Weight-based Uptravi dosing appropriate for PAH children: Study
Clinical study uses doses extrapolated from adult patient dosing
Body weight-adjusted Uptravi (selexipag) dosing for children and adolescents with pulmonary arterial hypertension (PAH) resulted in exposure to the treatment’s active ingredient comparable to that in adults with PAH, a study showed.
The study assessed the treatment’s pharmacokinetics — its movement into, through, and out of the body — in patients ages 2 to 17 exposed to body-adjusted doses extrapolated from adult patients.
“The presented [Uptravi] dose regimen for pediatric patients is considered appropriate for continuing the clinical evaluation of the safety and efficacy of selexipag in pediatric PAH patients [ages 2 and older],” the researchers wrote.
The study, “Population pharmacokinetics of selexipag for dose selection and confirmation in pediatric patients with pulmonary arterial hypertension,” was published in CPT: Pharmacometrics and Systems Pharmacology.
PAH is caused by the narrowing of pulmonary arteries, the small blood vessels that carry blood through the lungs. This restricts blood flow and causes high blood pressure, or hypertension. It also makes the heart work harder to pump blood, which can lead to right heart failure in advanced disease stages.
Pediatric treatment
Uptravi, marketed by Johnson & Johnson, is designed to delay disease progression and reduce the risk of PAH-related hospitalization. It works by binding to and activating the receptor for prostacyclin, a molecule that causes vessels to widen, lowering blood pressure.
The treatment is approved for adults with PAH at doses starting with 200 micrograms (mcg) twice daily, and gradually increasing at twice daily increments of 200 mcg according to each patient’s highest tolerated dose, up to a maximum of 1,600 mcg twice daily.
However, “to date, no treatment targeting the prostacyclin pathway is approved for use in pediatric patients,” the researchers wrote.
The team including researchers at Johnson & Johnson Innovative Medicine and Actelion Pharmaceuticals (also part of the Johnson & Johnson family of companies) aimed to identify a dosing regimen that results in similar exposures to selexipag and its active metabolite (product of metabolism) JNJ-68006861, to those shown to be effective in adults with PAH. They extrapolated from the treatment’s pharmacokinetics in adults defined in the Phase 3 trial GRIPHON (NCT01106014).
Based on this model, three dosing regimens were defined based on children’s body weight, at starting doses of 100 mcg twice daily for patients weighing 9 kg (about 20 pounds) to less than 25 kg (55 pounds), 150 mcg twice daily for those weighing 25 kg to less than 50 kg (110 pounds), and 200 mcg twice daily for patients weighing 50 kg or more. The maximum allowed doses were 800 mcg, 1,200 mcg, and 1,600 mcg twice daily, respectively, for the three body weight categories.
The proposed regimen was assessed in a Phase 2 clinical study (NCT03492177) enrolling 63 children and adolescents with PAH, ages 2 to 17, with body weight ranging from 9.9 kg (about 22 pounds) to 93.5 kg (206 pounds). Participants were divided into three groups according to their age: 12 to 17, 6 to 11, and 2 to 5. As in adults, the dose was adjusted to each patient’s maximum tolerated dose.
Overall, the body weight-adjusted dose regimen resulted in exposures to selexipag and its active metabolite comparable to those seen in adults with PAH, across all age groups. No clinically relevant differences in pharmacokinetics were observed between adults and children.
Based on the results, the presented dosing regimen was found adequate for the clinical evaluation of Uptravi in children and adolescents with PAH. The therapy’s safety and efficacy as an add-on to standard of care in this patient population are being evaluated in the Phase 3 SALTO trial (NCT04175600).
That study has enrolled 138 patients, randomly assigned to receive the treatment or a placebo for up to five years, followed by a three-year, open-label extension period.
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