麻豆传媒

ORLANDO -- New data from the so-called Einstein Jr. collaborative confirm dosing regimens for a pediatric oral suspension of rivaroxaban (Xarelto), suitable for children ranging from 2.6 to 70 kg in weight experiencing venous thromboembolism (VTE), that could form the basis for official labeling, researchers said here.

These dosing schemes -- from the standard adult dose of 20 mg once daily for 16-year-olds as big as adults down to 0.8 mg three times daily for those of newborn size -- produced blood levels giving the same 24-hour exposures seen in adult pharmacokinetic studies in the vast majority of children, reported Guy Young, MD, of Children's Hospital Los Angeles, at the American Society of Hematology (ASH) annual meeting.

In a secondary analysis of data, for which positive clinical outcome results were reported earlier this year, the data validate the dosing regimens tested in that study and reaffirm that the novel oral suspension can "provide a new alternative treatment option for VTE in children," Young said at an ASH press briefing.

ASH press briefing moderator Mark Crowther, MD, of McMaster University in Hamilton, Ontario, called the trial "critically important," and "a true landmark," providing the basis to make direct oral anticoagulants available to children with VTE.

ASH President Roy Silverstein, MD, of the Medical College of Wisconsin in Milwaukee, said during a separate press call that the study caps a program that will change practice. The oral rivaroxaban suspension "will be the new standard of care for children," he said, adding that he expects FDA approval "relatively soon."

Young explained that VTE is a growing problem in children, in large part because the healthcare-associated risk factors for the condition increasingly affect the young. "We're getting better at treating really sick children," he said, which leads to growing use of VTE-promoting interventions such as central venous catheters.

In parallel, it was recognized early in the development of direct oral anticoagulants, such as rivaroxaban, that these agents would improve VTE treatment in children. Standard therapy was (and remains) either warfarin -- available only in pill form and for which dosing is even more challenging than in adults, with weight to factor in as well as the unpredictable response to a given dose -- or injectables such as heparin analogues that have to be administered at home daily. The problem there, Young noted, is not hard to picture. "Imagine holding down your 2-year-old to inject twice a day," he said.

Consequently, in 2008 -- the same year rivaroxaban gained its first FDA approval for adults -- the Einstein Jr. collaborative began to consider how to adapt the medication to the wide range of pediatric body weights, while also recognizing that young, sick children often have trouble with pills.

Developing a suitable formulation turned out to be considerably more difficult than simply grinding up the regular pills and putting them in solution. (Indeed, speakers here emphasized that this is not something parents should try at home -- Young noted that one early effort using rivaroxaban granules simply didn't work in children, and the risks of overdosing are considerable).

The Einstein Jr. group worked with rivaroxaban's manufacturers to develop the current formulation, which was tested in phase I and II studies to set up the weight-based dosing plan evaluated in the pivotal phase III trial. This study enrolled 500 patients, from newborns to age 18, randomized 2:1 to weight-based rivaroxaban doses or standard treatment with heparin or vitamin K antagonists. The main study period was 3 months (1 month for children younger than 2 with catheter-related VTE), followed by open-label treatment for up to 12 additional months.

Early on, Young said, it became clear that once-daily dosing would not be appropriate for children smaller than 30 kg. The group eventually settled on twice-daily dosing for those with weights of 12-30 kg, and three times daily for children below 12 kg. In all, 12 dose levels below the standard for adults were established to span the 2.6-50 kg range (children weighing 50 kg or more got the regular adult dose).

Data from the phase III participants confirmed that these dose levels provided children with adequate yet not excessive drug exposure in three important pharmacokinetic measures: area under the 24-hour curve for blood levels (24-hour AUC), maximal concentration (C_max), and trough concentration (C_trough).

Of the 335 participants receiving rivaroxaban, only five exceeded the maximum for any of the three measures. No patient had a C_trough level below the target range. Five had C_max levels below target, and about 15 had suboptimal 24-hour AUCs. In total, 25 of 335 had measures out of the target ranges.

Also, only one patient with values outside of target had a suboptimal clinical outcome (24-hour AUC below target, no clinical improvement).

Young reported as well that, among patients with bleeding events, only one had a pharmacokinetic measure above target. Most bleeds were rated "trivial" and none were major.

Bayer has submitted a formal marketing application in Europe, Young said, with action possible in 2020. In the U.S., the situation is "more complicated," he added. Johnson & Johnson's Janssen unit holds U.S. development rights and hasn't yet filed for marketing approval, although that they expect to at some point.

But Young told 麻豆传媒 he didn't think more research will be needed to secure eventual approval for the VTE treatment indication. Additional studies are likely, though, to support other pediatric uses for the rivaroxaban suspension.

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