Projects & Collaborations 3 foundShow per page10 10 20 50 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 Research Project | 3 Project MembersCombined antiretroviral treatments have significantly improved the morbidity and mortality related to HIV infection thus transforming HIV infection into a chronic disease. However, the efficacy of antiretroviral treatments is highly dependent on the ability of infected individuals to adhere to life-long drug combination therapies. Incomplete treatment adherence can indeed promote the emergence of drug-resistant HIV viruses resulting in loss of virological control and leading consequently to the risk of HIV transmission. A major milestone will be achieved in 2019 with the marketing of the first long-acting intramuscular antiretroviral drugs, cabotegravir and rilpivirine, for the treatment and prevention of HIV infection. Intramuscular injections create a "depot" in the muscle from where the drug is released for an extended period thus allowing for infrequent drug administration (e.g. once a month or bimonthly) with the potential to improve adherence to therapy and treatment satisfaction. Although intramuscular formulations hold great promises for long-term treatment of HIV infection, a number of questions about their optimal use remain unresolved. The absorption and bioavailability of drugs administered intramuscularly is impacted by factors such as obesity, exercise and blood flow in the muscle, thus cabotegravir and rilpivirine pharmacokinetics in special HIV infected populations like obese, elderly or pregnant women is currently unknown. Furthermore, intramuscular release of drugs cannot be interrupted, therefore the management of drug-drug interactions (DDI) with any inducing/inhibiting comedications required to treat inaugural diseases (e.g. epilepsy, mycobacterial infection) while on long-acting intramuscular therapy is also unknown. The aims of this project are a) to characterize the pharmacokinetics of intramuscular cabotegravir and rilpivirine and dosing requirements in special populations and b) to simulate dosage adjustments to overcome DDIs using physiologically based pharmacokinetic (PBPK) modeling. This technique allows the prediction of drug pharmacokinetics in virtual individuals (generated considering anatomical and physiological changes related to a specific condition like obesity, aging or pregnancy) using in vitro data and a mathematical description of drug distribution after intramuscular administration thus offering the possibility to simulate clinical scenarios of interest. The performance of the PBK models will be verified by comparing simulated intramuscular profiles of cabotegravir and rilpivirine against available clinical data (obtained in a standard population). After successful prediction, simulations will be carried out in special populations. This research project is of particular clinical importance as it will provide guidance on dosing requirements in special populations, which have not been evaluated during drug development but which may also benefit from this novel treatment paradigm aiming to improve the chances of life-long maintenance of HIV suppression. In addition, this project will provide guidance on the management of DDIs, which are not always preventable because intramuscular injections are not reversible. Addressing these questions will enable to broaden the use of injectable antiretroviral drugs thus offering an effective strategy for the treatment and prevention of HIV infection and the perspective to curb the HIV epidemic. Furthermore, this project will provide a comprehensive knowledge of factors influencing intramuscular drug disposition. Physiologically based pharmacokinetic modeling of antiretroviral agents in special populations Research Project | 1 Project MembersThe 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 will become more complex as age-related decline in the function of organs may impact the pharmacokinetic of antiretroviral agents and thereby affect dosage requirements. Furthermore, due to improved health outcomes, HIV-infected individuals are becoming increasingly overweight or obese at a rate similar to the general population. Thus, obesity represents a new challenge in the treatment of HIV infection because the actual recommended drug doses may not be sufficient. Finally, the epidemiology of HIV infection has changed over the years so that women represent now a substantial proportion of infected adults. Thus, as more effective and tolerable antiretroviral drugs have become available, and as the prevention of mother-to-child transmission has becomes an achievable goal, more and more HIV-infected women are choosing to become pregnant and to have children. Even though the physiological changes associated with pregnancy are well known to cause pharmacokinetics alterations, there is a scarcity of data on dose optimization strategies for antiretroviral drugs during pregnancy. All together, the issue of antiretroviral drug dosing in these special populations relates to the fact that recommended doses are usually issued from clinical trials including a "standard" HIV-infected population which does not reflect the physiological changes and thereby pharmacokinetic changes occurring in the above mentioned conditions. The aim of this project is to characterize the dosing requirements in special populations using a 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 therapy optimization in special populations. This project is of clinical importance as, with the prolonged lifespan of HIV-infected individuals, the number of patients that will potentially require dose adjustments will gradually increase. Drug-drug interaction in a large HIV cohort study Research Project | 1 Project MembersDrug interactions from HIV therapies continue to increase as new drugs are approved and antiretroviral agent regimens become more complex. Drug interactions are associated with substantial risk of adverse pharmacokinetic or pharmacodynamic interactions, resulting in decreased therapeutic efficacy, increased incidence of drug toxicities, and subsequent emergence of drug resistance. Therefore, the identification, resolution, and prevention of drug-related problems are important determinants for patient clinical management. The proposed study investigates the prevalence (cross-sectional study part) of drug-drug interactions within the Swiss HIV Cohort Study patients using the University of Liverpool drug interaction database (www.hiv-druginteractions.org). This study further includes an intervention part, which informs the physician of clinically significant drug-drug interactions by using this database. A second survey will determine if the occurrence of potential drug-drug interactions is reduced for physicians who used the database. 1 1
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 Research Project | 3 Project MembersCombined antiretroviral treatments have significantly improved the morbidity and mortality related to HIV infection thus transforming HIV infection into a chronic disease. However, the efficacy of antiretroviral treatments is highly dependent on the ability of infected individuals to adhere to life-long drug combination therapies. Incomplete treatment adherence can indeed promote the emergence of drug-resistant HIV viruses resulting in loss of virological control and leading consequently to the risk of HIV transmission. A major milestone will be achieved in 2019 with the marketing of the first long-acting intramuscular antiretroviral drugs, cabotegravir and rilpivirine, for the treatment and prevention of HIV infection. Intramuscular injections create a "depot" in the muscle from where the drug is released for an extended period thus allowing for infrequent drug administration (e.g. once a month or bimonthly) with the potential to improve adherence to therapy and treatment satisfaction. Although intramuscular formulations hold great promises for long-term treatment of HIV infection, a number of questions about their optimal use remain unresolved. The absorption and bioavailability of drugs administered intramuscularly is impacted by factors such as obesity, exercise and blood flow in the muscle, thus cabotegravir and rilpivirine pharmacokinetics in special HIV infected populations like obese, elderly or pregnant women is currently unknown. Furthermore, intramuscular release of drugs cannot be interrupted, therefore the management of drug-drug interactions (DDI) with any inducing/inhibiting comedications required to treat inaugural diseases (e.g. epilepsy, mycobacterial infection) while on long-acting intramuscular therapy is also unknown. The aims of this project are a) to characterize the pharmacokinetics of intramuscular cabotegravir and rilpivirine and dosing requirements in special populations and b) to simulate dosage adjustments to overcome DDIs using physiologically based pharmacokinetic (PBPK) modeling. This technique allows the prediction of drug pharmacokinetics in virtual individuals (generated considering anatomical and physiological changes related to a specific condition like obesity, aging or pregnancy) using in vitro data and a mathematical description of drug distribution after intramuscular administration thus offering the possibility to simulate clinical scenarios of interest. The performance of the PBK models will be verified by comparing simulated intramuscular profiles of cabotegravir and rilpivirine against available clinical data (obtained in a standard population). After successful prediction, simulations will be carried out in special populations. This research project is of particular clinical importance as it will provide guidance on dosing requirements in special populations, which have not been evaluated during drug development but which may also benefit from this novel treatment paradigm aiming to improve the chances of life-long maintenance of HIV suppression. In addition, this project will provide guidance on the management of DDIs, which are not always preventable because intramuscular injections are not reversible. Addressing these questions will enable to broaden the use of injectable antiretroviral drugs thus offering an effective strategy for the treatment and prevention of HIV infection and the perspective to curb the HIV epidemic. Furthermore, this project will provide a comprehensive knowledge of factors influencing intramuscular drug disposition.
Physiologically based pharmacokinetic modeling of antiretroviral agents in special populations Research Project | 1 Project MembersThe 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 will become more complex as age-related decline in the function of organs may impact the pharmacokinetic of antiretroviral agents and thereby affect dosage requirements. Furthermore, due to improved health outcomes, HIV-infected individuals are becoming increasingly overweight or obese at a rate similar to the general population. Thus, obesity represents a new challenge in the treatment of HIV infection because the actual recommended drug doses may not be sufficient. Finally, the epidemiology of HIV infection has changed over the years so that women represent now a substantial proportion of infected adults. Thus, as more effective and tolerable antiretroviral drugs have become available, and as the prevention of mother-to-child transmission has becomes an achievable goal, more and more HIV-infected women are choosing to become pregnant and to have children. Even though the physiological changes associated with pregnancy are well known to cause pharmacokinetics alterations, there is a scarcity of data on dose optimization strategies for antiretroviral drugs during pregnancy. All together, the issue of antiretroviral drug dosing in these special populations relates to the fact that recommended doses are usually issued from clinical trials including a "standard" HIV-infected population which does not reflect the physiological changes and thereby pharmacokinetic changes occurring in the above mentioned conditions. The aim of this project is to characterize the dosing requirements in special populations using a 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 therapy optimization in special populations. This project is of clinical importance as, with the prolonged lifespan of HIV-infected individuals, the number of patients that will potentially require dose adjustments will gradually increase.
Drug-drug interaction in a large HIV cohort study Research Project | 1 Project MembersDrug interactions from HIV therapies continue to increase as new drugs are approved and antiretroviral agent regimens become more complex. Drug interactions are associated with substantial risk of adverse pharmacokinetic or pharmacodynamic interactions, resulting in decreased therapeutic efficacy, increased incidence of drug toxicities, and subsequent emergence of drug resistance. Therefore, the identification, resolution, and prevention of drug-related problems are important determinants for patient clinical management. The proposed study investigates the prevalence (cross-sectional study part) of drug-drug interactions within the Swiss HIV Cohort Study patients using the University of Liverpool drug interaction database (www.hiv-druginteractions.org). This study further includes an intervention part, which informs the physician of clinically significant drug-drug interactions by using this database. A second survey will determine if the occurrence of potential drug-drug interactions is reduced for physicians who used the database.
