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Selexipag (Uptravi) is an oral selective IP prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal GRIPHON study was the largest clinical study ever conducted in PAH patients, providing long-term data from 1,156 patients. PAH comedication did not affect exposure to selexipag, while exposure to its active metabolite ACT-333679 was reduced by 30% when taken in combination, clinically not relevant in the context of individual dose up-titration. Using log-linear regression models linking model-predicted steady-state exposure to pharmacodynamics (PD), exposure to selexipag and ACT-333679 showed some statistically significant, albeit not clinically relevant, effects on exercise capacity, laboratory values, and the occurrence of prostacyclin-related adverse events, but not on vital signs or adverse events denoting hemorrhage. Using suitable modeling techniques, the GRIPHON study yielded clinically relevant data with limited burden of pharmacokinetics (PK) blood sampling, demonstrating that PK/PD modeling enables firm conclusions even with sparse PK and PD sampling. [ABSTRACT FROM AUTHOR]

Aims To assess incidence rates ( IRs) of and identify risk factors for incident severe hypoglycaemia in patients with type 2 diabetes newly treated with antidiabetic drugs. Methods Using the UK-based General Practice Research Database, we performed a retrospective cohort study between 1994 and 2011 and a nested case-control analysis. Ten controls from the population at risk were matched to each case with a recorded severe hypoglycaemia during follow-up on general practice, years of history in the database and calendar time. Using multivariate conditional logistic regression analyses, we adjusted for potential confounders. Results Of 130 761 patients with newly treated type 2 diabetes (mean age 61.7 ± 13.0 years), 690 (0.5%) had an incident episode of severe hypoglycaemia recorded [estimated IR 11.97 (95% confidence interval, CI, 11.11-12.90) per 10 000 person-years ( PYs)]. The IR was markedly higher in insulin users [49.64 (95% CI, 44.08-55.89) per 10 000 PYs] than in patients not using insulin [8.03 (95% CI, 7.30-8.84) per 10 000 PYs]. Based on results of the nested case-control analysis increasing age [≥75 vs. 20-59 years; adjusted odds ratio ( OR), 2.27; 95% CI, 1.65-3.12], cognitive impairment/dementia (adjusted OR, 2.00; 95% CI, 1.37-2.91), renal failure (adjusted OR, 1.34; 95% CI, 1.04-1.71), current use of sulphonylureas (adjusted OR, 4.45; 95% CI, 3.53-5.60) and current insulin use (adjusted OR, 11.83; 95% CI, 9.00-15.54) were all associated with an increased risk of severe hypoglycaemia. Conclusions Severe hypoglycaemia was recorded in 12 cases per 10 000 PYs. Risk factors for severe hypoglycaemia included increasing age, renal failure, cognitive impairment/dementia, and current use of insulin or sulphonylureas. [ABSTRACT FROM AUTHOR]

Aims: Selexipag is a prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension. Cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. This study evaluated the interaction of selexipag and clopidogrel, a CYP2C8 inhibitor., Methods: The study had a 2-treatment, 1-sequence, crossover design. Pharmacokinetics (PK) and CYP2C8 genotype were assessed in healthy male subjects administered selexipag (200 μg twice daily [b.i.d.]) alone or with clopidogrel (300 mg single dose or 75 mg once daily [o.d.]). PK modelling and simulation were conducted to support dosing recommendations., Results: Clopidogrel had a comparatively small effect on selexipag (<1.5-fold difference in any PK variable). For ACT-333679, the major contributor to the drug effect, the area under the plasma concentration-time curve during a dose interval and the maximum plasma concentration increased 2.25-fold (90% confidence interval [CI] 2.06, 2.46) and 1.69-fold (90% CI 1.55, 1.84), respectively with clopidogrel 300 mg and 2.70-fold (90% CI 2.45, 2.96) and 1.90-fold (90% CI 1.72, 2.11), respectively with clopidogrel 75 mg. The effect of clopidogrel on selexipag and ACT-333679 exposure was comparable for all identified CYP2C8 genotypes. PK simulations predicted comparable exposure to ACT-333679 following selexipag 400 μg b.i.d., 400 μg o.d. in combination with clopidogrel 75 mg o.d and 200 μg b.i.d. with clopidogrel 75 mg o.d., Conclusion: Results suggest that ACT-333679 exposure can be maintained within the therapeutic range by reducing selexipag dosing frequency to o.d. or dose to half, when selexipag is coadministered with clopidogrel., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: To demonstrate the bioequivalence of macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of macitentan and tadalafil in healthy subjects., Methods: Studies AC-077-101 and AC-077-103 were single-centre, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods., Results: Bioequivalence of macitentan, its active metabolite ACT-132577, and tadalafil was established for FDC-2 in both studies AC-077-101 and AC-077-103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration-time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000-1.2500). No subject died and no serious adverse events were reported in either studies., Conclusion: The FDC-2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Based on in vitro data, there is evidence to suggest that cytochrome P450 (CYP) 2C8 is involved in the metabolism of selexipag and its active metabolite, ACT-333679. The present study evaluated the possible pharmacokinetic interactions of selexipag with gemfibrozil, a strong CYP2C8 inhibitor, and rifampicin, an inducer of CYP2C8., Methods: The study consisted of two independent parts, each conducted according to an open-label, randomized, crossover design. The pharmacokinetics and safety of selexipag and ACT-333679 were studied following single-dose administration either alone or in the presence of multiple-dose gemfibrozil (part I) or rifampicin (part II) in healthy male subjects., Results: Gemfibrozil had comparatively small effects on selexipag (less than 2-fold difference in any pharmacokinetic variable) but, with respect to ACT-333679, increased the maximum plasma concentration (C max ) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration-time curve from zero to infinity (AUC 0-∞ ) 11.1-fold (90% CI 9.2, 13.4). The marked increased exposure to ACT-333679, which mediates the majority of the pharmacological activity of selexipag, was accompanied by significantly more adverse events such as headache, nausea and vomiting. Coadministration of rifampicin increased the C max of selexipag 1.8-fold (90% CI 1.4, 2.2) and its AUC0 -∞ 1.3-fold (90% CI 1.1, 1.4); its effects on ACT-333679 were to increase its C max 1.3-fold (90% CI 1.1, 1.6), shorten its half-life by 63% and reduce its AUC0 -∞ by half (90% CI 0.45, 0.59)., Conclusion: Concomitant administration of selexipag and strong inhibitors of CYP2C8 must be avoided, whereas when coadministered with inducers of CYP2C8, dose adjustments of selexipag should be envisaged., (© 2017 The British Pharmacological Society.)

Aims: This study investigated the effect of a fixed dose combination of lopinavir/ritonavir on the pharmacokinetics (PK) of selexipag and its active metabolite ACT-333679., Methods: This was an open label, randomized, single centre, two way, crossover study. Twenty healthy male subjects were treated with a single dose of 400 µg selexipag alone and in combination with multiple doses of lopinavir/ritonavir (400/100 mg) twice daily., Results: The results showed that lopinavir/ritonavir approximately doubled the exposure to selexipag. The area under the plasma concentration-time curve from time zero to infinity (AUC(0,∞) and the maximum plasma concentration (Cmax) of selexipag were 2.2- and 2.1-fold higher, respectively, than under selexipag alone, with a 90% confidence interval (CI) of the geometric mean ratio (GMR) of 1.9, 2.7 and 1.7, 2.6, respectively. For ACT-333679, the clinically more relevant component of selexipag, systemic exposure was increased by 8% (GMR of AUC(0,∞) 1.1, 90% CI 0.9, 1.3), when lopinavir/ritonavir was co-administered with selexipag. The most frequently reported adverse event (AE) was headache. A single dose of selexipag, administered either alone or together with multiple doses of lopinavir/ritonavir, was safe and well tolerated., Conclusions: Lopinavir/ritonavir does not affect the PK parameters of selexipag and ACT-333679 to a clinically relevant extent. Therefore, adaptation of the selexipag dose is not required when co-administered with inhibitors of the organic anion-transporting polypeptide (OATP) 1B1/ 1B3, P-glycoprotein (P-gp) and/or CYP3A4., (© 2015 The British Pharmacological Society.)

What Is Already Known About This Subject: Clazosentan is a selective endothelin A receptor antagonist, formulated for parenteral use, which is in clinical development for the treatment of aneurysmal subarachnoid haemorrhage. The human ADME study showed that most of clazosentan is excreted via the biliary route. The pharmacokinetics (PK) of clazosentan are similar in healthy subjects and those with severe renal impairment., What This Study Adds: The results of the present study showed that there was an increase in the exposure to clazosentan with increasing severity of liver impairment. Changes in PK in subjects with mild liver impairment compared with healthy subjects are unlikely to be clinically relevant. There are significant differences in the PK parameters of clazosentan in subjects with moderate and severe liver impairment compared with healthy subjects. The results of this study will allow confident dosing of clazosentan in individuals with moderate and severe liver impairment. AIM To investigate the effect of mild, moderate and severe liver impairment on the pharmacokinetics (PK), tolerability and safety of clazosentan, an intravenous endothelin receptor antagonist., Methods: Healthy subjects with normal liver function (n= 8), subjects with mild (Child Pugh A, n= 8), and with moderate (Child-Pugh B, n= 8) liver impairment received a continuous intravenous infusion of 1 mg h(-1) and subjects with severe liver impairment (Child Pugh C, n= 8) received a continuous intravenous infusion of 0.5 mg h(-1) clazosentan for a duration of 6 h. The pharmacokinetic (PK) parameters of clazosentan were determined by both model-independent and model-dependent methods., Results: Mean plasma concentrations of clazosentan increased with increasing severity of liver impairment. Geometric means of area under the plasma concentration-time curve from 0 to infinity (AUC((0,∞)) ) were 1.41- (90% CI 1.04, 1.90), 2.37- (90% CI 1.75, 3.19), and 3.79- (90% CI 2.81, 5.11) fold higher in subjects with mild, moderate and severe liver impairment, respectively, compared with healthy subjects. Similar results were obtained by non-compartmental and two-compartmental analysis. A significant positive correlation between clazosentan AUC((0,∞)) and Child-Pugh score (r= 0.83), bilirubin (r= 0.78) and prothrombin time (r= 0.62), and a significant negative correlation with albumin concentrationl (r= 0.71) was observed. Administration of clazosentan was well tolerated in all groups., Conclusions: The increase in exposure to clazosentan in Child-Pugh A patients is not expected to be clinically relevant and no dose adjustment for these patients is proposed. It is recommended to reduce the dose of clazosentan to half in Child-Pugh B and to one fourth in Child-Pugh C patients., (© 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.)