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Use of physiologically based pharmacokinetic modeling to simulate drug-drug interactions between antiretroviral drugs and commonly prescribed co-medications in the aging HIV population

English title Use of physiologically based pharmacokinetic modeling to simulate drug-drug interactions between antiretroviral drugs and commonly prescribed co-medications in the aging HIV population
Applicant Battegay Manuel
Number 166204
Funding scheme Project funding (special)
Research institution Klinik für Infektiologie Bereich Innere Medizin Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Clinical Pharmacology
Start/End 01.02.2017 - 31.01.2020
Approved amount 366'380.70
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Keywords (7)

large nested project (SHCS); physiologically based pharmacokinetic modeling; large nested project (SHCS); drug-drug interactions; antiretroviral drugs; aging HIV population; dose adjustment

Lay Summary (German)

Lead
Der Fortschritt bei den HIV-Therapien hat die Morbidität und Mortalität bedingt durch HIV/AIDS in dramatischer Weise reduziert. HIV-infizierte Personen erreichen deshalb heute eine fast nicht eingeschränkte Lebenserwartung und der proportionale Anteil älterer Personen innerhalb der Gruppe der HIV-infizierten Menschen steigt stetig an. Die Behandlung der HIV-Infektion bei älteren Patienten ist komplex, weil häufig mehrere Krankheiten gleichzeitig bestehen und das Älterwerden generell mit einer Verminderung oder Verschlechterung von Organfunktionen einhergehen kann. Dies erhöht das Risiko für unerwünschte Wechselwirkungen mit HIV-Medikamenten, sodass unter Umständen der Abbau der HIV-Medikamente beeinflusst wird und eine Dosisanpassung von HIV-Medikamenten notwendig ist.
Lay summary

Es herrscht gegenwärtig ein Mangel an Daten über die Dosierungsanforderungen von HIV-Medikamenten bei betagten Personen. Die empfohlenen Dosierungen für HIV-Medikamente werden normalerweise anhand von Studien ermittelt, die auf einer mit HIV-infizierten „Standard“-Population basieren. Die veränderten Anforderungen von älteren oder gar betagten HIV-infizierten Personen wurden dabei bisher zu wenig berücksichtigt, insbesondere in Bezug auf den Medikamentenabbau. Somit können ältere Patienten, in Bezug auf die HIV-Therapie, dem Risiko einer Unter- oder Überdosierung ausgesetzt sein. Dazu kommt das erhöhte Risiko älterer Patienten von altersbedingten Komorbiditäten (welche oft zu Polypharmazie und somit zu Interaktionen zwischen den Medikamenten  [sog. DDI, drug-drug-interactions] führen).

Medikamenteninteraktionen können mit einem erhöhten Risiko für Toxizität oder verminderter Wirksamkeit und nachfolgend entstehender Wirkstoffresistenz einhergehen.

Die Ziele des Projektes sind a) Das Ausmass der Medikamenteninteraktionen (DDI) zwischen antiretroviralen Medikamenten und den üblicherweise verschriebenen Komedikationen bei älteren, HIV-infizierten Patienten zu untersuchen, b)  Dosierungsanpassungen mittels physiologisch (auf Körperfunktion) basiertem pharmakokinetischem (PBPK-)modelling  zu simulieren, um bestimmte DDI zu überwinden. Diese Technik ermöglicht Voraussagen über die Medikamentenwirkung auf virtuelle Patienten und  die Simulation von klinisch relevanten Szenarien. So könnten dann Dosisanpassungen bestimmte Interaktionseffekte kompensieren.

Dieses Forschungsprojekt sollte zu  Richtlinien führen, wie DDI für Medikamentenkombinationen gehandhabt werden sollen. Diese Daten sind speziell relevant in der alternden HIV-Population bei der gegebenen hohen Prävalenz von Multimorbiditäten. Darüber hinaus kann dieses Projekt auch Anwendung in anderen medizinischen Gebieten finden, um Therapien für die eher gefährdete  Gruppe der betagten Patienten zu optimieren.

Direct link to Lay Summary Last update: 05.04.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Analysis of inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study reveals gender inequity
Livio Françoise, Deutschmann Elisabeth, Moffa Giusi, Rrustemi Flamur, Stader Felix, Elzi Luigia, Braun Dominique L, Calmy Alexandra, Hachfeld Anna, Cavassini Matthias, Tarr Philip E, Wissel Kerstin, Battegay Manuel, Marzolini Catia, Aebi-Popp K, Anagnostopoulos A, Battegay M, Bernasconi E, Böni J, Braun D L, Bucher H C, Calmy A, Cavassini M, Ciuffi A, et al. (2020), Analysis of inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study reveals gender inequity, in Journal of Antimicrobial Chemotherapy, NA-NA.
Clinical Data Combined With Modeling and Simulation Indicate Unchanged Drug‐Drug Interaction Magnitudes in the Elderly
Stader Felix, Courlet Perrine, Kinvig Hannah, Penny Melissa A., Decosterd Laurent A., Battegay Manuel, Siccardi Marco, Marzolini Catia (2020), Clinical Data Combined With Modeling and Simulation Indicate Unchanged Drug‐Drug Interaction Magnitudes in the Elderly, in Clinical Pharmacology & Therapeutics, cpt.2017-cpt.2017.
Influence of drug-drug interactions on the pharmacokinetics of atorvastatin and its active metabolite ortho-OH-atorvastatin in people living with HIV
Courlet Perrine, Guidi Monia, Alves Saldanha Susana, Cavassini Matthias, Stader Felix, Stoeckle Marcel, Buclin Thierry, Marzolini Catia, Decosterd Laurent, Csajka Chantal (2020), Influence of drug-drug interactions on the pharmacokinetics of atorvastatin and its active metabolite ortho-OH-atorvastatin in people living with HIV, in Clinical Pharmacokinetics, 1037-1048.
Prevalence of Potential Drug–Drug Interactions in Patients of the Swiss HIV Cohort Study in the Era of HIV Integrase Inhibitors
Deutschmann Elisabeth, Bucher Heiner C, Jaeckel Steffen, Gibbons Sara, McAllister Katie, Scherrer Alexandra U, Braun Dominique L, Cavassini Matthias, Hachfeld Anna, Calmy Alexandra, Battegay Manuel, Cipriani Michela, Elzi Luigia, Young James, Lopez-Centeno Beatriz, Berenguer Juan, Khoo Saye, Moffa Giusi, Marzolini Catia (2020), Prevalence of Potential Drug–Drug Interactions in Patients of the Swiss HIV Cohort Study in the Era of HIV Integrase Inhibitors, in Clinical Infectious Diseases, NA-NA.
Effect of ageing on antiretroviral drug pharmacokinetics using clinical data combined with modelling and simulation
Stader Felix, Courlet Perrine, Kinvig Hannah, Battegay Manuel, Decosterd Laurent A., Penny Melissa A., Siccardi Marco, Marzolini Catia (2020), Effect of ageing on antiretroviral drug pharmacokinetics using clinical data combined with modelling and simulation, in British Journal of Clinical Pharmacology, bcp.14402-bcp.14402.
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, Alves Saldanha Susana, Marzolini Catia, Courlet Perrine (2020), Aging Does Not Impact Drug-Drug Interaction Magnitudes With Antiretrovirals: A Swiss HIV Cohort Study, in AIDS, 949-952.
Real-life management of drug-drug interactions between antiretrovirals and statins
Courlet Perrine, Livio Francoise, Alves Saldanha Susana, Scherrer Alexandra, Battegay Manuel, Cavassini Matthias, Stoeckle Marcel, Decosterd Laurent, Marzolini Catia (2020), Real-life management of drug-drug interactions between antiretrovirals and statins, in Journal of Antimicrobial Chemotherapy, 75, 1972-1980.
Polypharmacy, Drug-Drug Interactions, and Inappropriate Drugs: New Challenges in the Aging Population With HIV
Courlet Perrine, Livio Francoise, Guidi Monia, Cavassini Matthias, Battegay Manuel, Stoeckle Marcel, Buclin Thierry, Alves Saldanha Susana, Csajka Chantal, Marzolini Catia, Decosterd Laurent (2019), Polypharmacy, Drug-Drug Interactions, and Inappropriate Drugs: New Challenges in the Aging Population With HIV, in Open Forum Infectious Diseases, 6(12), ofz531.
Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly
Stader Felix, Kinvig Hannah, Penny Melissa A., Battegay Manuel, Siccardi Marco, Marzolini Catia (2019), Physiologically Based Pharmacokinetic Modelling to Identify Pharmacokinetic Parameters Driving Drug Exposure Changes in the Elderly, in Clinical Pharmacokinetics, 59(3), 383-401.
Prevalence and management of drug–drug interactions with antiretroviral treatment in 2069 people living with HIV in rural Tanzania: a prospective cohort study
Schlaeppi C, Vanobberghen F, Sikalengo G, Glass TR, Ndege RC, Foe G, Kuemmerle A, Paris DH, Battegay M, Marzolini C, Weisser M, Asantiel Aschola, Bani Farida, Byakuzana Theonestina, Chale Adolphina, Eichenberger Anna, Epimack Sauli John, Francis Gideon, Furrer Hansjakob, Gamell Anna, Hwaya Speciosa, Kasuga Bryson, Kimera Namvua, Katende Andrew, et al. (2019), Prevalence and management of drug–drug interactions with antiretroviral treatment in 2069 people living with HIV in rural Tanzania: a prospective cohort study, in HIV Medicine, 21(1), 51-63.
Current Challenges and Solutions in Research and Clinical Care of Older Persons Living with HIV: Findings Presented at the 9th International Workshop on HIV and Aging.
Sundermann E, Erlandson KM, Pope CN, Rubtsova A, Montoya J, Moore AA, Marzolini C, O'Brien KK, Pahwa S, Payne BAI, Rubin LH, Walmsley S, Haughey NJ, Montano M, Karris MY, Margolick JB, Moore DJ (2019), Current Challenges and Solutions in Research and Clinical Care of Older Persons Living with HIV: Findings Presented at the 9th International Workshop on HIV and Aging., in AIDS Res Hum Retroviruses, 35(11-12), 985-998.
Pharmacokinetic profiles of boosted darunavir, dolutegravir and lamivudine in aging patients enrolled in the Swiss HIV Cohort Study
Courlet Perrine, Stader Felix, Guidi Monia, Saldanha Susana Alves, Stoeckle Marcel, Cavassini Matthias, Battegay Manuel, Buclin Thierry, Decosterd Laurent Arthur, Marzolini Catia (2019), Pharmacokinetic profiles of boosted darunavir, dolutegravir and lamivudine in aging patients enrolled in the Swiss HIV Cohort Study, in AIDS, 34(1), 104-108.
Prescribing issues in elderly individuals living with HIV.
Marzolini C, Livio F (2019), Prescribing issues in elderly individuals living with HIV., in Expert Rec Clin Pharmacol, 12(7), 643-659.
Pharmacokinetics, Placental and Breast Milk Transfer of Antiretroviral Drugs in Pregnant and Lactating Women Living with HIV
Hodel E.M., Marzolini C., Waitt C., Rakhmanina N. (2019), Pharmacokinetics, Placental and Breast Milk Transfer of Antiretroviral Drugs in Pregnant and Lactating Women Living with HIV, in Current Pharmaceutical Design, 25(5), 556-576.
A comprehensive framework for physiologically based pharmacokinetic modelling in Matlab®.
Stader Felix, Penny Melissa, Siccardi Marco, Marzolini Catia (2019), A comprehensive framework for physiologically based pharmacokinetic modelling in Matlab®., in CPT Pharmacometrics Sys Pharmacol, 8(7), 444-459.
Repository Describing an Aging Population to Inform Physiologically Based Pharmacokinetic Models Considering Anatomical, Physiological, and Biological Age-Dependent Changes
Stader Felix, Siccardi Marco, Battegay Manuel, Kinvig Hannah, Penny Melissa A., Marzolini Catia (2018), Repository Describing an Aging Population to Inform Physiologically Based Pharmacokinetic Models Considering Anatomical, Physiological, and Biological Age-Dependent Changes, in Clinical Pharmacokinetics, 58(4), 483-501.
Analysis of Clinical Drug-Drug Interaction Data To Predict Magnitudes of Uncharacterized Interactions between Antiretroviral Drugs and Comedications
Stader Felix, Kinvig Hannah, Battegay Manuel, Khoo Saye, Owen Andrew, Siccardi Marco, Marzolini Catia (2018), Analysis of Clinical Drug-Drug Interaction Data To Predict Magnitudes of Uncharacterized Interactions between Antiretroviral Drugs and Comedications, in Antimicrobial Agents and Chemotherapy, 62(7), e00717-18-e00717-18.

Collaboration

Group / person Country
Types of collaboration
Laboratory of Clinical Pharmacology, University Hospital Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Department of Molecular and Clinical Pharmacology, University of Liverpool Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
27th Conference on Retroviruses and Opportunistic Infections Poster Aging does not impact drug-drug interaction magnitudes involving antiretroviral drugs 05.03.2020 Boston, United States of America Stader Felix; Marzolini Catia; Battegay Manuel;
27th Conference on Retroviruses and Opportunistic Infections Poster Real-life management of drug-drug interactions between antiretrovirals and statins 05.03.2020 Boston, United States of America Battegay Manuel; Marzolini Catia;
27th Conference on Retroviruses and Opportunistic Infections Poster Anticholinergic drug use in > 65 year old patients of the Swiss HIV Cohort Study 05.03.2020 Boston, United States of America Marzolini Catia;
15th Residential course on clinical pharmacology of antiretrovirals Talk given at a conference Deprescribing: the fight back against polypharmacy 15.01.2020 Torino, Italy Marzolini Catia;
Post-graduate medical training at the regional hospital of Bellinzona Talk given at a conference Polypharmacy, drug-drug interactions and prescribin errors in elderly PLWH 27.11.2019 Bellinzona, Switzerland Marzolini Catia;
17th European AIDS Conference Talk given at a conference Are there gender and age differences in antiretroviral drugs pharmacokinetics? 07.11.2019 Basel, Switzerland Stader Felix;
17th European AIDS Conference (EACS) Talk given at a conference Drug-drug interactions in the EACS guidelines 07.11.2019 Basel, Switzerland Marzolini Catia;
17th European AIDS Conference (EACS) Talk given at a conference Prevalence of potential drug-drug interactions in patients of the Swiss HIV Cohort Study in the era of HIV integrase inhibitors 06.11.2019 Basel, Switzerland Marzolini Catia; Battegay Manuel;
21st International Workshop on Comorbidities and Adverse Drug Reactions in HIV Talk given at a conference Polypharmacy, drug-drug interactions and inappropriate prescribing errors in elderly PLWH 04.11.2019 Basel, Switzerland Marzolini Catia;
10th American Conference on Pharmacometrics Poster Adult age does not impact the magnitude of drug-drug interactions - a pilot study using physiologically-based pharmacokinetic modelling 20.10.2019 Orlando, United States of America Battegay Manuel; Stader Felix; Marzolini Catia;
Dienstagsclub, University Hospital Bern Individual talk Drug-drug interactions in an aging HIV population 10.09.2019 Bern, Switzerland Marzolini Catia;
10th IAS Conference on HIV Science Talk given at a conference Antiviral therapy in elderly individuals living with HIV 24.07.2019 Mexico City, Mexico Marzolini Catia;
10th IAS Conference on HIV Science Talk given at a conference Considerations for polypharmacy in clinical practice 24.07.2019 Mexico City, Mexico Marzolini Catia;
10th IAS Conference of HIV Science Poster Risk of polypharmacy and inappropriate prescribing in persons living with HIV > 65 years of age 21.07.2019 Mexico city, Mexico Marzolini Catia;
28th meeting on Population Approach Group Europe (PAGE) Poster Physiologically based pharmacokinetic modelling to identify pharmacokinetic parameters driving age-related changes in drug exposure in the elderly 11.06.2019 Stockholm, Sweden Battegay Manuel; Stader Felix; Marzolini Catia;
2nd Update on clinical topics in antiretroviral therapy Talk given at a conference Top DDIs in clinical practice. Still relevant? 31.05.2019 Barcelona, Spain Marzolini Catia;
20th International Workshop on Clinical Pharmacology of HIV, hepatitis & other antiviral drugs Talk given at a conference Clinical case presentation on polypharmacy 14.05.2019 Noordwijk, Netherlands Marzolini Catia;
20th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy Talk given at a conference Physiologically based pharmacokinetic modelling to determine pharmacokinetic alterations driving ritonavir exposure changes in aging people living with HIV 14.05.2019 Noordwijk, Netherlands Stader Felix; Battegay Manuel; Marzolini Catia;
17th Innsbruck HIV Update Talk given at a conference Drug-drug interactions in HIV therapy 04.05.2019 Kuhtai, Austria Marzolini Catia;
26th Conference on Retroviruses and Opportunistic Infections Poster Drug-drug interaction magnitudes in young vs elderly: example of rivaroxaban-darunavir/r 04.03.2019 Seattle, United States of America Marzolini Catia; Stader Felix; Battegay Manuel;
26th Conference on Retroviruses and Opportunistic Infections Poster The role of OATP1B1 in grazoprevir drug-drug interactions and the elderly 04.03.2019 Seattle, United States of America Stader Felix; Marzolini Catia;
26th Conference on Retroviruses and Opportunistic Infections Poster Polypharmacy, inappropriate drugs, and drug-drug interactions in HIV-infected elderly 04.03.2019 Seattle, United States of America Marzolini Catia; Battegay Manuel;
Clinical Research Day at the University Hospital Basel Talk given at a conference Polypharmacy, drug-drug interactions and potentially inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study 24.01.2019 Basel, Switzerland Marzolini Catia; Battegay Manuel; Stader Felix;
14th Residential course on clinical pharmacology of antiretrovirals Talk given at a conference Polypharmacy in HIV and HCV patients: not only drug interactions 18.01.2019 Torino, Italy Marzolini Catia;
14th International Congress on drug therapy in HIV infection Talk given at a conference The top 10 DDIs in day to day clinical management of HIV 28.10.2018 Glasgow, Great Britain and Northern Ireland Marzolini Catia;
8ème Congrès VIH sur les Complications et Comorbidités Talk given at a conference Gestion des interactions: anticoagulants et psychotropes 20.09.2018 Biarritz, French Southern Territories Marzolini Catia;
9th International Workshop on HIV & Aging Talk given at a conference Polypharmacy 13.09.2018 New York City, United States of America Marzolini Catia;
22nd International AIDS Conference Talk given at a conference Polypharmacy and DDI in an aging population 23.07.2018 Amsterdam, Netherlands Marzolini Catia;
22nd International AIDS Conference Poster Prevalence and management of drug-drug interactions in a rural Tanzanian HIV Cohort 23.07.2018 Amsterdam, Netherlands Battegay Manuel; Marzolini Catia;
Post graduate medical training, University hospital Milano Individual talk Drug-drug interactions with HIV therapy 15.06.2018 Milano, Italy Marzolini Catia;
27th meeting on Population Approach Group Europe (PAGE) Poster A population database for healthy elderly to inform physiologically-based pharmacokinetic models considering anatomical, physiological and biological system parameters 29.05.2018 Montreux, Switzerland Battegay Manuel; Stader Felix; Marzolini Catia;
Post graduate medical training at Johns Hopkins Medical School Individual talk Prescribing issues in elderly individuals living with HIV 25.05.2018 Baltimore, United States of America Marzolini Catia;
19th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy Talk given at a conference Polypharmacy, drug-drug interactions and potentially inappropriate prescribing in elderly patients of the Swiss HIV Cohort Study 22.05.2018 Baltimore, United States of America Marzolini Catia; Battegay Manuel; Stader Felix;
1st Geriatric HIV Medicine Summit Talk given at a conference General prescribing in the elderly: iatrogenic triad and cART 05.02.2018 Rome, Italy Marzolini Catia;
13th Residential course on clinical pharmacology of antiretrovirals, Torino Talk given at a conference Management of polypharmacy in the aging patient 17.01.2018 Torino, Italy Marzolini Catia;
State of the HAART: HIV and the Body Talk given at a conference Interactions médicamenteuses au sens large du terme 07.12.2017 Geneva, Switzerland Marzolini Catia;
16th European AIDS Conference (EACS) Poster Effective approach to quantify CYP3A4 mediated drug-drug interactions between antiretroviral drugs and co-medicatons to guide clinical dosing recommendations. 25.10.2017 Milano, Italy Marzolini Catia; Battegay Manuel; Stader Felix;
16th European AIDS Conference Talk given at a conference Drug-drug interactions section in the EACS Guidelines 25.10.2017 Milano, Italy Marzolini Catia;
16th European AIDS Conference Talk given at a conference How to handle polypharmacy best 25.10.2017 Milano, Italy Marzolini Catia;
Post graduate medical training, University hospital Basel Individual talk Therapeutic challenges in the aging HIV infected individuals 16.05.2017 Basel, Switzerland Marzolini Catia;
Post graduate medical training, University Hospital Zurich Individual talk Drug-drug interactions in the HIV positive aging patient 15.05.2017 Zurich, Switzerland Marzolini Catia;


Awards

Title Year
Prize for the best oral presentation at the 20th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy for the work: physiologically based pharmacokinetic modelling to determine pharmacokinetic alterations driving ritonavir exposure chnages in aging people living with HIV. 2019
SHCS Prize for the research project on model-based simulation and clinical validation of drug-drug interactions in the SHCS 2017

Associated projects

Number Title Start Funding scheme
188504 Use of physiologically based pharmacokinetic modelling to simulate dosing requirements of long-acting intramuscular antiretroviral drugs in special populations and to manage drug-drug interactions 01.04.2020 Project funding (special)
188504 Use of physiologically based pharmacokinetic modelling to simulate dosing requirements of long-acting intramuscular antiretroviral drugs in special populations and to manage drug-drug interactions 01.04.2020 Project funding (special)

Abstract

The use of combined antiretroviral therapy has dramatically reduced the morbidity and mortality related to HIV infection. As a result, HIV-infected individuals live longer and the proportion of older individuals within the HIV infected population is constantly growing. Thus, the management of HIV infection is becoming more complex as patients encounter more age related chronic but also severe morbidities such as hypertension, diabetes, tumors or acute diseases leading to polypharmacy and consequently to potential drug-drug interactions (DDI). In addition, aging is characterized by the decline in the function of organs which may impact the pharmacokinetics of drugs and thereby the magnitude of DDI. Many HIV drugs are recognized to be “risky drugs” for clinically significant DDI. Drug interactions may be associated with a substantial risk for toxicity, decreased efficacy and subsequent emergence of drug resistance. Importantly, the recurrence of HIV replication may increase the risk of HIV transmission to seronegative partners as a viral load below the threshold of 50 copies/ ml is highly preventive of HIV transmission. For these reasons, the management of drug interactions is crucial for the care of patients. However, one of the current issues is that there are limited clinical data on DDI and therefore potential DDI are mostly predicted based on in vitro drug metabolism data.The aims of this project are a) to characterize the magnitude of DDI between antiretroviral drugs and commonly prescribed co-medications in older HIV-infected patients and b) to simulate dosage adjustments to overcome a given DDI using physiologically based pharmacokinetic (PBPK) modeling. This technique allows prediction of drug pharmacokinetics in virtual patients using in vitro data and a mathematical description of drug distribution, thus offering the possibility to simulate clinically relevant scenarios such as DDI and the related dosage adjustments to compensate for the interaction effect. The simulations will be performed considering the impact of age on the pharmacokinetics of antiretroviral drugs and consequently their related potential to inhibit or induce co-administered drugs. The developed models will be initially validated by comparing the magnitude of simulated DDI using probe drugs to that observed in clinical studies. Subsequent clinical validations for the drug combinations of interest will include data issued from the TDM repository of the Swiss HIV Cohort Study. In addition, full pharmacokinetic profiles will be generated to validate DDI of particular interest.This research project is of particular clinical importance as it will provide guidance on how to manage DDI for drug combinations not evaluated in clinical studies. These data are particularly relevant in the aging HIV population given the high prevalence of comorbidities and/or acute complications and the related treatments which exacerbate the risk of DDI with the antiretroviral therapy. Furthermore, the findings related to this project may serve to define a comprehensive knowledge of the physiological and anatomical factors that influence drug disposition in elderly also for other drug classes. Finally, the PBPK modelling approach allows acquiring data which can support the design of clinical trials based on pharmacological priorities.
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