Research  Focus: Pediatric Pulmonary Hypertension

from Practice Update, Winter 2004

The staff at The Children’s Hospital Heart Institute is involved in numerous leading-edge clinical trials and research projects. A continuing commitment to advance pediatric cardiac treatment relies on the willingness to incorporate research into every-day medicine. The following is a brief description of a clinical trial for the treatment of pulmonary arterial hypertension, a rare and debilitating disease associated with high morbidity and related to diseases such as congenital heart defects.

Pharmacokinetics, Safety and Efficacy of Bosentan in Pediatric Patients with Pulmonary Arterial Hypertension

Without lung or heart-lung transplantation, prolonged pulmonary arterial hypertension (PAH) leads to increased pulmonary vascular resistance and progressive right-sided heart failure and death. Historically, treatment options for PAH have been limited, and despite therapy, most patients continue to have symptoms and have a poor prognosis.

Results of a cooperative study at two of the nation’s leading pediatric pulmonary hypertension programs, The Children’s Hospital, in Denver , and New York Presbyterian Hospital , showed that the pharmacokinetics of bosentan in pediatric patients with pulmonary arterial hypertension and healthy adults are similar, and treatment with bosentan resulted in hemodynamic improvement. Bosentan is the first orally active, nonpeptide, dual antagonist of ET receptors developed for PAH. (Endothelin, ET, is a promoter of cell proliferation and a potent vasoconstrictor.) The study suggests that ET receptor antagonism may be a promising approach for the treatment of PAH.

After a screening period, 19 pediatric patients with pulmonary arterial hypertension were enrolled and stratified for body weight and epoprostenol use to determine dosing regimens. Bosentan produced hemodynamic improvement and was well tolerated. The mean change from baseline in mean pulmonary artery pressure was 8.0 mm Hg and that in pulmonary vascular resistance index was 300 dyne · s · m2/cm5.

The concomitant administration of bosentan and epoprostenol was also evaluated. Epoprostenol infusion has been shown to be effective in improving the quality of life, exercise capacity, and survival rate in patients with severe PAH. The benefit of epoprostenol treatment was similar to that reported for patients with primary pulmonary hypertension. However, epoprostenol treatment requires permanent, continuous intravenous infusion with a portable pump and thus is associated with potentially life-threatening complications, as well as side effects related to epoprostenol.

After 12 weeks of bosentan therapy, 15 patients had a decrease in mean pulmonary arterial pressure (PAPm), 17 had a decrease in pulmonary vascular resistance index (PVRI), and 11 had an increase in cardiac index. In the group as a whole, significant decreases were observed in PAPm and PVRI. Eight of 12 children who performed exercise testing had an increase in either walk distance or peak VO2 or both. By week 12, five children improved by one WHO (World Health Organization) functional class.

The most frequently reported adverse events were flushing (4 children) and headache and increased liver transaminase levels (3 patients each). Other adverse events known to be associated with bosentan treatment include edema (3 patients) and anemia (none). Two children had serious adverse events (tachycardia, hypertension, tremor, and dizziness in one child and a marked increase in ALT in another child).

When compared with the value in healthy subjects, peak drug levels appear to be shorter in pediatric patients. However, the relatively short tmax of bosentan in pediatric PAH patients is unlikely to be clinically relevant.

Data from this study show that epoprostenol had no statistically significant influence on the pharmacokinetics of bosentan in the pediatric population studied. On the basis of the markedly different metabolism and excretion profiles of bosentan and epoprostenol, no pharmacokinetic interaction was anticipated between these two drugs. However, epoprostenol may influence the pharmacokinetics of other drugs by increasing gastrointestinal, liver, or kidney blood flow. This mechanism may account for the decrease in digoxin oral clearance observed in patients with congestive heart failure receiving epoprostenol.

The limited data available indicate that when bosentan was given concomitantly to patients with or without stable epoprostenol treatment it improved the hemodynamics. These results suggest that the addition of bosentan to epoprostenol may allow a subsequent decrease in epoprostenol dose, potentially decreasing the prostanoid-related side effects and providing a new option for the treatment of pediatric PAH.

This article is adapted from “Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension,” published in Clinical Pharmacology & Therapeutics, volume 73, number 4, April 2003. Robyn J. Barst, MD, Dunbar Ivy, MD, Jasper Dingemanse, PhD, Allison Widlitz, MS, PA, Kelly Schmitt, RN, Aimee Doran, RN, CPNP, Deborah Bingaman, RN, CPNP, Ngoc Nguyen, BS, Michael Gaitonde, MB, MRCP, and Paul L. M. van Giersbergen, PhD New York, NY, Denver, CO, and Allschwil, Switzerland.