Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study

center dot Exposure to bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg-1 when compared with adult PAH patients. center dot In healthy adult subjects, bosentan pharmacokinetics are less than dose-proportional at doses of >= 500 mg. WHAT THIS STUDY ADDS center dot The pharmacokinetics of a new paediatric bosentan formulation were characterized in paediatric PAH patients. center dot The level of exposure to bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. center dot In paediatric PAH patients, nondose-proportional pharmacokinetics of bosentan occur at lower doses when compared with healthy adult subjects. AIM To show equivalent bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation. METHODS Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with bosentan 2 mg kg-1 b.i.d. and then for 8 weeks with 4 mg kg-1 b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales. RESULTS Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration-time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg-1 were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in bosentan-naive patients, whereas the rare worsenings occurred in patients already on bosentan prior to study initiation. The paediatric formulation was well accepted and bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported. CONCLUSIONS Exposure to bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit-risk profile for bosentan at 2 mg kg-1 b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerate

A randomized, double-blind, placebo-controlled study of high-dose bosentan in patients with stage IV metastatic melanoma receiving first-line dacarbazine chemotherapy

Background: The endothelin system is implicated in the pathogenesis of melanoma. We evaluated the effects of bosentan - a dual endothelin receptor antagonist - in patients receiving first-line dacarbazine therapy for stage IV metastatic cutaneous melanoma in a phase 2, proof-of-concept study. Results: Eligible patients had metastatic cutaneous melanoma naïve to chemotherapy or immunotherapy, no central nervous system involvement, and serum lactate dehydrogenase <1.5 × upper limit of normal. Treatment comprised bosentan 500 mg twice daily or matching placebo, in addition to dacarbazine 1000 mg/m² every three weeks. Eighty patients were randomized (double-blind) and 38 in each group received study treatment. Median time to tumor progression (primary endpoint) was not significantly different between the two groups (placebo, 2.8 months; bosentan, 1.6 months; bosentan/placebo hazard ratio, 1.144; 95% CI, 0.717-1.827; p = 0.5683). Incidences of most adverse events and clinically relevant increases in hepatic transaminases were similar between treatment groups although hemoglobin decrease to >8 and ≤ 10 g/dL and ≤ 8 g/dL was more common in the bosentan group. Conclusions: In patients receiving dacarbazine as first-line chemotherapy for metastatic melanoma, the addition of high-dose bosentan had no effect on time to tumor progression or other efficacy parameters. There were no unexpected safety findings. Trial registration: This study is registered in ClinicalTrials.gov under the unique identifier NCT01009177

MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis, which is characterised by destruction of normal lung architecture and excessive deposition of lung extracellular matrix. The heterogeneity of disease progression in patients with IPF poses significant obstacles to patient care and prevents efficient development of novel therapeutic interventions. Blood biomarkers, reflecting pathobiological processes in the lung, could provide objective evidence of the underlying disease. Longitudinally collected serum samples from the Bosentan Use in Interstitial Lung Disease (BUILD)-3 trial were used to measure four biomarkers (metalloproteinase-7 (MMP-7), Fas death receptor ligand, osteopontin and procollagen type I C-peptide), to assess their potential prognostic capabilities and to follow changes during disease progression in patients with IPF. In baseline BUILD-3 samples, only MMP-7 showed clearly elevated protein levels compared with samples from healthy controls, and further investigations demonstrated that MMP-7 levels also increased over time. Baseline levels of MMP-7 were able to predict patients who had higher risk of worsening and, notably, baseline levels of MMP-7 could predict changes in FVC as early as month 4. MMP-7 shows potential to be a reliable predictor of lung function decline and disease progression

A Phase II study of bosentan, a dual endothelin receptor antagonist, as monotherapy in patients with stage IV metastatic melanoma

There is no effective systemic therapy for disseminated metastatic melanoma. Data suggest that endothelin may play a role in pathophysiology of melanoma and that the dual endothelin receptor antagonist bosentan may have anti-tumor activity. This multicenter, open-label, single-arm, prospective, proof-of-concept study assessed the effects of bosentan monotherapy (500 mg oral tablets, bid) on tumor response in patients with stage IV metastatic melanoma. Patients were treated until disease progression, death or serious adverse event leading to premature study drug discontinuation. Tumor response was assessed at 6-weekly intervals using the Response Evaluation Criteria in Solid Tumors (RECIST). Among the 35 patients included in this study with stage IV metastatic melanoma, 21 (60%) were stage M1C, 10 (29%) stage M1B and 4 (11%) stage M1A (American Joint Committee on Cancer [AJCC] classification). Nine patients (26%) had received prior therapy for stage IV melanoma. Disease stabilization was observed in 6 of the 32 patients analyzed per protocol at week 6 with confirmatory evaluation at week 12, 5 of whom were still stable at ≥24 weeks. Of the 6 patients with disease stabilization, 2 were stage M1A, 1 was stage M1B and the remaining 3 were stage M1C. Partial or complete response was not observed. Progressive disease was observed in 17 (49%) patients at week 12 and in 25 (71%) patients at the end of the study (data base closure). The most frequent adverse events were typical for the underlying disease or known to be associated with bosentan: headache (43%), fatigue (34%), nausea (31%), back pain (23%) and abnormal hepatic function (23%). Bosentan might have benefit in disease stabilization in certain patients with metastatic melanoma and deserves further investigation in combination with other anticancer drugs