Researchers developed a pharmacokinetic (PK) model of ambrisentan (Letairis®) and showed that its exposure was similar between pediatric and adult populations with pulmonary arterial hypertension (PAH).

The study, which was recently published in the Journal of Clinical Pharmacology, suggests that body-weight-based dosing is appropriate in pediatric patients with PAH.

“The population PK model adequately described the pediatric data, showing no obvious systematic bias in model predictions,” the researchers explained. “It was based on a 2-compartment model with first-order absorption and elimination with an absorption lag time that was previously established for ambrisentan in an adult population.”

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The researchers found good agreement between the model-derived average pediatric and adult ambrisentan exposure at both low and high doses of the drug. Pediatric patients receiving low doses of ambrisentan (ie, 5 mg once daily) had a 3% lower geometric mean area under the concentration–time curve at steady state (AUCss) than adult patients. Pediatric and adult patients receiving high doses of ambrisentan (ie, 10 mg once daily) had a similar AUCss.

In addition, pediatric patients receiving low and high doses of ambrisentan had 11% and 18% higher geometric mean maximum plasma concentrations at steady state, respectively, than adult patients.

The exposure-response evaluation showed no clear associations between ambrisentan systemic exposure and treatment efficacy, as measured by 6-minute walk distance change from baseline, at 12 and 24 weeks in the pediatric or adult population. Moreover, it suggested no obvious association between ambrisentan exposure and the incidence of ambrisentan-related adverse events in pediatric patients.

The pediatric cohort included in the study (NCT01332331) was enrolled in a 6-month, randomized, open-label phase 2b study evaluating the safety, PK, and efficacy of high- and low-dose ambrisentan in patients with PAH aged 8 to 18 years.


Okour M, Thapar MM, Farrell C, Lukas MA, Beghetti M, Beerahee M. Pediatric population pharmacokinetic modeling and exposure-response analysis of ambrisentan in pulmonary arterial hypertension and comparison with adult data. J Clin Pharmacol. Published online December 29, 2022. doi:10.1002/jcph.2199