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Jasper Dingemanse - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Jasper DingemanseAbstract:The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist.Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles.Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups.Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.
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Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment.
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Ivan Ulč, Jasper DingemanseAbstract:AIM The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist. METHODS Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles. RESULTS Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups. CONCLUSIONS Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.
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Influence of Mild and moderate liver Impairment on the pharmacokinetics and metabolism of almorexant, a dual orexin receptor antagonist.
European Journal of Pharmaceutical Sciences, 2013Co-Authors: Kasra Shakeri-nejad, Matthias Hoch, Petra Hoever, Jasper DingemanseAbstract:Abstract This single-dose study aimed at investigating the effect of different degrees of Hepatic Impairment on the pharmacokinetics (PK), metabolism, and tolerability of almorexant, a first-in-class dual orexin receptor antagonist. Subjects with Mild (Child-Pugh A, Group A, n = 8) and moderate (Child-Pugh B, Group B, n = 9) liver Impairment and subjects with normal liver function (Group DA and DB, both n = 9) received a dose of 100 mg almorexant. PK parameters of almorexant and its four primary metabolites were determined. Almorexant exposure increased with severity of Hepatic Impairment. Geometric mean ratios (90% confidence interval) of AUC0−∞ were 2.8 (1.5–5.4), 7.2 (3.7–14.1), and 3.3 (1.7–6.4) comparing A vs. DA, B vs. DB, and B vs. A, respectively. The four metabolic pathways involved in the formation of the primary metabolites were affected in a different fashion. Geometric mean AUC0−∞ ratios comparing A vs. DA were 6.9, 1.1, 1.4, and 3.6 for M3, M5, M6, and M8, respectively. Comparing B vs. DB the corresponding figures were 7.3, 2.0, 5.4, and 1.3, respectively. Significant effects of Hepatic Impairment on the PK of almorexant suggested the need for dose adjustment in subjects with Mild Hepatic Impairment and did not support its use in subjects with moderate or severe Hepatic Impairment.
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Clinical Pharmacology of Bosentan, a Dual Endothelin Receptor Antagonist
Clinical Pharmacokinetics, 2004Co-Authors: Jasper Dingemanse, Paul L. M. GiersbergenAbstract:Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH). Following oral administration, bosentan attains peak plasma concentrations after approximately 3 hours. The absolute bioavailability is about 50%. Food does not exert a clinically relevant effect on absorption at the recommended dose of 125mg. Bosentan is approximately 98% bound to albumin and, during multiple-dose administration, has a volume of distribution of 30L and a clearance of 17 L/h. The terminal half-life after oral administration is 5.4 hours and is unchanged at steady state. Steady-state concentrations are achieved within 3–5 days after multiple-dose administration, when plasma concentrations are decreased by about 50% because of a 2-fold increase in clearance, probably due to induction of metabolising enzymes. Bosentan is mainly eliminated from the body by Hepatic metabolism and subsequent biliary excretion of the metabolites. Three metabolites have been identified, formed by cytochrome P450 (CYP) 2C9 and 3A4. The metabolite Ro 48-5033 may contribute 20% to the total response following administration of bosentan. The pharmacokinetics of bosentan are dose-proportional up to 600mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in paediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure. Severe renal Impairment (creatinine clearance 15–30 mL/min) and Mild Hepatic Impairment (Child-Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. No dosage adjustment in adults is required based on sex, age, ethnic origin and bodyweight. Bosentan should generally be avoided in patients with moderate or severe Hepatic Impairment and/or elevated liver aminotransferases. Ketoconazole approximately doubles the exposure to bosentan because of inhibition of CYP3A4. Bosentan decreases exposure to ciclosporin, glibenclamide, simvastatin (and β-hydroxyacid simvastatin) and ( R )- and ( S )-warfarin by up to 50% because of induction of CYP3A4 and/or CYP2C9. Coadministration of ciclosporin and bosentan markedly increases initial bosentan trough concentrations. Concomitant treatment with glibenclamide and bosentan leads to an increase in the incidence of aminotransferase elevations. Therefore, combined use with ciclosporin and glibenclamide is contraindicated and not recommended, respectively. The possibility of reduced efficacy of CYP2C9 and 3A4 substrates should be considered when coadministered with bosentan. No clinically relevant interaction was detected with the P-glycoprotein substrate digoxin. In healthy subjects, bosentan doses >300mg increase plasma levels of endothelin-1. The drug moderately reduces blood pressure, and its main adverse effects are headache, flushing, increased liver aminotransferases, leg oedema and anaemia. In a pharmacokinetic-pharmacodynamic study in PAH patients, the haemodynamic effects lagged the plasma concentrations of bosentan.
Priska Kaufmann - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Jasper DingemanseAbstract:The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist.Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles.Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups.Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.
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Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment.
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Ivan Ulč, Jasper DingemanseAbstract:AIM The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist. METHODS Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles. RESULTS Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups. CONCLUSIONS Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.
Atef Halabi - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94-8862) in Individuals with Mild or Moderate Hepatic Impairment
European Journal of Drug Metabolism and Pharmacokinetics, 2019Co-Authors: Roland Heinig, Johannes Nagelschmitz, Marc Lambelet, Abir Alatrach, Atef HalabiAbstract:Background and Objectives Finerenone (BAY 94-8862) is a selective, nonsteroidal mineralocorticoid receptor antagonist. The aim of this study was to assess the effect of Mild or moderate Hepatic Impairment on the pharmacokinetics, safety and tolerability of finerenone. Methods The study was conducted in a single-center, nonrandomized, noncontrolled, nonblinded observational design with group stratification. A single oral 5-mg dose of finerenone was administered as a tablet to participants with Mild or moderate Hepatic Impairment (Child–Pugh A, score 5–6 [ n = 9], or Child–Pugh B, score 7–9 [ n = 9], respectively) and to age-, weight- and sex-matched healthy participants ( n = 9). The pharmacokinetics of finerenone and its metabolites were assessed in plasma and urine, and safety and tolerability were monitored. Results Finerenone area under the plasma concentration–time curve (AUC) and unbound AUC were 38% and 55% greater, respectively, in participants with moderate Hepatic Impairment than in healthy participants, whereas maximum plasma concentration ( C _max) was unchanged. No clear effects on AUC or C _max were seen in participants with Mild Hepatic Impairment. Finerenone was safe and well tolerated in all participants. Conclusion The effects of Mild or moderate Hepatic Impairment on systemic exposure of finerenone are small, consistent with its low Hepatic extraction and preponderance of gastrointestinal over Hepatic first-pass clearance. Considering the small increases in AUC and the absence of changes in C _max, a dose adaptation does not appear to be warranted in patients with Mild or moderate Hepatic Impairment.
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Effect of Hepatic Impairment on the pharmacokinetics of vilaprisan: An open-label, single-dose, parallel-group study.
British Journal of Clinical Pharmacology, 2019Co-Authors: Niladri Chattopadhyay, Atef Halabi, Kai Riecke, Sandra Ligges, Torsten Zimmermann, Marcus‐hillert Schultze‐mosgauAbstract:AIMS The study objective was to evaluate the pharmacokinetics of the selective progesterone receptor modulator vilaprisan in participants with Hepatic Impairment. Additionally, the safety and tolerability of vilaprisan were investigated. METHODS In this phase 1, open-label, nonrandomised, parallel-group, pharmacokinetic study, men and women with Mild or moderate Hepatic Impairment (Child-Pugh grade A or B) and control participants with normal Hepatic function matched by age, weight and sex received a single oral 2 mg dose of vilaprisan. Key pharmacokinetic parameters, relationships between parameters and safety outcomes were measured. RESULTS Thirty-six participants completed the study: 9 with Mild Hepatic Impairment, 9 with moderate Hepatic Impairment and 18 matched control participants with normal Hepatic function. Vilaprisan reached maximum plasma concentrations after 1-2 hours. Unbound vilaprisan exposure was 1.44-fold higher for participants with Mild Hepatic Impairment vs controls (90% confidence interval: 0.91-2.26), and 1.74-fold higher for participants with moderate Impairment vs controls (90% confidence interval: 1.09-2.78). The maximum observed unbound peak concentrations were similar for participants with Hepatic Impairment and matched controls. Vilaprisan 2 mg was well tolerated and the incidence of treatment-emergent adverse events was similar across cohorts. CONCLUSION Only Mild increases of
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pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Jasper DingemanseAbstract:The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist.Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles.Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups.Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.
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Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment.
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Ivan Ulč, Jasper DingemanseAbstract:AIM The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist. METHODS Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles. RESULTS Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups. CONCLUSIONS Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.
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Pharmacokinetics of afatinib in subjects with Mild or moderate Hepatic Impairment
Cancer Chemotherapy and Pharmacology, 2014Co-Authors: David Schnell, Sven Wind, Peter Stopfer, Susanne Buschke, Holger Fuchs, Dietmar Gansser, Rainer-georg Goeldner, Martina Uttenreuther-fischer, Marc Petersen-sylla, Atef HalabiAbstract:Afatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-Hepatic system. This trial assessed whether Mild or moderate Hepatic Impairment influences the pharmacokinetics of afatinib. This was an open-label single-dose study. Pharmacokinetic parameters after afatinib 50 mg were investigated in subjects with Mild (n = 8) or moderate (n = 8) Hepatic Impairment (Child-Pugh A and B) and healthy controls (n = 16) matched for age, weight and gender. Plasma and urine samples for pharmacokinetic assessment were collected before and up to 10 days after dosing. Additional blood samples were drawn to determine ex vivo plasma protein binding of afatinib. Primary endpoints were comparisons of afatinib C max and AUC0–∞ between subjects with Hepatic Impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and C max of afatinib. Afatinib pharmacokinetic profiles and plasma protein binding were similar in subjects with impaired liver function and healthy controls. Compared with matched controls, the afatinib-adjusted geometric mean ratio for AUC0–∞ was 92.6 % (90 % CI 68.0–126.3 %) and C max was 109.5 % (90 % CI 82.7–144.9 %) for subjects with Mild Hepatic Impairment, and 94.9 % (90 % CI 72.3–124.5 %) and 126.9 % (90 % CI 86.0–187.2 %), respectively, for subjects with moderate Hepatic Impairment. For all parameters, the 90 % CI included 100 %. Afatinib was generally well tolerated with no serious adverse events reported. Mild to moderate Hepatic Impairment had no clinically relevant effect on the pharmacokinetics of a single 50 mg dose of afatinib, implying that adjustments to the starting dose of afatinib are not considered necessary in this patient population.
Andreas Krause - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Jasper DingemanseAbstract:The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist.Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles.Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups.Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.
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Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment.
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Ivan Ulč, Jasper DingemanseAbstract:AIM The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist. METHODS Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles. RESULTS Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups. CONCLUSIONS Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.
Hans G Cruz - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Jasper DingemanseAbstract:The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist.Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles.Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups.Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.
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Pharmacokinetics of the novel oral prostacyclin receptor agonist selexipag in subjects with Hepatic or renal Impairment.
British Journal of Clinical Pharmacology, 2016Co-Authors: Priska Kaufmann, Hans G Cruz, Atef Halabi, Andreas Krause, Ivan Ulč, Jasper DingemanseAbstract:AIM The aim of the present study was to explore the effect of Hepatic or renal dysfunction on the pharmacokinetics (PK), tolerability and safety of selexipag, an orally active prostacyclin receptor agonist. METHODS Two prospective, open-label studies evaluated the PK of selexipag and its active metabolite ACT-333679 in healthy subjects and in subjects with Mild, moderate and severe Hepatic Impairment or severe renal function Impairment (SRFI). A single dose of 200 μg or 400 μg was administered. The PK parameters were derived from plasma concentration-time profiles. RESULTS Exposure increased with the severity of Hepatic Impairment. Geometric mean ratios and 90% confidence intervals of the area under the concentration-time curve from time zero to infinity (AUC0-∞ ) for selexipag and ACT-333679 increased 2.1-fold (1.7-2.6) and 1.2-fold (0.9-1.6) in subjects with Mild Hepatic Impairment, and 4.5-fold (3.4-5.8) and 2.2-fold (1.7-2.8) in subjects with moderate Hepatic Impairment when compared with healthy subjects. The two subjects with severe Hepatic Impairment showed similar dose-normalized exposure to that of subjects with moderate Hepatic Impairment. A 1.7-fold increase in the AUC0-∞ of selexipag and ACT-333679 was observed with SRFI compared with healthy subjects. Although exposure to selexipag and/or ACT-333679 was higher in subjects with Mild or moderate Hepatic Impairment or SRFI vs. healthy subjects, no safety concerns were raised in these groups. CONCLUSIONS Based on these observations, the PK data suggest that the clinically used starting dose needs no adjustments in patients with Mild or moderate Hepatic Impairment or SRFI. However, doses should be up-titrated with caution in these patients. The small number of subjects limits the interpretation of selexipag PK in subjects with severe Hepatic Impairment.