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Modélisation, Simulation et Validation clinique des Interactions Médicamenteuses dans la Swiss HIV Cohort Study

English title Model-Based Simulation and Clinical Validation of Drug-Drug Interactions in the Swiss HIV Cohort Study
Applicant Decosterd Laurent Arthur
Number 165956
Funding scheme Project funding (special)
Research institution Département des laboratoires CHUV
Institution of higher education University of Lausanne - LA
Main discipline Clinical Pharmacology
Start/End 01.09.2016 - 31.08.2019
Approved amount 430'500.00
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Keywords (9)

drugs interactions; anti HCV drugs; large nested project (SHCS); pharmacogenetics; clinical pharmacokinetics; Population pharmacokinetics; antiretrovirals; Model-based simulation; liquid chromatography tandem mass spectrometry

Lay Summary (French)

Lead
Les médicaments antirétroviraux ont transformé le pronostic de l’infection HIV qui est maintenant devenue une maladie chronique: les patients vivent plus longtemps et deviennent âgés. Ils sont ainsi progressivement confrontés aux pathologies liées au vieillissement et reçoivent des médicaments contre l’hypertension, les problèmes cardio-vasculaires, le diabète, les problèmes neuropsychologiques ainsi que le cancer. De plus, jusqu’à 30% des patients HIV-positifs sont co-infectés par le virus de l'hépatite C (VHC) et sont susceptibles d’être traités par les nouveaux médicaments anti-VHC. Nos connaissances sur le potentiel d'interactions complexes de toutes ces associations médicamenteuses avec les agents antirétroviraux reposent le plus souvent sur des données dérivées d’études in vitro et leurs impacts à long terme ne sont pas complètement caractérisés.
Lay summary

Notre programme de recherche vise à réaliser au niveau de l’Etude Suisse de Cohorte HIV (SHCS) une analyse systématique des interactions médicamenteuses existant entre les traitements antiviraux et les autres médicaments pris par les patients infectés par le VIH et/ou VHC. Les concentrations sanguines des médicaments antiviraux et des principales co-médications des patients SHCS vont être mesurées simultanément par spectrométrie de masse et analysées par des approches de pharmacocinétique de population. Ces analyses intégreront également la patho-physiologie des patients, leur profil pharmacogénétique, ainsi que la réponse et la tolérance aux traitements médicamenteux. La modélisation pharmacocinétique et la simulation des interactions médicamenteuses problématiques seront validées cliniquement. Ce programme s’inscrit dans le domaine émergeant de l’individualisation des traitements et de la médecine personnalisée.

 

Direct link to Lay Summary Last update: 05.08.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
04. Aging does not impact drug-drug interaction magnitudes with antiretrovirals a Swiss HIV Cohort Study
Stader Felix, Decosterd Laurent, Stoeckle Marcel, Cavassini Matthias, Battegay Manuel, Saldanha Susana Alves, Marzolini Catia, Courlet Perrine, SwissHIVCohortStudy (2020), 04. Aging does not impact drug-drug interaction magnitudes with antiretrovirals a Swiss HIV Cohort Study, in AIDS, 1-1.
05. Pharmacokinetic profiles of boosted darunavir, dolutegravir and lamivudine in aging people living with HIV
Courlet Perrine, Stader Felix, Guidi Monia, Alves Saldanha Susana, Stoeckle Marcel, Cavassini Matthias, Battegay Manuel, Buclin Thierry, Decosterd Laurent Arthur, Marzolini Catia, SwissHIVCohortStudy (2020), 05. Pharmacokinetic profiles of boosted darunavir, dolutegravir and lamivudine in aging people living with HIV, in AIDS, 34(1), 103-108.
06. The Neurocognitive Assessment in the Metabolic and Aging Cohort ( NAMACO ) study: baseline participant profile
Métral M, Darling KEA, Locatelli I, Nadin I, Santos G, Brugger P, Kovari H, Cusini A, Gutbrod K, Tarr PE, Calmy A, Lecompte TD, Assal F, Monsch A, Kunze U, Stoeckle M, Schwind M, Schmid P, Pignatti R, Di Benedetto C, Du Pasquier R, Cavassini M, Cavassini Matthias, Du Pasquier Renaud, et al. (2020), 06. The Neurocognitive Assessment in the Metabolic and Aging Cohort ( NAMACO ) study: baseline participant profile, in HIV Medicine, 21(1), 30-42.
15. How helpful are the European AIDS Clinical Society cognitive screening questions in predicting cognitive impairment in an aging, well‐treated HIV‐positive population?
Metral M, Nadin I, Locatelli I, Tarr PE, Calmy A, Kovari H, Brugger P, Cusini A, Gutbrod K, Schmid P, Schwind M, Kunze U, Di Benedetto C, Pignatti R, Du Pasquier R, Darling KEA, Cavassini M, Cavassini Matthias, Pasquier Renaud Du, Métral Mélanie, Simioni Samanta, Brugger Peter, Gutbrod Klemens, Monsch Andreas U, et al. (2019), 15. How helpful are the European AIDS Clinical Society cognitive screening questions in predicting cognitive impairment in an aging, well‐treated HIV‐positive population?, in HIV Medicine, hiv.12828-hiv.12828.
07. Polypharmacy, Drug–Drug Interactions, and Inappropriate Drugs: New Challenges in the Aging Population With HIV
Courlet Perrine, Livio Françoise, Guidi Monia, Cavassini Matthias, Battegay Manuel, Stoeckle Marcel, Buclin Thierry, Alves Saldanha Susana, Csajka Chantal, Marzolini Catia, Decosterd Laurent, SwissHIVCohortStudy (2019), 07. Polypharmacy, Drug–Drug Interactions, and Inappropriate Drugs: New Challenges in the Aging Population With HIV, in Open Forum Infectious Diseases, 6(12), 1-8.
13. Noninferiority of Simplified Dolutegravir Monotherapy Continued Combination Antiretroviral Therapy Initiated During Primary HIV Infection: A Randomized, Controlled, Noninferiority Trial
Braun Dominique L, Turk Teja, Tschumi Fabian, Grube Christina, Hampel Benjamin, Depmeier Carsten, Schreiber Peter W, Brugger Silvio D, Greiner Michael, Steffens Daniela, De Torrenté-Bayard Cornelia, Courlet Perrine, Neumann Kathrin, Kuster Herbert, Flepp Markus, Bertisch Barbara, Decosterd Laurent, Böni Jürg, Metzner Karin J, Kouyos Roger D, Günthard Huldrych F (2019), 13. Noninferiority of Simplified Dolutegravir Monotherapy Continued Combination Antiretroviral Therapy Initiated During Primary HIV Infection: A Randomized, Controlled, Noninferiority Trial, in Clinical Infectious Diseases, 69(9), 1489-1497.
08. UHPLC-MS/MS assay of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin with its active metabolites for population-scale drug-drug interactions studies in people living with HIV
Courlet Perrine, Spaggiari Dany, Desfontaine Vincent, Cavassini Matthias, Alves Saldanha Susana, Buclin Thierry, Marzolini Catia, Csajka Chantal, Decosterd Laurent-Arthur (2019), 08. UHPLC-MS/MS assay of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin with its active metabolites for population-scale drug-drug interactions studies in people living with HIV, in Journal of Chromatography B, 1125, 121733-121733.
09. Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting
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, SwissHIVCohortStudy (2019), 09. Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting, in Journal of Antimicrobial Chemotherapy, 74(9), 2690-2697.
11. Emtricitabine and lamivudine concentrations in saliva: a simple suitable test for treatment adherence
Courlet Perrine, Decosterd Laurent Arthur, Brown Jennifer Anne, Alves Saldanha Susana, Marzolini Catia, Cavassini Matthias, Stoeckle Marcel, Csajka Chantal, Labhardt Niklaus Daniel, Calmy Alexandra, SwissHIVCohortStudy (2019), 11. Emtricitabine and lamivudine concentrations in saliva: a simple suitable test for treatment adherence, in Journal of Antimicrobial Chemotherapy, 74(8), 2468-2470.
10. Escitalopram population pharmacokinetics in people living with human immunodeficiency virus and in the psychiatric population: Drug–drug interactions and probability of target attainment
Courlet Perrine, Guidi Monia, Glatard Anaïs, Alves Saldanha Susana, Cavassini Matthias, Buclin Thierry, Marzolini Catia, Eap Chin B., Decosterd Laurent A., Csajka Chantal, SwissHIVCohortStudy (2019), 10. Escitalopram population pharmacokinetics in people living with human immunodeficiency virus and in the psychiatric population: Drug–drug interactions and probability of target attainment, in British Journal of Clinical Pharmacology, 85(9), 2022-2032.
14. Development & validation of a multiplex UHPLC-MS/MS method for the determination of the investigational antibiotic against multi-resistant tuberculosis macozinone (PBTZ169) and five metabolites
Spaggiari Dany, Desfontaine Vincent, Cruchon Sandra, Guinchard Sylvie, Vocat Anthony, Blattes Emilyne, Pitteloud Jeff, Ciullini Lorenzo, Bardinet Carine, Ivanyuk Anton, Makarov Vadim, Ryabova Olga, Buclin Thierry, Cole Stewart T., Decosterd Laurent A. (2019), 14. Development & validation of a multiplex UHPLC-MS/MS method for the determination of the investigational antibiotic against multi-resistant tuberculosis macozinone (PBTZ169) and five metabolites, in PLOS ONE, 14(5), e0217139-e0217139.
12. Severe rosuvastatin accumulation with rhabdomyolysis due to drug interactions and low cardiac output syndrome
Previsdomini Marco, Graziano Elisa, Decosterd Laurent, Courlet Perrine, Perren Andreas, Ceschi Alessandro (2019), 12. Severe rosuvastatin accumulation with rhabdomyolysis due to drug interactions and low cardiac output syndrome, in British Journal of Clinical Pharmacology, 85(7), 1616-1618.
17. Stable HIV-1 reservoirs on dolutegravir maintenance monotherapy: the MONODO study
Sculier D, Doco-Lecompte T, Yerly S, Metzner KJ, Decosterd LA, Calmy A (2018), 17. Stable HIV-1 reservoirs on dolutegravir maintenance monotherapy: the MONODO study, in HIV Medicine, 19(8), 572-577.
16. Boosted darunavir, emtricitabine and tenofovir pharmacokinetics in the early and late postgastric bypass surgery periods
Baettig Veronika, Courlet Perrine, Delko Tarik, Battegay Manuel, Marzolini Catia (2018), 16. Boosted darunavir, emtricitabine and tenofovir pharmacokinetics in the early and late postgastric bypass surgery periods, in AIDS, 32(13), 1903-1905.
18. Determination of nucleosidic/tidic reverse transcriptase inhibitors in plasma and cerebrospinal fluid by ultra-high-pressure liquid chromatography coupled with tandem mass spectrometry
Courlet Perrine, Spaggiari Dany, Cavassini Matthias, Du Pasquier Renaud, Alves Saldanha Susana, Buclin Thierry, Marzolini Catia, Csajka Chantal, Decosterd Laurent (2018), 18. Determination of nucleosidic/tidic reverse transcriptase inhibitors in plasma and cerebrospinal fluid by ultra-high-pressure liquid chromatography coupled with tandem mass spectrometry, in Clinical mass Spectrometry, 8, 8-20.
19. Darunavir concentrations in CSF of HIV-infected individuals when boosted with cobicistat versus ritonavir
BartelsHanni, DecosterdLaurent, BattegayManuel, MarzoliniCatia (2017), 19. Darunavir concentrations in CSF of HIV-infected individuals when boosted with cobicistat versus ritonavir, in J Antimicrobial Chemotherapy, 72, 2574-2577.
20. Population Pharmacokinetics and Pharmacogenetics Analysis of Rilpivirine in HIV-1-Infected Individuals
AouriManel, BarceloCatalina, GuidiMonia, RotgerMargalida, CavassiniMatthias, HizrelCedric, BuclinThierry, DecosterdLaurent A, CsajkaChantal, SwissHIVCohortStudy (2017), 20. Population Pharmacokinetics and Pharmacogenetics Analysis of Rilpivirine in HIV-1-Infected Individuals, in Antimicrobial Agents Chemotherapy, 61((1) pii: e), 1-10.
01.Influence of drug-drug interactions on the pharmacokinetics of atorvastatin and its major active metabolite ortho-OH-atorvastatin in aging people living with HIV
Courlet Perrine, Decosterd Laurent, Alves Saldanha Susana, Cavassini Matthias, Stader Felix, Stoeckle Marcel, Buclin Thierry, Marzolini Catia, Csajka Chantal, Guidi Monia, SwissHIVCohortStudy, 01.Influence of drug-drug interactions on the pharmacokinetics of atorvastatin and its major active metabolite ortho-OH-atorvastatin in aging people living with HIV, in Clinical Pharmacokinetics.
02. Development and validation of a multiplex UHPLC-MS/MS assay with isotopic internal standards for the monitoring of bictegravir, cabotegravir, doravirine and rilpivirine in people living with HIV
Courlet Perrine, Alves Saldanha Susana, Cavassini Matthias, Marzolini Catia, Choong Eva, Csajka Chantal, Günthard Huldrych F, André Pascal, Buclin Thierry, Desfontaine Vincent, Decosterd Laurent A, 02. Development and validation of a multiplex UHPLC-MS/MS assay with isotopic internal standards for the monitoring of bictegravir, cabotegravir, doravirine and rilpivirine in people living with HIV, in J Mass Spectrometry.
03. Real-life management of drug-drug interactions between antiretrovirals and statins.
Courlet Perrine, Livio Françoise, Alves Saldanha Susana, Scherrer Alexandra, Battegay Manuel, Cavassini Matthias, Stoeckle Marcel, Decosterd Laurent A, Marzolini Catia, SwissHIVCohortStudy, 03. Real-life management of drug-drug interactions between antiretrovirals and statins., in J Antimicrobial Chemotherapy.

Collaboration

Group / person Country
Types of collaboration
PD Dr Philip E. Tarr (SHCS), Kantonspital Baselland Bruderholz Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof M. Battegay, Division of Infectious Diseases, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Dr Hugues Henry, Platform of Chromatography/ Mass spectrometry, CHUV University Hospital Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof Chin Eap, Laboratory of Biochemistry and Psychopharmacology, University Hospital Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
Prof Marc Pfister, Professor of Systems Pharmacology and Pharmacometrics Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr Mylène Docquier, Genomics Platform, CMU Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof Jacques Fellay, Global Health Institute, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof Darius Moradpour CHUV Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof Huldrych Günthard, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS (CROI) 2020 Poster Real-life management of drug-drug interactions between antiretrovirals and statins 21.12.2019 Boston, United States of America Courlet Perrine; Decosterd Laurent Arthur; Cavassini Matthias;
17th European AIDS Conference Poster Central nervous system penetration of antiretroviral drugs in HIV-positive patients with neurocognitive impairment, assessed from paired plasma-CSF concentrations (Poster PE27/9) ) 06.11.2019 Bâle, Switzerland Cavassini Matthias; Buclin Thierry; Decosterd Laurent Arthur; Courlet Perrine;
28th Meeting of the Population Approach Group in Europe Poster Influence of drug-drug interactions on population pharmacokinetics of atorvastatin and its active metabolite ortho-OH-atorvastatin in people living with HIV 11.06.2019 Stockholm, Sweden Decosterd Laurent Arthur; Buclin Thierry; Csajka Chantal; Courlet Perrine;
CONFERENCE ON RETROVIRUSES AND OPPORTUNISTIC INFECTIONS (CROI) 2019 Poster Polypharmacy, inappropriate drugs and drug-drug interactions in HIV-infected elderly. 04.03.2019 Seattle, United States of America Cavassini Matthias; Courlet Perrine; Decosterd Laurent Arthur; Csajka Chantal;
27th Meeting of the Population Approach Group in Europe Poster Comparison of escitalopram pharmacokinetics in HIV-infected individuals with an uninfected psychiatric cohort. 29.05.2018 Montreux, Switzerland Buclin Thierry; Courlet Perrine; Decosterd Laurent Arthur; Csajka Chantal; Guidi Monia;
2nd Spring Congress of Swiss Society of General Internal Medicine Poster Prevalence of polypharmacy in the Swiss HIV Cohort Study (SHCS). 03.05.2017 Lausanne, Switzerland Cavassini Matthias; Courlet Perrine; Spaggiari Dany; Csajka Chantal; Decosterd Laurent Arthur; Guidi Monia;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media La bonne dose du bon médicament au bon patient Le Temps Western Switzerland 2017

Awards

Title Year
Winner of the Swiss HIV Cohort Study Grant 2017Abbvie Prize to Prof Laurent Decosterd and PD Dr Catia Marzolini for the project: "Model-based Simulation and Clinical Validation of Drug-Drug Interactions in the Swiss HIV Cohort Study" 2017

Associated projects

Number Title Start Funding scheme
121314 Demande de soutien pour l'acquisition d'un instrument de chromatographie à ultra performance couplé à un détecteur de masse triple quadripôles en tandem (UPLC-MS/MS) pour la recherche biomédicale 01.08.2008 R'EQUIP
192449 Novel Long Acting Injectable Antiretrovirals: Real-Life Monitoring in the Swiss HIV Cohort Study 01.11.2020 Project funding (special)
192449 Novel Long Acting Injectable Antiretrovirals: Real-Life Monitoring in the Swiss HIV Cohort Study 01.11.2020 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)

Abstract

Highly active antiretroviral treatments (ARTs) have transformed HIV infection from a deadly disease into a manageable chronic condition. As a consequence, HIV-infected individuals live longer and become older. Besides therapeutic effectiveness, drug tolerability and long term health impact become key issues for treatments to be taken indefinitely. Moroever, aging patients encounter chronic conditions such as hypertension, cardiovascular problems, diabetes, neurocognitive impairement and malignancies, which lead to increasingly complex drugs associations with a high potential of drug-drug interactions (DDIs). Moreover, renal and hepatic functions become altered in a fraction of patients, necessitating appropriate treatment adjustments. Thus, HIV infection management becomes increasingly complex, not to mention metabolic complications and other cumulative deleterious effects of ARTs over decades. In addition, a significant percentage of HIV patients (up to 30% in the Swiss HIV Cohort Study, SHCS) are co-infected with hepatitis C virus and are likely to receive the last wave of anti-HCV drugs. Still their drug interaction potential, notably with ARTs, and their long-term safety are incompletely characterized. More generally, most information from DDI databases used by healthcare providers is extrapolated from current knowledge of drug metabolic pathways identified in vitro, which poorly account for the complexity of multiple and opposing in vivo effects, not to mention induction or pharmacogenetic issues. In the growing movement of personalized medicine, research efforts must be pursued to improve the prescription of ARTs not only with regard to antiretroviral efficacy but also according to tolerability, long-term safety and potential DDIs, possibly modulated by patients’ pharmacogenetics traits. These issues will be best addressed by an integrated strategy of drug selection and dosage individualization based on relevant demographic/clinical factors, genetic markers (precision medicine) and measurement of circulating concentrations (Therapeutic Drug Monitoring, TDM). To this end, during the last funding period, we have:1.Developped mass spectrometry assays for the TDM of new anti-HIV and anti-HCV drugs, as well as metabolites profiles analysis in various body compartments. 2.Extended our modelling expertise from single-drug population pharmacokinetic analysis to drug-drug and drug-gene interactions studies and to the kinetics of biological markers in patients from the SHCS.3.Established a logistical framework for the prospective capture of TDM data for novel anti-HIV and anti-HCV agents. Building up on our population mass spectrometry facilities, modeling expertise and established frameworks, we intend to launch a systematic analysis of complex drug-drug interactions relevant to antiviral treatments and comedication in patients infected by HIV and/or HCV. Specifically, we propose in the present request for grant renewal: 1.Large-scale, cross-sectional capture, at the occasion of the bi-annual cohort visit of SHCS patients, of TDM samples along with relevant therapeutic information (date/time of last dose and blood sampling), not only for antiviral treatments but also for all other drugs part of their co-medication (i.e. statins, cardiovascular and psychotropic drugs, anticancer agents, etc.) 2. Multiplex mass spectrometry analyses of antiviral drugs and relevant comedication in TDM samples. 3.Population kinetic modeling of the exposure to antiviral drugs and to selected comedication in genotyped SHCS patients, which will culminate to:4. Nested case-control and network analyses of drugs-drug interactions observed in active SHCS individuals in real-life conditions, followed by model-based simulations and formal small-scale validation studies of problematic drug interactions. The major strength of this proposal is to address two key issues in current therapeutics of HIV- and/or HCV-infected patients: the complexity and the long-term consequences of treatments. This pharmacokinetic-pharmacoepidemiologic analysis will contribute to personalize drug treatment (via both pharmacogenetics and TDM) while addressing the problem of DDIs actually encountered in real-life conditions
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