Pharmacokinetics of a Microdosed Cocktail Containing Rivaroxaban, Apixaban, and Edoxaban in Children with Congenital Heart Defects

Background: Direct oral anticoagulants (DOACs) are direct inhibitors of coagulation factor Xa and are approved for the use in adults, but not in children. Current anticoagulation regimes in children with congenital heart defects (CHD) consist of phenprocoumon or (low-molecular-weight) heparin. Disadvantages of these regimes comprise invasive monitoring (phenprocoumon) or invasive administration techniques (heparin). The present study examines simultaneously the pharmacokinetics (PK) of the three FXa inhibitors apixaban, edoxaban, and rivaroxaban in children after heart surgery aged 6 months to 6 years.

Method: A single-center, open label, fixed-sequence clinical trial (EudraCT 2019-001759-38) was performed in children aged 6 months to 6 years with acyanotic congenital heart defects. Study participants received a single oral microdosed cocktail containing apixaban, rivaroxaban, and edoxaban at least 48 hours after surgery. Plasma concentrations over 24/25 hours were quantified by UHPLC-MS/MS and major PK parameters of each drug were calculated. Eleven children could be included, the data of 9 children were analyzed so far.

Results: The mean age of the 9 children (4 m/5 f) is 2.7 (0.8–5.9) years and mean bodyweight (BW) is 12.6 (7.7–21.2) kg. All patients underwent corrective heart surgery with CPB without complications and received concomitant treatment per standard of care. PK profiles of all three DOACs are different compared to a cohort of 18 healthy adult volunteers. The oral clearance (Cl/F) is 3.2- (apixaban), 3.5- (edoxaban), and 2.1- (rivaroxaban) fold lower in children than in healthy young adults, respectively. The BW-adjusted oral clearance for apixaban is 1.88 versus 0.92 mL/min/kg, for edoxaban 21.60 versus 10.27 mL/min/kg, and for rivaroxaban 4.76 versus 1.59 mL/min/kg (children vs. adults per kg BW). Regarding safety, no relevant bleeding events or changes in INR and aPTT were noted.

Conclusion: This small heterogenic cohort delivers first, preliminary information on the PK of DOACs in young children up to 6 years of age. The application of the FXaI microdose cocktail together with highly sensitive analytical methods appears to be a safe and effective methodology to evaluate narrow therapeutic index drugs such as DOACs in vulnerable pediatric populations. After completion of this study, the DOAC with the most favorable PK profile and least variability will be chosen and administered as a therapeutic dose. Thus it is expected that the future use of DOACs will ultimately improve compliance and overall safety of anticoagulant therapies in pediatric heart patients.

Publication History

Article published online:
28 January 2023