Studies on the clinical pharmacology of antiretroviral agents
Sammanfattning: This thesis begins with an account of the development of the antiretroviral treatment paradigm for HIV infection, focusing on the emergence of present day principles of antiretroviral therapy (e.g., how to rationally combine drugs, the monitoring of treatment effect, the definition of treatment failure, and the use of ritonavir-boosting to augment drug exposure). The implications of the evolving treatment paradigm for drug development and the conduct of clinical trials are emphasized (e.g., the definition of study populations, the role of biomarkers and the definition of endpoints). Following this, the promises and limitations of therapeutic drug monitoring (TDM) of antiretrovirals is described, as well as the pharmacogenetics of HIV therapy, and the mechanisms of the substantial drug-drug interaction potential of some major antiretroviral agents. The introduction concludes with a discussion of the conduct, findings and implications of the four papers comprising the thesis, insofar as there is a need for justification or further comments beyond what is stated in the articles, or where important new data have appeared since the time of writing the papers. Paper 1 reports a study of the impact of pharmacogenetic variability at CYP3A on the metabolism of the HIV protease inhibitor (PI) saquinavir. This drug was shown to be a CYP3A5 substrate. Paper 2 describes a pilot study of ritonavir-boosted atazanavir maintenance monotherapy, which was prematurely terminated due to an excess of protocol-defined treatment failure. Atazanavir plasma drug concentrations did not predict failure in this study, though on-treatment serum bilirubin (an increase of which is an exposure dependent side effect of atazanavir) did. Paper 3 describes the effects of three different antiretroviral drug regimens (based on efavirenz, ritonavir-boosted atazanavir and ritonavir-boosted lopinavir) on the plasma concentration of 4b-hydroxycholesterol, a suggested endogenous marker of CYP3A activity. This marker performed according to hypothesis in the efavirenz and ritonavir/boosted atazanavir arms (increase and decrease, respectively, due to CYP3A induction and inhibition), but failed to clearly reflect the profound CYP3A inhibition in the ritonavir-boosted lopinavir arm. Paper 4 reports the relation of the plasma concentrations of efavirenz, atazanavir and lopinavir, and treatment outcome in the NORTHIV clinical trial in treatment-naïve patients. No relation of drug concentration and effects was demonstrated thought there was a trend towards a relation of plasma bilirubin and outcome in patients treated with atazanavir. It is concluded that: (a) Genetic variability in CYP3A5 is unlikely to have any measurable clinical impact on present day boosted PI regimens. (b) Though boosted PI maintenance monotherapy may be an option in selected patients, there are important concerns about, e.g., CNS penetration. Increasing PI doses beyond those presently recommended is unlikely to alter the efficacy of boosted PI monotherapy. (c) Plasma bilirubin is a useful marker for adherence in atazanavir-treated patients. (d) Routine TDM of antiretrovirals is not mandated.
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