Reference Range of Rivaroxaban-calibrated Anti-Xa Activity in Chinese Children with Giant Coronary Artery Aneurysm after Kawasaki Disease: Insights from a Population PKPD Analysis
Bijue Liu(1), Guang-an Dai(2), Nuo Xu(1), Fang Liu(2), Xiao Zhu(1).
Affiliations:
1 Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, China.
2 Pediatric Heart Center, Children’s Hospital of Fudan University, Shanghai, China.
Introduction: Rivaroxaban, a direct factor Xa inhibitor, is considered a highly promising treatment for pediatric patients with giant coronary artery aneurysm (GCAA) after Kawasaki disease (KD). However, its pharmacokinetic-pharmacodynamic (PKPD) study in Chinese pediatrics remains limited. The appropriate target range also needs to be identified to guide the long-term medication in rapidly maturing pediatric patients.
Aims: To 1) characterize the PKs of rivaroxaban and its correlation with anti-Xa activity; 2) recommend reference range of anti-Xa activity in Chinese children with GCAA after KD.
Methods: Sparse sampling rivaroxaban concentration (Criva) and rivaroxaban-calibrated anti-Xa activity data from a prospective clinical study conducted at Children’s Hospital of Fudan University (NCT05643651) were analyzed using NONMEM®. The PKPD model was developed sequentially following a PPP&D modelling approach (by fixing the PK parameters first, then developing the PKPD model). Anti-Xa activity, favored rivaroxaban monitoring index, was linked to Criva in either a linear or Emax relationship. Individual PKPD parameters were used to derive participants’ anti-Xa time-course, as a reference for expected exposure of peak and trough.
Result: 145 rivaroxaban samples and 85 anti-Xa activity samples were collected from 35 children in over 1 year. The median (range) age and weight were 8.1 years (2.0-15.5) and 25.0 kg (12.0-73.0). A two-compartment model with first-order elimination best described the PK data. The absorption rate constant (ka) was 0.384 /h with an inter-individual variability (IIV) of 35.5%. Apparent clearance (CL/F) was 7.28 L/h (IIV 38.2%) at a reference weight of 25 kg and scaled by weight with an exponent of 0.287. The apparent central (Vc/F) and peripheral (Vp/F) volume of distribution were 20.5 L and 72.6 L, respectively, in a 25 kg subject, and scaled by weight with an exponent of 0.712. Apparent intercompartmental clearance (Q/F) was 1.49 L/h. A linear model (Anti-Xa =0.954×Criva+4.29) was chosen to describe the relationship between Criva and anti-Xa activity (Criva within the range of 0.5-500 ng/mL). All parameters were precisely estimated (relative standard error ≤ 50%), and both GOF and VPC plots demonstrated the satisfactory predictive performance of the model. Anti-Xa activity of participants, who all responded well to the medication, was regarded as the reference range for balancing the therapeutic effect and safety in Chinese pediatrics with GCAA after KD. The recommended anti-Xa activity range is 111.9 ng/mL (50.8-186.0) at peak (2-4 hour after last dose), and 10.6 ng/mL (5.8-24.0) at trough (22-24 hour after last dose).
Conclusion: The developed population PKPD model could be used to describe Criva and anti-Xa activity simultaneously. Recommended expected rivaroxaban-calibrated anti-Xa activity range could be used to guide rivaroxaban precision medicine in Chinese children with GCAA after KD.