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

Daily exposure was measured by the area under the plasma concentration-time curve over a period of 24 hours \[AUC(0-24)\]. Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. AUC(0-24) was calculated as a multiple of AUCtau, which is the AUC over a dosing interval (AUCtau x 2 for the b.i.d. dosing regimen and AUCtau x 3 for the t.i.d. regimen). As the smallest dose unit was 8 mg (1/4 tablet), it was not possible to achieve the exact target dose of 2 mg/kg. Therefore, AUC(0-24) was corrected to 2 mg/kg (target dose) \[AUC(0-24c)\].

Time frame: 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment

Population: Per-protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.

The GCIS is an assessment tool providing a single global assessment of the patient's current overall clinical condition: Very Good, Good, Neither Good or Bad, Bad and Very Bad. The assessment was performed both by the physician and the parents / legal representatives independently. Global clinical impression (GCI) at end of study was compared to GCI at baseline and the number of patients with clinical condition considered as worsened, improved or unchanged are determined.

Time frame: Baseline, up to Week 24 on average

Population: All-randomized set. Because all 64 randomized patients were treated with at least one dose of study drug, the All-randomized set was identical to the All-treated set.

The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension (PH): Class I (FC I): No limitation of physical activity. Class II (FC II): Slight limitation of physical activity. Class IIII (FC III): Marked limitation of physical activity. Class IV (FC IV): Inability to carry out any physical activity without symptoms. Number of patients with improvement (shift from a higher to a lower class), worsening (shift from a lower to a higher class) or no change in WHO functional class at end of study compared to baseline are determined.

Time frame: Baseline, up to Week 24 on average

Population: All-randomized set. Because all 64 randomized patients were treated with at least one dose of study drug, the All-randomized set was identical to the All-treated set.

Concentrations of the metabolites were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. Daily exposure to the metabolites corresponds to the area under the concentration-time curve \[AUC(0-24)\] of the corresponding metabolite over a period of 24 hours, and was calculated in the same manner as the primary endpoint. AUC(0-24c) was corrected to 2 mg/kg (target dose) \[AUC(0-24c)\].

Time frame: 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment

Population: Per protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.

Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. The peak plasma concentration (Cmax) of bosentan was directly obtained from the measured plasma concentrations and was dose-corrected to the target dose of 2 mg/kg (Cmaxc).

Time frame: 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment

Population: Per-protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.

Number of patients with marked hemoglobin decreases (absolute values below 10 g/dL). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date.

Time frame: Baseline, up to Week 24

Population: All randomized patients who received at least one dose of study drug and with available data.

Number of patients with increase in alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) above 3 times upper limit of normal (ULN). The worst post-baseline value was considered. The treatment-emergent period was defined as study treatment start date up to 7 calendar days after study treatment end date.

Time frame: Baseline, up to Week 24

Population: All randomized patients who received at least one dose of study drug and with available data.

Concentrations of bosentan were measured directly in blood samples collected prior to study drug administration and up to 8 hours or up to 12 hours post-dose for the t.i.d and b.i.d. dosing regimen, respectively. tmax was obtained directly from the measured plasma concentrations.

Time frame: 0, 0.5, 1, 3, 5 (or 7.5), 8 (or 12 hours) post-dose at Week 4, after at least 2 weeks of stable study drug treatment

Population: Per protocol PK analysis set (PK set): All patients included in the bosentan 2 mg/kg b.i.d. and bosentan 2 mg/kg t.i.d. groups who received at least one dose of bosentan and who were able to provide at least 5 blood samples for PK assessments and who did not violate the protocol in a way that might affect the evaluation of the PK main endpoint.