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A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3.

ABSTRACT: AIM:The aim of the present study was to investigate whether increasing the bosentan dosing frequency from 2 mg kg-1 twice daily (b.i.d.) to 2 mg kg-1 three times daily (t.i.d.) in children with pulmonary arterial hypertension (PAH) (from ?3 months to <12 years of age) would increase exposure. METHODS:An open-label, prospective, randomized, multicentre, multiple-dose, phase III study was conducted. Patients (n = 64) were randomized 1:1 to receive oral doses of bosentan of 2 mg kg-1 b.i.d. or t.i.d. The main pharmacokinetic endpoint was the daily exposure to bosentan over 24 h corrected to the 2 mg kg-1 dose (AUC0-24C ). The maximum plasma concentration corrected to the 2 mg kg-1 dose (CmaxC ), the time to reach the maximum plasma concentration (tmax ) and safety endpoints were also assessed. RESULTS:The geometric mean [95% confidence interval (CI)] for AUC0-24C was 8535 h.ng ml-1 (6936, 10?504) and 7275 h.ng ml-1 (5468, 9679) for 2 mg kg-1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.85 (0.61, 1.20)]. The geometric mean (95% CI) for CmaxC was 743 ng ml-1 (573, 963) and 528 ng ml-1 (386, 722) for 2 mg kg-1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.71 (0.48, 1.05)]. The median (range) for tmax was 3.0 h (0.0-7.5) and 3.0 h (1.0-8.0) for 2 mg kg-1 b.i.d. and t.i.d., respectively. The proportions of patients who experienced ?1 adverse event were similar in the b.i.d. (66.7%) and t.i.d. (67.7%) groups. CONCLUSIONS:There appeared to be no clinically relevant difference in exposure to bosentan, or in safety, when increasing the frequency of bosentan dosing from b.i.d. to t.i.d. Therefore, the present study provides no indication that the dosing recommendation should be changed, and 2 mg kg-1 b.i.d. remains the recommended dosing regimen for bosentan in paediatric PAH patients.

SUBMITTER: Berger RMF

PROVIDER: S-EPMC5510076 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3.

Berger Rolf M F RMF Gehin Martine M Beghetti Maurice M Ivy Dunbar D Kusic-Pajic Andjela A Cornelisse Peter P Grill Simon S Bonnet Damien D

British journal of clinical pharmacology 20170323 8

<h4>Aim</h4>The aim of the present study was to investigate whether increasing the bosentan dosing frequency from 2 mg kg<sup>-1</sup> twice daily (b.i.d.) to 2 mg kg<sup>-1</sup> three times daily (t.i.d.) in children with pulmonary arterial hypertension (PAH) (from ≥3 months to <12 years of age) would increase exposure.<h4>Methods</h4>An open-label, prospective, randomized, multicentre, multiple-dose, phase III study was conducted. Patients (n = 64) were randomized 1:1 to receive oral doses of ...[more]

PMID: 28213957

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Project description:This analysis aimed to characterize the pharmacokinetics (PK) and PK/pharmacodynamic (PK/PD) relationship of riociguat and its metabolite M1 in patients with chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). Blood samples were collected in two phase 3 studies-PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 12 weeks; PAH) and CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 16 weeks; CTEPH)-and long-term extensions. Patients were initially randomized to receive placebo or riociguat, and they received riociguat in the extensions. Nonlinear mixed-effects modeling was used to develop a population PK model describing riociguat PK. PK/PD relationships were investigated by comparing derived PK parameters with changes in PD parameters. Covariate analyses included smoking status, bosentan comedication, bilirubin levels, and baseline creatinine clearance. The PK of riociguat/M1 was described by a one-compartment model. Mean population estimates for riociguat absorption rate constant, clearance, and volume of distribution were 2.17/h, 1.81 L/h, and 32.3 L, respectively; for M1 they were 0.258/h, 3.16 L/h, and 124 L. Interindividual variability was moderate for riociguat and moderate to high for M1. There was no evidence of time- or dose-dependent changes in riociguat/M1 PK. Riociguat clearance was higher in smokers (120% increase) and bosentan-treated patients (36% increase) than in nonsmokers and those not receiving bosentan. There was an inverse correlation between bilirubin and riociguat clearance. In PK/PD analyses, 6-minute walk distance was related to hemodynamic parameters, particularly pulmonary vascular resistance. Riociguat PK were described by a one-compartment model. Effects of covariates on riociguat and M1 PK were established, and a PK/PD relationship was demonstrated. (ClinicalTrials.gov identifiers: PATENT-1, NCT00810693; PATENT-2, NCT00863681; CHEST-1, NCT00855465; CHEST-2, NCT00910429.).

Dataset Information

A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3.

Publications

A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3.

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