Antithrombotics' Therapeutic Optimization in Hospitalized Patients Using Physiologically- and Population-based Pharmacokinetic Modeling

Cardiovascular Diseases Clinical Trial

— OptimAT  

Official title:

Antithrombotics' Therapeutic Optimization in Hospitalized Patients Using Physiologically- and Population-based Pharmacokinetic Modeling

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03477331
• Other study ID #: 2017-00225
• Status: Completed
• Start date: January 14, 2018
• Est. completion date: January 31, 2024

Study information

• Verified date: April 2024
• Source: University Hospital, Geneva
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 444
• Est. completion date: January 31, 2024
• Est. primary completion date: January 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cardiovascular Diseases

Locations

Country	Name	City	State
Switzerland	Hopitaux universitaires de Genève, 4 rue Gabrielle-Perret-Gentil	Genève	GE

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Geneva

Country where clinical trial is conducted

Switzerland, 

References & Publications (3)

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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Area Under the Curve (AUC)	Difference between observed and PBPK model-predicted AUC (mean prediction error)	2 years
Secondary	Trough Concentration (Cmin)	Difference between observed and PBPK model-predicted Cmin (mean prediction error)	2 years
Secondary	Area Under the Curve (AUC) (stability of the model over time)	Difference between observed and model-predicted AUC during patients' rehospitalization (stability of the model over time)	2 years
Secondary	Major bleeding event-free survival	Major bleeding event-free survival according to drug exposure (AUC) during a prospective during a follow-up of two years for DOACs (dabigatran, rivaroxaban, apixaban) and P2Y12 receptor inhibitors (clopidogrel, ticragrelor, prasugel)	2 years
Secondary	Peak concentration (Cmax)	Difference between observed and PBPK model-predicted Cmax (mean prediction error)	2 years
Secondary	Thrombosis event-free survival	Thrombosis event-free survival according to drug exposure (AUC) during a prospective during a follow-up of two years for DOACs (dabigatran, rivaroxaban, apixaban) and P2Y12 receptor inhibitors (clopidogrel, ticragrelor, prasugel)	2 years

External Links

•   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
•   Liquid Biopsy for Patient Characterization in Cardiovascular Disease: Verification against Markers of Cytochrome P450 and P-Glycoprotein Activities
•   Population pharmacokinetics of apixaban in a real-life hospitalized population from the OptimAT study