Clinical trial NCT03477331: Antithrombotics' Therapeutic Optimization in Hospitalized Patients Using Physiologically- and Population-based Pharmacokinetic Modeling
Official title: Antithrombotics' Therapeutic Optimization in Hospitalized Patients Using Physiologically- and Population-based Pharmacokinetic Modeling
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cardiovascular Diseases
Keywords: Direct oral anticoagulant
P2Y12 inhibitors
Physiologically-based pharmacokinetic model (PBPK)
Population-based pharmacokinetic model (POPPK)
Lead sponsor: University Hospital, Geneva
Sponsor class: OTHER
First posted: 2018-03-26
Enrollment: 444
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Hospitalized patients

Brief summary: The main goal of the OptimAT study main goal is to validate a PBPK model for 3 direct oral anticoagulants (rivaroxaban, apixaban, dabigatran) and 3 P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel) in hospitalized patients.

Detailed description: Patients treated with antithrombotics are at risk of both severe ischemic and bleeding events. However, current clinical scores are insufficiently discriminant to predict the most favorable drug and dosing for an improved net clinical benefit. Physiologically and population-based pharmacokinetic models (PBPK and POPPK respectively) incorporate substrate specific properties obtained from experimental in-vitro experiments as well as patients' demographic, genetic and physiological in vivo data in order to characterize the dose-concentration relationships. As such, they can be used to simulate and predict PK profiles accounting for specific patients' characteristics and are the basis of dosing optimization. These models could be a valuable tool to predict antithrombotic blood concentration in a given patient. Our main goal is to elaborate predictive models characterizing the dose-concentration relationship with influencing variables of three direct oral anticoagulants (DOAC) (rivaroxaban, apixaban, dabigatran) and three P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor) in hospitalized patients, which will serve as basis for drug selection and dosage optimization.

Eligibility criteria: Inclusion Criteria:

* Hospitalized patients at any of the Geneva University Hospitals 18 yo and older
* Treated with DOAC (dabigatran, rivaroxaban, apixaban) or/and P2Y12 (clopidogrel, ticragrelor et prasugel) at the time of study blood sampling
* Understanding of French language and able to give an inform consent.

Exclusion Criteria:

* Patients with a reduced life span (\<6 mois)
* Exclusion criteria during follow up
* Change in dosage or cessation of the DOAC or P2Y12 taken by the participant follow up data will be censored at the time of change.

Primary outcomes:
measure: Area Under the Curve (AUC)
timeFrame: 2 years
Secondary outcomes:
measure: Trough Concentration (Cmin)
timeFrame: 2 years
measure: Area Under the Curve (AUC) (stability of the model over time)
timeFrame: 2 years
measure: Major bleeding event-free survival
timeFrame: 2 years
measure: Peak concentration (Cmax)
timeFrame: 2 years
measure: Thrombosis event-free survival
timeFrame: 2 years
Other outcomes:
Locations:
city: Genève
country: Switzerland
facility: Hopitaux universitaires de Genève, 4 rue Gabrielle-Perret-Gentil
state: GE
Study officials:
affiliation: University Hospital, Geneva
name: Jean-Luc Reny, Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: Terrier J, Gaspar F, Gosselin P, Raboud O, Lenoir C, Rollason V, Csajka C, Samer C, Fontana P, Daali Y, Reny JL; OptimAT study group. Apixaban and rivaroxaban's physiologically-based pharmacokinetic model validation in hospitalized patients: A first step for larger use of a priori modeling approach at bed side. CPT Pharmacometrics Syst Pharmacol. 2023 Dec;12(12):1872-1883. doi: 10.1002/psp4.13036. Epub 2023 Oct 4.
citation: Gaspar F, Terrier J, Favre S, Gosselin P, Fontana P, Daali Y, Lenoir C, Samer CF, Rollason V, Reny JL, Csajka C, Guidi M. Population pharmacokinetics of apixaban in a real-life hospitalized population from the OptimAT study. CPT Pharmacometrics Syst Pharmacol. 2023 Oct;12(10):1541-1552. doi: 10.1002/psp4.13032. Epub 2023 Sep 18.
citation: Achour B, Gosselin P, Terrier J, Gloor Y, Al-Majdoub ZM, Polasek TM, Daali Y, Rostami-Hodjegan A, Reny JL. Liquid Biopsy for Patient Characterization in Cardiovascular Disease: Verification against Markers of Cytochrome P450 and P-Glycoprotein Activities. Clin Pharmacol Ther. 2022 Jun;111(6):1268-1277. doi: 10.1002/cpt.2576. Epub 2022 Mar 28.