A Randomized, Controlled Pharmacokinetic and Pharmacodynamics Trial of Ambrisentan After Fontan Surgery

Abstract

Objectives: To determine the pharmacokinetics, pharmacodynamics, and safety of the hepatically metabolized endothelin receptor antagonist, ambrisentan in children after Fontan surgery.

Design: Prospective, randomized, double-blind, placebo-controlled pharmacokinetic/pharmacodynamics and safety trial.

Setting: Single-center, postoperative cardiac ICU.

Patients: Children undergoing elective Fontan surgery.

Interventions: Subjects 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 results: Plasma 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.

Conclusions: Ambrisentan 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.

Figure 1.

Plasma Ambrisentan Concentration vs. Time Profile in Children after Fontan

Figure 2.

Prediction-corrected visual predictive check for the final PopPK model. Shaded areas define 95% predictions intervals for the 5^th(blue), 50^th(red), and 95^th(blue) percentiles based on 1000 model simulations.

Figure 3.

Simulated ambrisentan exposures following enteral administration of 0.1 mg/kg (A) and 0.2 mg/kg (B) doses in pediatric subjects with single ventricle heart defects (n=1000) compared to observed exposures from adult PAH patients from the literature[17]. For pediatric simulations, AUC represents the area under of the concentration-time curve from zero in infinity (AUC_0−∞) following single dose administration. For observed adult data, AUC represents the steady-state area under of the concentration-time curve over the 24 hour dosing interval (AUC_0–24hrs,ss). Points represent the geometric mean of simulated and observed data. Error bars depict 1 geometric standard deviation below/above the geometric mean. Areas (violin plots) depict the probability density of exposures associated with pediatric simulations. The horizontal width of each area is proportional to the density of data.