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Pharmacocinétique de population, pharmacogénétique, et profils métaboliques de la thérapie anti-HIV

English title Population Pharmacokinetics, Pharmacogenetics, and Metabolic Profiling of Antiretroviral Therapy
Applicant Decosterd Laurent Arthur
Number 124943
Funding scheme Project funding (special)
Research institution Division de Pharmacologie clinique Département de Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Clinical Pharmacology
Start/End 01.04.2009 - 31.03.2012
Approved amount 375'000.00
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Keywords (6)

antiretrovirals; clinical pharmacokinetics; pharmacogenetics; metabolite profiling; liquid chromatography tandem mass spectrometry; Swiss HIV Cohort Study

Lay Summary (English)

Lead
Lay summary
Lead:Clinical pharmacokinetic and pharmacogenetic research efforts have to be pursued in HIV therapeutics because of the prevalence of toxicity, the life-long nature of treatment, and the complexity inherent to multidrug therapy.Abstract:The proposed research project aims at increasing the current understanding of the complex gene-environmental interplay influencing toxicity and efficacy of antiretroviral treatment at the patient and the population levels, thus offering new possibilities for improving the long term tolerability and response to antiretroviral treatments. Drug pharmacokinetics is a phenotypic trait influenced by complex genetic and non-genetic factors affecting drug transport and metabolism. Pharmacogenetics aim at determining patients genetic predisposition influencing drug exposure, toxicity and clinical response. However, current approaches in pharmacokinetics have focused almost exclusively on the parent drug concentrations while current approaches in pharmacogenetics have examined one or few candidate genes for a limited number of genes variants. Aim:This current research project addresses the Pharmacology and Pharmacogenetics of new antiretroviral drugs via the a) Integration of drug metabolite profiling and pharmacogenetics analysis of all pathways likely to be implicated in the absorption, distribution, metabolism and excretion of antiretroviral agents b) Development of population pharmacokinetic/pharmacogenetics models. c) Translation to clinical studies aiming at validating the usefulness of new pharmacokinetic and pharmacogenetic tools. Significance:Pharmacogenetics is likely to have a profound impact on our current understanding of the variability observed in drug exposure (pharmacokinetics), clinical response and toxicity (pharmacodynamics) of antiretroviral agents. Pharmacogenetic tests are being developed in sight of determining genetic predispositions to toxicity and unsatisfactory clinical response, thereby identifying the antiretroviral regimen most likely to be effective and with limited drug toxicity in a given patient.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Determinants of sustained viral suppression in HIV-infected patients with self-reported poor adherence to antiretroviral therapy.
Glass Tracy R, Rotger Margalida, Telenti Amalio, Decosterd Laurent, Csajka Chantal, Bucher Heiner C, Günthard Huldrych F, Rickenbach Martin, Nicca Dunja, Hirschel Bernard, Bernasconi Enos, Wandeler Gilles, Battegay Manuel, Marzolini Catia, Swiss HIV Cohort Study (2012), Determinants of sustained viral suppression in HIV-infected patients with self-reported poor adherence to antiretroviral therapy., in PloS one, 7(1), 29186-29186.
Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.
Arab-Alameddine Mona, Fayet-Mello Aurélie, Lubomirov Rubin, Neely Michael, di Iulio Julia, Owen Andrew, Boffito Marta, Cavassini Matthias, Günthard Huldrych F, Rentsch Katharina, Buclin Thierry, Aouri Manel, Telenti Amalio, Decosterd Laurent Arthur, Rotger Margalida, Csajka Chantal, Swiss HIV Cohort Study Group (2012), Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals., in Antimicrobial agents and chemotherapy, 56(6), 2959-66.
Antimicrobial agents
Csajka C, Marchetti O, Manuel O, Decosterd LA, Telenti A (2012), Antimicrobial agents, in U. Zanger, P. Anzenbacher (ed.), Wiley/Verlag Chemie , Weinheim , 379-402.
Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia
Aouri M., Decosterd L. A., Buclin T., Hirschel B., Calmy A., Livio F. (2012), Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia, in AIDS, 26, 776-778.
HIV and Antiretroviral Therapy. Principles of Pharmacogenetics and Pharmacogenomics,
Telenti A. (2012), HIV and Antiretroviral Therapy. Principles of Pharmacogenetics and Pharmacogenomics,, in Russ B. Altman, David B. Goldstein, David Flockhart (ed.), Cambridge University Press, UK, 238-248.
Dosage optimization of treatments using population pharmacokinetic modeling and simulation
Guidi M, Arab-Alameddine M, Rotger M, Aouri M, Telenti A, Decosterd LA, Buclin T, Csajka C (2012), Dosage optimization of treatments using population pharmacokinetic modeling and simulation, in Chimia, 66, 291-295.
Successful efavirenz dose reduction guided by therapeutic drug monitoring.
Fayet Mello Aurélie, Buclin Thierry, Decosterd Laurent A, Delhumeau Cécile, di Iulio Julia, Fleurent Alessandra, Schneider Marie-Paule, Cavassini Matthias, Telenti Amalio, Hirschel Bernard, Calmy Alexandra (2011), Successful efavirenz dose reduction guided by therapeutic drug monitoring., in Antiviral therapy, 16(2), 189-97.
Pharmacogenomics of HIV therapy: summary of a workshop sponsored by the National Institute of Allergy and Infectious Diseases
Haas D. W., Kuritzkes D. R., Ritchie M. D., Amur S., Gage B. F., Maartens G., Masys D., Fellay J., Phillips E., Ribaudo H. J., Freedberg K. A., Petropoulos C., Manolio T. A., Gulick R. M., Haubrich R., Kim P., Dehlinger M., Abebe R., Telenti A. (2011), Pharmacogenomics of HIV therapy: summary of a workshop sponsored by the National Institute of Allergy and Infectious Diseases, in HIV Clin Trials, 12, 277-285.
Cell disposition of raltegravir and newer antiretrovirals in HIV-infected patients: high inter-individual variability in raltegravir cellular penetration.
Fayet Mello Aurélie, Buclin Thierry, Franc Claudia, Colombo Sara, Cruchon Sandra, Guignard Nicole, Biollaz Jérôme, Telenti Amalio, Decosterd Laurent A, Cavassini Matthias (2011), Cell disposition of raltegravir and newer antiretrovirals in HIV-infected patients: high inter-individual variability in raltegravir cellular penetration., in The Journal of antimicrobial chemotherapy, 66(7), 1573-81.
Antiretroviral drug toxicity in relation to pharmacokinetics, metabolic profile and pharmacogenetics.
Arab-Alameddine Mona, Décosterd Laurent Arhtur, Buclin Thierry, Telenti Amalio, Csajka Chantal (2011), Antiretroviral drug toxicity in relation to pharmacokinetics, metabolic profile and pharmacogenetics., in Expert opinion on drug metabolism & toxicology, 7, 609-622.
No longitudinal mitochondrial DNA sequence changes in HIV-infected individuals with and without lipoatrophy
Ortiz M., Poloni E. S., Furrer H., Kovari H., Martinez R., Arnedo M., Elzi L., Bernasconi E., Vernazza P., Hirschel B., Cavassini M., Ledergerber B., Gunthard H. F., Telenti A., Tarr P. E. (2011), No longitudinal mitochondrial DNA sequence changes in HIV-infected individuals with and without lipoatrophy, in The Journal of infectious diseases, 203, 620-624.
Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study.
Lubomirov Rubin, Colombo Sara, di Iulio Julia, Ledergerber Bruno, Martinez Raquel, Cavassini Matthias, Hirschel Bernard, Bernasconi Enos, Elzi Luigia, Vernazza Pietro, Furrer Hansjakob, Günthard Huldrych F, Telenti Amalio, Swiss HIV Cohort Study (2011), Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study., in The Journal of infectious diseases, 203(2), 246-57.
A randomized crossover study to compare efavirenz and etravirine treatment.
Nguyen Alain, Calmy Alexandra, Delhumeau Cécile, Mercier Isabelle K, Cavassini Matthias, Fayet-Mello Aurélie, Elzi Luigia, Genné Daniel, Rauch Andri, Bernasconi Enos, Hirschel Bernard, Swiss HIV Cohort Study (2011), A randomized crossover study to compare efavirenz and etravirine treatment., in AIDS (London, England), 25(1), 57-63.
Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers.
Neely Michael, Decosterd Laurent, Fayet Aurélie, Lee Janice Soo Fern, Margol Ashley, Kanani Meera, di Iulio Julia, von Schoen-Angerer Tido, Jelliffe Roger, Calmy Alexandra (2010), Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers., in Antimicrobial agents and chemotherapy, 54(11), 4619-25.
Genetic screening for metabolic and age-related complications in HIV-infected persons
Tarr P. E., Telenti A. (2010), Genetic screening for metabolic and age-related complications in HIV-infected persons, in F1000 Med Rep, 2(83), 1-5.
Impact of single nucleotide polymorphisms and of clinical risk factors on new-onset diabetes mellitus in HIV-infected individuals
Rotger M., Gsponer T., Martinez R., Taffe P., Elzi L., Vernazza P., Cavassini M., Bernasconi E., Hirschel B, Furrer H., Weber R., Ledergerber B., Egger M., Telenti A., Tarr P. E. (2010), Impact of single nucleotide polymorphisms and of clinical risk factors on new-onset diabetes mellitus in HIV-infected individuals, in Clinical infectious diseases , 51(2010), 1090-1098.
ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir.
Lubomirov Rubin, di Iulio Julia, Fayet Aurélie, Colombo Sara, Martinez Raquel, Marzolini Catia, Furrer Hansjakob, Vernazza Pietro, Calmy Alexandra, Cavassini Matthias, Ledergerber Bruno, Rentsch Katharina, Descombes Patrick, Buclin Thierry, Decosterd Laurent A, Csajka Chantal, Telenti Amalio, Swiss HIV Cohort Study (2010), ADME pharmacogenetics: investigation of the pharmacokinetics of the antiretroviral agent lopinavir coformulated with ritonavir., in Pharmacogenetics and genomics, 20(4), 217-30.
Dyslipidemia in HIV-infected individuals: from pharmacogenetics to pharmacogenomics
Tarr P. E., Rotger M., Telenti A. (2010), Dyslipidemia in HIV-infected individuals: from pharmacogenetics to pharmacogenomics, in Pharmacogenomics, 11, 587-594.
Determination of Unbound Antiretroviral Drug Concentrations by a Modified Ultrafiltration Method Reveals High Variability in the Free Fraction (vol 30, pg 511, 2008)
Fayet A, Beguin A, de Tejada BM (2010), Determination of Unbound Antiretroviral Drug Concentrations by a Modified Ultrafiltration Method Reveals High Variability in the Free Fraction (vol 30, pg 511, 2008), in THERAPEUTIC DRUG MONITORING, 32(1), 117-117.
Contribution of genome-wide significant single-nucleotide polymorphisms and antiretroviral therapy to dyslipidemia in HIV-infected individuals: a longitudinal study
Rotger M., Bayard C., Taffe P., Martinez R., Cavassini M., Bernasconi E., Battegay M., Hirschel B., Furrer H., Witteck A., Weber R., Ledergerber B., Telenti A., Tarr P. E. (2009), Contribution of genome-wide significant single-nucleotide polymorphisms and antiretroviral therapy to dyslipidemia in HIV-infected individuals: a longitudinal study, in Circulation. Cardiovascular genetics, 2, 621-628.
Pharmacogenetics-based population pharmacokinetic analysis of efavirenz in HIV-1-infected individuals.
Arab-Alameddine M, Di Iulio J, Buclin T, Rotger M, Lubomirov R, Cavassini M, Fayet A, Décosterd L A, Eap C B, Biollaz J, Telenti A, Csajka C, Swiss HIV Cohort Study (2009), Pharmacogenetics-based population pharmacokinetic analysis of efavirenz in HIV-1-infected individuals., in Clinical pharmacology and therapeutics, 85(5), 485-94.
In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function.
di Iulio Julia, Fayet Aurélie, Arab-Alameddine Mona, Rotger Margalida, Lubomirov Rubin, Cavassini Matthias, Furrer Hansjakob, Günthard Huldrych F, Colombo Sara, Csajka Chantal, Eap Chin B, Decosterd Laurent A, Telenti Amalio, Swiss HIV Cohort Study (2009), In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function., in Pharmacogenetics and genomics, 19(4), 300-9.
Time (again) for a randomized trial of pharmacogenetics of antiretroviral therapy
Telenti A (2009), Time (again) for a randomized trial of pharmacogenetics of antiretroviral therapy, in Pharmacogenomics, 10, 515-516.
A LC-tandem MS assay for the simultaneous measurement of new antiretroviral agents: Raltegravir, maraviroc, darunavir, and etravirine.
Fayet A, Béguin A, Zanolari B, Cruchon S, Guignard N, Telenti A, Cavassini M, Günthard H F, Buclin T, Biollaz J, Rochat B, Decosterd L A (2009), A LC-tandem MS assay for the simultaneous measurement of new antiretroviral agents: Raltegravir, maraviroc, darunavir, and etravirine., in Journal of chromatography. B, Analytical technologies in the biomedical and life sciences, 877(11-12), 1057-69.
Determination of unbound antiretroviral drug concentrations by a modified ultrafiltration method reveals high variability in the free fraction
Fayet A, Beguin A, de Tejada BM, Colombo S, Cavassini M, Gerber S, Eap CB, Telenti A, Buclin T, Biollaz J, Decosterd LA (2008), Determination of unbound antiretroviral drug concentrations by a modified ultrafiltration method reveals high variability in the free fraction, in THERAPEUTIC DRUG MONITORING, 30(4), 511-522.
Free and total plasma levels of lopinavir during pregnancy, at delivery and in post-partum: implication for dosage adjustments in pregnant women
Fayet-Mello A, Buclin T, Guignard N, Cruchon S, Cavassini M, Grawe C, Gremlich E, Aebi Popp K, Schmid F, Eap CB, Telenti A, Biollaz J, Decosterd LA*, Martinez de Tejada B*, Free and total plasma levels of lopinavir during pregnancy, at delivery and in post-partum: implication for dosage adjustments in pregnant women, in Antiviral Therapy, in press.
Pharmacokinetic and Pharmacodynamic Analysis of Efavirenz Dose Reduction Using an In Vitro-In Vivo Extrapolation Model.
Siccardi M, Almond L, Schipani A, Csajka C, Marzolini C, Wyen C, Brockmeyer N H, Boffito M, Owen A, Back D, Pharmacokinetic and Pharmacodynamic Analysis of Efavirenz Dose Reduction Using an In Vitro-In Vivo Extrapolation Model., in Clinical pharmacology and therapeutics.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
21th Meeting of Population Approach group in Europe (PAGE) 05.06.2012 Venice Italy
13th International Workshop on Clinical Pharmacology of HIV Therapy 16.04.2012 Barcelona Spain
Symposium on "Genomics: Gene Discovery and Clinical Applications for Cardiovascular, Lung, and Blood Diseases", NIH, USA, 12.09.2011 Washington DC
20th Meeting of PAGE (Population Approach Group in Europe) 07.06.2011 Athenes Greece
12th International Workshop on Clinical Pharmacology of HIV Therapy 15.04.2011 Miami FL
CROI Conference on Retroviruses and Opportunistic Infections 27.02.2011 Boston USA
CROI Conference on Retroviruses and Opportunistic Infections 16.02.2010 San Francisco USA
5th IAS Conference 19.07.2009 Cape Town South Africa
10th International Workshop on Clinical Pharmacology of HIV Therapy. 15.04.2009 Amsterdam


Associated projects

Number Title Start Funding scheme
113127 Genotyping and transcriptome analyses; illumina platform 01.10.2006 R'EQUIP
134277 Swiss HIV Cohort Study (SHCS) 01.01.2011 Cohort Studies Large
141234 Pharmacologie clinique et pharmacogénétique de la prise en charge complexe des sujets infectés par HIV ou co-infectés par HIV et HCV 01.04.2012 Project funding (special)
141234 Pharmacologie clinique et pharmacogénétique de la prise en charge complexe des sujets infectés par HIV ou co-infectés par HIV et HCV 01.04.2012 Project funding (special)
112655 Managing variability in HIV therapy: integration of pharmacogenetics, pharmacokinetics and pharmacodynamics of antiretroviral drugs 01.04.2006 Project funding (special)
110012 Host genetic and genomic determinants of susceptibility to HIV-1 01.11.2005 Project funding
108787 Swiss HIV Cohort Study 01.04.2006 Cohort Studies Large
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large

Abstract

Clinical pharmacokinetic and pharmacogenetic research efforts have been pursued in HIV therapeutics because of the prevalence of toxicity, the life-long nature of treatment, and the complexity inherent to multidrug therapy. Drug pharmacokinetics is a phenotypic trait influenced by complex genetic and non-genetic factors affecting drug transport and metabolism. Pharmacogenetics aim at determining patients genetic predisposition influencing drug exposure, toxicity and clinical response. Current approaches in pharmacokinetics have focused almost exclusively the parent drug concentrations. Current approaches in pharmacogenetics have examined one or few candidate genes for a limited number of allelic variants. Over the last funding period we have:1.Developed methodologies by using a new capacity of technical tools (mass spectrometry facility, triple quadripole and linear trap instruments), 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 a number of coordinated research projects integrating basic and applied pharmacogenetic, pharmacokinetic and pharmacodynamic aspects of HIV therapy.The current proposal addresses the:1.Pharmacology and pharmacogenetics of new antiretroviral drugs.2.Integration of drug metabolite profiling and whole ADME pharmacogenetics analysis. 3.Development of population pharmacokinetic/pharmacogenetics models.4.Translation to a number of clinical studies aiming at validating the usefulness of new pharmacokinetic and pharmacogenetic tools. The proposed strategy aims at increasing the current understanding of the complex gene-environmental interplay influencing toxicity and efficacy of antiretroviral treatment at the patient and the population levels, thus offering new possibilities for improving the long term tolerability and response to antiretroviral treatments.
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