Tailored rivaroxaban regimens safe, effective for children with venous thromboembolism
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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
Reference:
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.
Perspective
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Maria T. DeSancho, MD, MSc
VTE in on the rise in children mainly due to hospital-acquired thrombosis. The main anticoagulant used in children is an injection of low-molecular-weight heparin. The EINSTEIN-Jr. phase 3 clinical trial compared the standard-of-care treatment for blood clots in children with an oral direct blood thinner, which is widely used among adults with blood clots. In this study, researchers enrolled a total of 365 children, the majority of whom were aged 12 to 18 years with only 34 aged younger than 2 years and 109 aged between 2 and 12 years. Researchers assessed two formulations of the drug — a tablet and a suspension — with the dose of the blood thinner adjusted to the body weight. Based on the results, with a less than 1% recurrence of the blood clots and no major bleeding, I feel very comfortable using this medication in children, specifically hose aged 12 to 18 years. However, I would like to have additional studies evaluating this oral blood thinner in a large number of infants before this medication is licensed for its use in children aged younger than 2 years.
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