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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 (AUC 0-24C ). The maximum plasma concentration corrected to the 2 mg kg -1 dose (C maxC ), the time to reach the maximum plasma concentration (t max ) and safety endpoints were also assessed., Results: The geometric mean [95% confidence interval (CI)] for AUC 0-24C 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 C maxC 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 t max 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., (© 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan., Materials and Methods: Two 12-week double-blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan-treated patients., Results: Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, -34.4% vs -26.3% for 0.75 mg/d ( P  = .44) and -48.0% vs -28.9% for 1.25 mg/d ( P  = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration; P  = .024). Body surface area (β = -1.09 per m 2 ; P  < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/dL increment; P  = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations., Conclusion: The higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan-induced sodium retention., (© 2016 John Wiley & Sons Ltd.)

Aim: To study the mutual pharmacokinetic interactions between macitentan, an endothelin receptor antagonist, and sildenafil in healthy male subjects., Methods: In this open-label, randomized, three way crossover study, 12 healthy male subjects received the following oral treatments: A) a loading dose of 30 mg macitentan on day 1 followed by 10 mg once daily for 3 days, B) sildenafil 20 mg three times a day for 3 days and a single 20 mg dose on day 4 and C) both treatments A and B concomitantly. Plasma concentration-time profiles of macitentan and its active metabolite ACT-132577 (treatments A and C) and sildenafil and its N-desmethyl metabolite (treatments B and C) were determined on day 4 and analyzed non-compartmentally., Results: The pharmacokinetics of macitentan were not affected by sildenafil. In the presence of sildenafil Cmax and AUCτ of the metabolite ACT-132577 decreased with geometric mean ratios (90% confidence interval (CI)) of 0.82 (0.76, 0.89) and 0.85 (90% CI 0.80, 0.91), respectively. In the presence of macitentan, plasma concentrations of sildenafil were higher than during treatment with sildenafil alone, resulting in increased Cmax and AUCτ values. The respective geometric mean ratios were 1.26 (90% CI 1.07, 1.48) and 1.15 (90% CI 0.94, 1.41). The pharmacokinetics of N-desmethylsildenafil were not affected by macitentan. All treatments were well tolerated., Conclusion: A minor, not clinically relevant, pharmacokinetic interaction was observed between macitentan and sildenafil. Based on these results, no dose adjustment of either compound appears necessary during concomitant treatment with macitentan and sildenafil., (© 2014 The British Pharmacological Society.)

Aims: The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination., Methods: We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Sixteen healthy volunteers received therapeutic doses of bosentan (125 mg twice daily) for 14 days and clarithromycin (500 mg twice daily) concomitantly for the last 4 days, and bosentan pharmacokinetics was assessed on days 1, 10 and 14., Results: Clarithromycin significantly increased bosentan area under the plasma concentration-time curve of the dosing interval 3.7-fold and peak concentration 3.8-fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance., Conclusions: Clarithromycin substantially increases the exposure to bosentan, suggesting that dose reductions may be necessary., (© 2013 The British Pharmacological Society.)