Tailored rivaroxaban regimens safe, effective for children with venous thromboembolism
ORLANDO — Body weight-adjusted regimens of rivaroxaban appeared to be safe and effective for children with venous thromboembolism, according to results of a dose-exposure-response evaluation of the phase 3 EINSTEIN-Jr. study presented at ASH Annual Meeting and Exposition.
“VTE in children is different than adults because the vast majority of cases occur in acute or chronic serious illnesses,” Guy Young, MD, director of the hemostasis and thrombosis program at Children's Hospital Los Angeles and professor of pediatrics at Keck School of Medicine of University of Southern California, told Healio. “This is because we tend to use central venous catheters to administer medication and draw blood for treating sick kids. Clotting is more common in the upper extremities, where the catheter is inserted for treatment. In adults, clotting is mostly in the legs.”
Young added that healthy children can also develop blood clots related to trauma or in girls on birth control.
Anticoagulant options are limited when treating children, and include injectable medications and warfarin. However, warfarin is difficult to use because of the lack of a liquid version and its potential to negatively react to other medications, Young added.
Subcutaneous dalteparin (Fragmin, Pfizer) is the only anticoagulant currently licensed for pediatric use, and no child-appropriate formulations of direct oral anticoagulants are commercially available.
In some cases, doctors prescribe off-label rivaroxaban (Xarelto, Janssen) to children aged 16 and 17 years.
“The drug is only licensed for people aged 18 years and older,” Young said. “To call a 16 or 17-year-old who is 6 feet tall a child is a little weird. If they are 14 or 15, it depends on their size. Children younger than 14 don’t usually ever get it because we don’t have the right tablet size or the liquid formulation.”
In the randomized phase 3 EINSTEIN-Jr. study, rivaroxaban demonstrated safety and effectiveness similar to that of standard anticoagulation for treating pediatric VTE.
Young and colleagues reported the dose-exposure and response relationship of rivaroxaban from the study, with regimens determined based on previous phase 1 and phase 2 data among children and through pharmacokinetic modeling.
The study included 316 children evaluable for pharmacokinetic analysis who received body weight-adjusted rivaroxaban in tablet (n = 121) or suspension (liquid) formulation (n = 195). Investigators grouped patients by age from birth to 0.5 years (n = 13), 0.5 years to younger than 2 years (n = 21), 2 years to younger than 6 years (n = 44), 6 years to younger than 12 years (n = 65), and 12 years to younger than 18 years (n = 173).
Treatment was administered once daily to children weighing 30 kg or more, twice daily to children weighing 12 kg to less than 30 kg, and three times daily to children with body weights less than 12 kg.
Researchers used population pharmacokinetic modeling to derive 24-hour area under the plasma concentration-time curve, trough and maximum steady-state plasma concentrations. They used exposure-response graphs to study the potential relationship of individual pharmacokinetic parameters with recurrent VTE, thrombus burden change at repeat imaging and bleeding or adverse events.
Symptomatic recurrent VTE occurred among two patients during treatment.
Repeat imaging outcomes among asymptomatic patients were classified as normal (n = 124), improved (n = 125), no relevant change (n = 16) or deteriorated (n = 1). Results of repeat imaging were uncertain in 48 patients.
Researchers observed no major bleeding events related to rivaroxaban treatment. However, clinically relevant nonmajor bleeding occurred in 10 patients and trivial bleeding occurred in 111 patients.
In evaluating the dose-exposure relationship, researchers found that most individual values fell within the 5th to 95th percentile for area under the curve 24-hour steady state, maximum steady-state and trough steady-state plasma concentrations.
Researchers also did not observe any clustering for any of the pharmacokinetic modeling parameters in efficacy, bleeding or adverse events. Results appeared similar with the tablet or suspension formulation, the latter of which demonstrated favorable acceptability and palatability.
“Developing a drug like rivaroxaban — which has been approved for many years for adults —and having it available to children will be a huge step forward in making the treatment of VTE a lot simpler and less painful,” Young said. “The FDA is putting up a few more roadblocks because they want more data on kids with heart disease who may need it, but I think that’s unfair and that it should be approved now for VTE based on the data we already have available. They can always expand the indication later.”– by John DeRosier
Young G, et al. Abstract 164. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Young reports advisory/consultant roles with and honoraria from Bioverativ/Sanofi, CSL Behring, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Shire/Takeda, Spark and uniQure, and research funding from Genentech/Roche. Please see the study for all other authors’ relevant financial disclosures.