• Kevin D Hill, Anil R Maharaj, Jennifer S Li, Elizabeth Thompson, BarkerPiers C APCADivision of Pediatric Cardiology, Department of Pediatrics, Duke University Pediatric and Congenital Heart Center, Durham, NC., and Christoph P Hornik.
• Division of Pediatric Cardiology, Department of Pediatrics, Duke University Pediatric and Congenital Heart Center, Durham, NC.
• Pediatr Crit Care Me. 2020 Sep 1; 21 (9): e795e803e795-e803.

ObjectivesTo determine the pharmacokinetics, pharmacodynamics, and safety of the hepatically metabolized endothelin receptor antagonist, ambrisentan in children after Fontan surgery.DesignProspective, randomized, double-blind, placebo-controlled pharmacokinetic/pharmacodynamics and safety trial.SettingSingle-center, postoperative cardiac ICU.PatientsChildren undergoing elective Fontan surgery.InterventionsSubjects randomized on postoperative day number 1 to short-term (3 d) treatment with oral ambrisentan (2.5 mg in suspension, daily) versus placebo (4:1 randomization).Measurements And Main ResultsPlasma drug concentrations were measured at 0.5, 1, 2, 4, and 18-36 hours after the first dose. We developed a population pharmacokinetic model in NONMEM 7.2 (Icon Solutions, Ellicott City, MD) and applied the model to dose-exposure simulations. Pharmacodynamics endpoints were assessed at baseline and 3 hours after study drug administration, using postoperative hemodynamic monitoring lines. The analysis included 16 patients, 13 on ambrisentan (77 plasma samples); median age 36 months (range, 26-72 mo), weight 13.3 kg (11.1-17.6 kg), and nine males. There were no differences in baseline characteristics between ambrisentan and controls. A one-compartment model with first-order absorption and lag-time characterized the data well. Allometrically scaled weight was the only covariate retained in the final model. Typical values for clearance and volume of distribution were lower than previously reported in adults, 1 L/hr/70 kg and 13.7 L/70 kg, respectively. Simulated exposures with doses of 0.1-0.2 mg/kg approximated therapeutic exposures in adults with pulmonary arterial hypertension receiving 5 mg or 10 mg doses. Ambrisentan lowered plasma brain natriuretic peptide concentrations (452 ± 479 to 413 ± 462; p = 0.046), Fontan pressures (16.8 ± 2.9 to 15.6 ± 2.9; p = 0.01), and indexed pulmonary vascular resistance (2.3 ± 0.9 to 1.8 ± 0.6; p = 0.01) with no drug-related adverse events.ConclusionsAmbrisentan clearance is reduced following Fontan surgery, perhaps reflecting abnormal hepatic metabolism in this population. The observed safety profile appears favorable and hemodynamic effects of ambrisentan may be beneficial for Fontan patients.

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