large nested project (SHCS); physiologically based pharmacokinetic modeling; large nested project (SHCS); drug-drug interactions; antiretroviral drugs; aging HIV population; dose adjustment
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
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
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
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
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
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
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
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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.
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.
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.
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.
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.
Marzolini C, Livio F (2019), Prescribing issues in elderly individuals living with HIV., in Expert Rec Clin Pharmacol
, 12(7), 643-659.
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.
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.
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.
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.
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.