clinical pharmacokinetics; metabolite profiling; antiretrovirals; pharmacogenetics; liquid chromatography tandem mass spectrometry; drug-drug interactions; personalized medicine; HCV protease inhibitors; large nested project; Swiss HIV Cohort Study
Barcelo Catalina, Aouri Manel, Courlet Perrine, Guidi Monia, Braun Dominique L, Günthard Huldrych F, Piso Rein J, Cavassini Matthias, Buclin Thierry, Decosterd Laurent A, Csajka Chantal, Anagnostopoulos A, Battegay M, Bernasconi E, Böni J, Braun D L, Bucher H C, Calmy A, Cavassini M, Ciuffi A, Dollenmaier G, Egger M, Elzi L, Fehr J, et al. (2019), Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting, in Journal of Antimicrobial Chemotherapy
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Coordinated research projects integrating basic and applied pharmacogenetic, pharmacokinetic and pharmacodynamic aspects of HIV therapeutics remain a high priority because of the prevalence of toxicity, the life-long nature of treatment, and the complexity inherent to multidrug therapy. Genetic and non-genetic factors influence drug exposure, toxicity and clinical response to therapy. Pharmacogenetics has a profound impact on our current understanding of the variability observed in drug exposure (pharmacokinetics), clinical response and toxicity (pharmacodynamics). However, the important interindividual pharmacokinetic variability observed for antiretroviral agents is not only explained by pharmacogenetic predisposition affecting drug’s transport and metabolism, but also by pathophysiological conditions and by environmental influences, including co-administered drugs.Over the last funding period we have:1.Stengthened our technical methodologies (mass spectrometry facility for antiretroviral drugs and metabolites profiles analysis, massive and facilitated access to integrated pharmacology and genetics databases, population pharmacokinetics expertise (NONMEM) and pharmacogenetics plateforms for high throughput genotyping and genome analysis). 2.Completed coordinated research projects integrating basic and applied pharmacogenetic, pharmacokinetics and pharmacodynamic aspects of HIV therapy.The present proposal aims at pursuing and expanding our research program on complex gene-drug-environmental interplay relevant to antiviral treatment in HIV-infected patients. Specifically, coinfection with the Hepatitis C Virus (HCV) is common in HIV-infected individuals; these patients will be increasingly treated by the latest generation of HCV protease inhibitors (HCV-PI). These new molecules have a high potential of drug interactions.The successful exploitation of the Swiss HIV Cohort Study (SHCS) Pharmacology database from the National Therapeutic Drug Monitoring Service focusing on new antiretroviral drugs will be reinforced by prospective clinical studies realized within the framework of the SHCS, integrating the clinical pharmacokinetics/dynamics and (pharmaco)genetics analysis of first-line antiretroviral regimen in treatment-naïve HIV patients, and of the novel HCV-PI-based therapy in HIV/HCV co-infected patients. Thus, the current proposal addresses the:1.Development of population pharmacokinetic /pharmacogenetics models for the newest antiretroviral and antiviral drugs2.Clinically relevant issues of drug interactions between antiretroviral agents and new HCV-PIs 3.Translation into clinical trials aiming at validating the usefulness of optimized pharmacokinetic and pharmacogenetic tools for personalized drug prescription. The project aims at responding to clinically relevant therapeutic issues such as the importance of new pharmacogenetics and pharmacokinetics tools for improving the long-term tolerability and response to antiviral treatment, and should open the way to personalized prescription of antiviral drugs. The ultimate goal is the selection of first-line regimens according to patients’ genetic background, and the careful dosage adjustment through population pharmacokinetics-based therapeutic drug monitoring.