledge on the relationships between pharmacokinetics and treatment outcomes is summarised into practical guidelines for TDM. In subsequent chapters the pharmacokinetics of selected PIs and NNRTIs are studied in representative patient populations. Moreover, determinants of pharmacokinetic variability are assessed. Several studies have been performed in view of the large international randomised 2NN study. This was the first study to compare the safety and efficacy of nevirapine and efavirenz containing regimens in treatment-naive HIV-1-infected patients. Within this trial, several clinical pharmacological substudies were performed. A requirement to perform these substudies is the availability of validated bioanalytical methods to assess quantitatively plasma concentrations of nevirapine and efavirenz. In this thesis, the development and validation for the simultaneous determination of the NNRTIs efavirenz and nevirapine in human plasma is described. Afterwards, population pharmacokinetics of nevirapine and efavirenz and its determinants were characterised in several studies. In addition, relationships between the pharmacokinetics and adverse events were investigated. Altogether, the results of these studies may contribute further to the safe and effective treatment of HIV-infected individuals

Topics: Farmacie, HIV, antiretroviral drugs, non-nucleoside reverse transcriptase inhibitor, NNRTI, protease inhibitor, PI, (population) pharmacokinetics, (clinical) pharmacology, NONMEM, bioanalysis, 2NN study
Publisher: Utrecht University
Year: 2005
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