Effects of Two Dosing Regimens of Bosentan in Children With Pulmonary Arterial Hypertension

An Open-label, Prospective Multicenter Study to Assess the Pharmacokinetics, Tolerability, Safety and Efficacy of the Pediatric Formulation of Bosentan Two Versus Three Times a Day in Children With Pulmonary Arterial Hypertension

The primary objective of AC-052-373 was to assess the pharmacokinetic (PK) profile of two dosing regimens of the pediatric formulation of bosentan in children with pulmonary arterial hypertension (PAH) <12 years of age.

Inclusion Criteria:

1. PAH diagnosis confirmed with right heart catheterization (RHC):

   • Idiopathic or heritable PAH, or
   • Associated PAH persisting after complete repair of a congenital heart defect (PAH has to be persistent for at least 6 months after surgery) or
   • PAH-Congenital Heart Disease (PAH-CHD) associated with systemic-to-pulmonary shunts (after global amendment dated 09 May 2012)

2. World Health Organization functional Class (WHO FC) I, II or III

3. Male or female ≥ 3 months and < 12 years of age (maximum age at randomization is 11.5 years)

4. Body weight ≥ 3.5 kg

5. Peripheral oxygen saturation (SpO2) ≥ 88% (at rest, on room air)

6. Baseline PAH-therapy (Calcium channel blocker, bosentan, prostanoid, phosphodiesterase type-5 inhibitor) if present, has to be stable for at least 3 months prior to screening. During the study, all background treatments should remain stable

7. Signed informed consent by the parents or legal representatives

Exclusion Criteria:

1. PAH etiologies other than listed above

2. Non-stable disease status

3. Need or plan to wean patient from intravenous epoprostenol or intravenous or inhaled iloprost

4. Systolic blood pressure < 80% of the lower limit of normal range

5. Aspartate aminotransferase and/or alanine aminotransferase values > 1.5 times the upper limit of normal range.

6. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C

7. Hemoglobin and/or hematocrit levels < 75% of the lower limit of normal range.

8. Known intolerance or hypersensitivity to bosentan or any of the excipients of the dispersible Tracleer tablet

9. Treatment with forbidden medication within 2 weeks or at least 5 times the half-life prior to randomization, whichever is the longest:

   • Glibenclamide (glyburide)
   • Cyclosporin A
   • Sirolimus
   • Tacrolimus
   • Fluconazole
   • Rifampicin (rifampin)
   • Ritonavir
   • Co-administration of CYP2C9 inhibitors (e.g., amiodarone, voriconazole) and moderate/strong CYP3A4 inhibitors (e.g., amprenavir, erythromycin, ketoconazole, diltiazem, itraconazole)
   • Endothelin receptor antagonists (ERAs) other than bosentan

10. Treatment with another investigational drug within 1 month prior to randomization or planned treatment