The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Jasper Dingemanse - One of the best experts on this subject based on the ideXlab platform.
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single dose pharmacokinetics and tolerability of aprocitentan a dual Endothelin Receptor Antagonist in subjects with severe renal function impairment
Clinical Drug Investigation, 2019Co-Authors: P. N. Sidharta, Ivan Ulč, Jasper DingemanseAbstract:BACKGROUND The orally active dual Endothelin Receptor Antagonist aprocitentan targets a novel pathway in the treatment of hypertension and could be a key player in the treatment of salt/volume-dependent hypertension. Its pharmacokinetic profile supports a once-daily dosing strategy. OBJECTIVE As hypertensive patients may also experience concomitant renal disease, the objectives of this study were to evaluate the pharmacokinetics and tolerability of aprocitentan in subjects with severe renal function impairment (SRFI) and compare these with matched healthy subjects. DESIGN, SETTING, PARTICIPANTS In this open-label, single-center, phase 1 study (NCT03165071) eight subjects with SRFI (mean estimated glomerular filtration rate [eGFR] 21.9 mL/min/1.73 m2) and eight healthy subjects (mean eGFR 94.9 mL/min/1.73 m2) received a single dose of 50 mg of aprocitentan followed by an observation period of up to 17 days. Plasma pharmacokinetic parameters of aprocitentan were derived by noncompartmental analysis of the plasma concentration-time profiles. Differences in pharmacokinetic parameters were explored using geometric means ratio (GMR) and 90% confidence intervals (CIs) with SRFI subjects as test group and healthy subjects as reference group. Safety and tolerability evaluations included adverse events (AEs), electrocardiograms, vital signs, and clinical laboratory tests. RESULTS All 16 subjects received aprocitentan and completed the study. The pharmacokinetics of aprocitentan were similar in SRFI and healthy subjects with maximum plasma concentrations reached at 7.6 h and 5.0 h, respectively. Maximum plasma concentrations did not differ as indicated by a GMR (90% CI) of 1.04 (0.85-1.28). Due to a slightly lower observed clearance in SRFI subjects, half-life was longer (53.2 h compared to 47.4 h in healthy subjects), while exposure expressed as area under the curve was 34% higher (GMR 90% CI 1.13-1.58). There were no differences in plasma protein binding (> 99% bound). Aprocitentan was well tolerated in subjects with SRFI with no notable difference compared to healthy subjects. CONCLUSIONS Based on these single-dose results, subjects with mild, moderate, or severe renal function can be included in clinical studies without the need for dose adjustment.
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Receptors ET A and ET
2016Co-Authors: Shirin Bruderer, P. N. Sidharta, Gerard Hopfgartner, Michael Seiberling, Janine Wank, Er Treiber, Jasper DingemanseAbstract:N’-propylsulfuric diamide)) is a tissue-targeting, dual Endothelin Receptor Antagonist, under phase 3 investi-gation in pulmonary arterial hypertension. Macitentan is a lipophilic compound, which inhibits endotheli
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Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan
Clinical Pharmacokinetics, 2015Co-Authors: P. N. Sidharta, A. Treiber, Jasper DingemanseAbstract:Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, which leads to right-sided heart failure and ultimately death if untreated. Treatments to regulate the pulmonary vascular pressure target the prostacyclin, nitric oxide, and Endothelin (ET) pathways. Macitentan, an oral, once-daily, dual ET_A and ET_B Receptor Antagonist with high affinity and sustained Receptor binding is the first ET Receptor Antagonist to show significant reduction of the risk of morbidity and mortality in PAH patients in a large-scale phase III study with a long-term outcome. Here we present a review of the available clinical pharmacokinetic, pharmacodynamic, pharmacokinetic/pharmacodynamic relationship, and drug–drug interaction data of macitentan in healthy subjects, patients with PAH, and in special populations.
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safety tolerability pharmacokinetics and pharmacodynamics of macitentan an Endothelin Receptor Antagonist in an ascending multiple dose study in healthy subjects
The Journal of Clinical Pharmacology, 2013Co-Authors: P. N. Sidharta, Paul L. M. Van Giersbergen, Jasper DingemanseAbstract:This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new Endothelin Receptor Antagonist (ERA) with sustained Receptor binding and enhanced tissue penetration properties compared to other ERAs. Healthy male subjects (n = 32) received once daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. Administration of macitentan was safe and well tolerated. Macitentan had no effect on bile salts, suggesting an improved liver safety profile. The multiple-dose pharmacokinetics of macitentan were dose-proportional and were characterized by a median tmax and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48 hours and accumulated approximately 8.5-fold. Compared to placebo, administration of macitentan caused a dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A small dose-dependent increase in the 6β-hydroxycortisol/cortisol urinary excretion ratio was observed, although there were no statistically significant differences between treatments including placebo. Effects of macitentan on cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET-1-dependent pathologies.
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Pharmacokinetics of the novel dual Endothelin Receptor Antagonist macitentan in subjects with hepatic or renal impairment
Journal of clinical pharmacology, 2013Co-Authors: P. N. Sidharta, Nicolas Lindegger, Ivan Ulč, Jasper DingemanseAbstract:Macitentan is under development for the treatment of pulmonary arterial hypertension (PAH). Patients with PAH may suffer from comorbidities such as renal or hepatic impairment. Two prospective, single-center, open-label studies evaluated the pharmacokinetics of macitentan and its metabolites (pharmacologically active ACT-132577 and inactive ACT-373898) in healthy subjects and in subjects with mild, moderate, and severe hepatic impairment or severe renal function impairment (SRFI). After administering a single oral dose of 10 mg macitentan the pharmacokinetic parameters including area under the curve from zero to infinity (AUC∞) were derived from plasma concentration-time profiles. Exposure to macitentan and ACT-132577 was lower in hepatically impaired versus healthy subjects, with no correlation with the degree of hepatic impairment. Exposure to ACT-373898 was lower in subjects with moderate hepatic impairment only. Plasma concentration-time profiles for macitentan and ACT-132577 (active) were similar in healthy subjects and subjects with SRFI. AUC∞ of ACT-373898 (inactive) was 7.3-fold higher in subjects with SRFI versus healthy subjects. No safety concerns were raised in either study. Based on these observations, pharmacokinetic alterations of macitentan due to hepatic or renal function impairment are not considered clinically relevant and no dose adjustment is necessary in these patients.
Eliot H Ohlstein - One of the best experts on this subject based on the ideXlab platform.
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Endothelin Receptors Receptor classification novel Receptor Antagonists and potential therapeutic targets
Medicinal Research Reviews, 1996Co-Authors: Eliot H Ohlstein, John D. Elliott, Giora Z Feuerstein, Robert R RuffoloAbstract:The development of Endothelin Receptor Antagonists has progressed rapidly since the initial discovery of Endothelin. Highly potent, orally active nonpeptide Endothelin Receptor Antagonists have been identified, and are being used as pharmacological tools to elucidate the role of Endothelin in pathological disorders. Subtype selective Endothelin Receptor Antagonists will also be useful in understanding the physiological and pathological roles of the different subtypes of the Endothelin Receptors. The selectivity profile for the ideal Endothelin Receptor Antagonist is presently unknown, and it may actually be that the optimal profile for a compound may depend on the clinical indication. In the near future, data from clinical trials with Endothelin Receptor Antagonists will become available and will help to establish the role of Endothelin in the etiology of human disease, as well as to provide valuable information concerning the optimum Endothelin Receptor subtype selectivity for Antagonists needed for therapeutic agents.
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sb 209670 a rationally designed potent nonpeptide Endothelin Receptor Antagonist
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Eliot H Ohlstein, Stephen A Douglas, Ponnal Nambi, Richard M Edwards, M Gellai, A Lago, J D Leber, Russell D Cousins, A Gao, James S FrazeeAbstract:Abstract An extremely potent and highly specific non-peptide, subnanomolar Endothelin (ET) Receptor Antagonist, SB 209670, has been synthesized and characterized. SB 209670, which was rationally designed using conformational models of ET-1, selectively inhibits binding of 125I-labeled ET-1 to cloned human ET Receptor subtypes ETA and ETB (Ki = 0.2 and 18 nM, respectively). SB 209670 produces concentration-dependent inhibition of ET-1-mediated vasoconstriction in isolated vascular tissues and in vivo following either intravenous or intraduodenal administration. SB 209670 produces a dose-dependent reduction in blood pressure in hypertensive rats, protects from ischemia-induced neuronal degeneration in a gerbil stroke model, and attenuates neointima formation following rat carotid artery balloon angioplasty. SB 209670 will be useful in characterizing and classifying the physiological and pathophysiological effects of ET.
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a role for endogenous Endothelin 1 in neointimal formation after rat carotid artery balloon angioplasty protective effects of the novel nonpeptide Endothelin Receptor Antagonist sb 209670
Circulation Research, 1994Co-Authors: Stephen A Douglas, Giora Z Feuerstein, Calvert Louden, Lynne M Vickeryclark, B L Storer, T Hart, J D Elliott, Eliot H OhlsteinAbstract:The observation that levels of the mitogenic peptide Endothelin-1 are elevated in the human coronary sinus after percutaneous transluminal coronary angioplasty (PTCA) has implicated Endothelin-1 in the etiology of vascular restenosis. The present study examined this hypothesis in both an in vitro and an in vivo rat model of neointimal formation by using the novel nonpeptide Endothelin Receptor Antagonist SB 209670. In vitro, Endothelin-1 (1 nmol/L) induced a ninefold increase in rat aortic vascular smooth muscle [3H]thymidine incorporation. This Endothelin A Receptor-mediated effect was completely inhibited by SB 209670 (IC50, 6.2 +/- 2.2 nmol/L). In vivo, acute intra-arterial administration of exogenous Endothelin-1 (5 to 500 pmol/kg over a 30-minute period immediately after angioplasty) dose-dependently augmented the degree of neointimal formation (by up to 150% when assessed 14 days after surgery). This response was evident as early as 7 days after angioplasty. Hemodynamic studies indicated that this action was unrelated to a systemic pressor action of the peptide. Administration of SB 209670 (2.5 mg/kg IP, twice a day for 3 days before and for 2 weeks after surgery) reduced neointimal formation by approximately 50% relative to control animals. Thus, the data indicate for the first time that (1) Endothelin-1 promotes neointimal formation in vivo and (2) endogenous Endothelin-1 is involved in the pathogenesis of angioplasty-induced lesion formation in the rat. Endothelin Receptor Antagonists such as SB 209670 may therefore serve as useful adjuncts to PTCA, attenuating the degree of vascular restenosis observed after vascular wall injury.
Aline Frey - One of the best experts on this subject based on the ideXlab platform.
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Abstract 43: Effect of Clazosentan on Clinical Outcome After Aneurysmal Subarachnoid Hemorrhage and Endovascular Coiling: Results of the CONSCIOUS-3 Study
Stroke, 2012Co-Authors: R. L. Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Isabel Wanke, Doris Bach, Andrew J. Molyneux, Aline FreyAbstract:Introduction: In CONSCIOUS-1, clazosentan, an Endothelin Receptor Antagonist, significantly and dose-dependently reduced angiographic vasospasm (VSP) after aneurysmal subarachnoid hemorrhage (aSAH)...
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clazosentan an Endothelin Receptor Antagonist in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping a randomised double blind placebo controlled phase 3 trial conscious 2
Lancet Neurology, 2011Co-Authors: Loch R Macdonald, Peter Vajkoczy, Andreas Raabe, Randall T Higashida, Emanuela Keller, Stephan A Mayer, Andy Molyneux, Isabel Wanke, Doris Bach, Aline FreyAbstract:Summary Background Clazosentan, an Endothelin Receptor Antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality. Methods In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311. Findings In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI −4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (−18%, −45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups. Interpretation Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH. Funding Actelion Pharmaceuticals.
Stephen A Douglas - One of the best experts on this subject based on the ideXlab platform.
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sb 209670 a rationally designed potent nonpeptide Endothelin Receptor Antagonist
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Eliot H Ohlstein, Stephen A Douglas, Ponnal Nambi, Richard M Edwards, M Gellai, A Lago, J D Leber, Russell D Cousins, A Gao, James S FrazeeAbstract:Abstract An extremely potent and highly specific non-peptide, subnanomolar Endothelin (ET) Receptor Antagonist, SB 209670, has been synthesized and characterized. SB 209670, which was rationally designed using conformational models of ET-1, selectively inhibits binding of 125I-labeled ET-1 to cloned human ET Receptor subtypes ETA and ETB (Ki = 0.2 and 18 nM, respectively). SB 209670 produces concentration-dependent inhibition of ET-1-mediated vasoconstriction in isolated vascular tissues and in vivo following either intravenous or intraduodenal administration. SB 209670 produces a dose-dependent reduction in blood pressure in hypertensive rats, protects from ischemia-induced neuronal degeneration in a gerbil stroke model, and attenuates neointima formation following rat carotid artery balloon angioplasty. SB 209670 will be useful in characterizing and classifying the physiological and pathophysiological effects of ET.
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a role for endogenous Endothelin 1 in neointimal formation after rat carotid artery balloon angioplasty protective effects of the novel nonpeptide Endothelin Receptor Antagonist sb 209670
Circulation Research, 1994Co-Authors: Stephen A Douglas, Giora Z Feuerstein, Calvert Louden, Lynne M Vickeryclark, B L Storer, T Hart, J D Elliott, Eliot H OhlsteinAbstract:The observation that levels of the mitogenic peptide Endothelin-1 are elevated in the human coronary sinus after percutaneous transluminal coronary angioplasty (PTCA) has implicated Endothelin-1 in the etiology of vascular restenosis. The present study examined this hypothesis in both an in vitro and an in vivo rat model of neointimal formation by using the novel nonpeptide Endothelin Receptor Antagonist SB 209670. In vitro, Endothelin-1 (1 nmol/L) induced a ninefold increase in rat aortic vascular smooth muscle [3H]thymidine incorporation. This Endothelin A Receptor-mediated effect was completely inhibited by SB 209670 (IC50, 6.2 +/- 2.2 nmol/L). In vivo, acute intra-arterial administration of exogenous Endothelin-1 (5 to 500 pmol/kg over a 30-minute period immediately after angioplasty) dose-dependently augmented the degree of neointimal formation (by up to 150% when assessed 14 days after surgery). This response was evident as early as 7 days after angioplasty. Hemodynamic studies indicated that this action was unrelated to a systemic pressor action of the peptide. Administration of SB 209670 (2.5 mg/kg IP, twice a day for 3 days before and for 2 weeks after surgery) reduced neointimal formation by approximately 50% relative to control animals. Thus, the data indicate for the first time that (1) Endothelin-1 promotes neointimal formation in vivo and (2) endogenous Endothelin-1 is involved in the pathogenesis of angioplasty-induced lesion formation in the rat. Endothelin Receptor Antagonists such as SB 209670 may therefore serve as useful adjuncts to PTCA, attenuating the degree of vascular restenosis observed after vascular wall injury.
P. N. Sidharta - One of the best experts on this subject based on the ideXlab platform.
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single dose pharmacokinetics and tolerability of aprocitentan a dual Endothelin Receptor Antagonist in subjects with severe renal function impairment
Clinical Drug Investigation, 2019Co-Authors: P. N. Sidharta, Ivan Ulč, Jasper DingemanseAbstract:BACKGROUND The orally active dual Endothelin Receptor Antagonist aprocitentan targets a novel pathway in the treatment of hypertension and could be a key player in the treatment of salt/volume-dependent hypertension. Its pharmacokinetic profile supports a once-daily dosing strategy. OBJECTIVE As hypertensive patients may also experience concomitant renal disease, the objectives of this study were to evaluate the pharmacokinetics and tolerability of aprocitentan in subjects with severe renal function impairment (SRFI) and compare these with matched healthy subjects. DESIGN, SETTING, PARTICIPANTS In this open-label, single-center, phase 1 study (NCT03165071) eight subjects with SRFI (mean estimated glomerular filtration rate [eGFR] 21.9 mL/min/1.73 m2) and eight healthy subjects (mean eGFR 94.9 mL/min/1.73 m2) received a single dose of 50 mg of aprocitentan followed by an observation period of up to 17 days. Plasma pharmacokinetic parameters of aprocitentan were derived by noncompartmental analysis of the plasma concentration-time profiles. Differences in pharmacokinetic parameters were explored using geometric means ratio (GMR) and 90% confidence intervals (CIs) with SRFI subjects as test group and healthy subjects as reference group. Safety and tolerability evaluations included adverse events (AEs), electrocardiograms, vital signs, and clinical laboratory tests. RESULTS All 16 subjects received aprocitentan and completed the study. The pharmacokinetics of aprocitentan were similar in SRFI and healthy subjects with maximum plasma concentrations reached at 7.6 h and 5.0 h, respectively. Maximum plasma concentrations did not differ as indicated by a GMR (90% CI) of 1.04 (0.85-1.28). Due to a slightly lower observed clearance in SRFI subjects, half-life was longer (53.2 h compared to 47.4 h in healthy subjects), while exposure expressed as area under the curve was 34% higher (GMR 90% CI 1.13-1.58). There were no differences in plasma protein binding (> 99% bound). Aprocitentan was well tolerated in subjects with SRFI with no notable difference compared to healthy subjects. CONCLUSIONS Based on these single-dose results, subjects with mild, moderate, or severe renal function can be included in clinical studies without the need for dose adjustment.
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Receptors ET A and ET
2016Co-Authors: Shirin Bruderer, P. N. Sidharta, Gerard Hopfgartner, Michael Seiberling, Janine Wank, Er Treiber, Jasper DingemanseAbstract:N’-propylsulfuric diamide)) is a tissue-targeting, dual Endothelin Receptor Antagonist, under phase 3 investi-gation in pulmonary arterial hypertension. Macitentan is a lipophilic compound, which inhibits endotheli
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Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan
Clinical Pharmacokinetics, 2015Co-Authors: P. N. Sidharta, A. Treiber, Jasper DingemanseAbstract:Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, which leads to right-sided heart failure and ultimately death if untreated. Treatments to regulate the pulmonary vascular pressure target the prostacyclin, nitric oxide, and Endothelin (ET) pathways. Macitentan, an oral, once-daily, dual ET_A and ET_B Receptor Antagonist with high affinity and sustained Receptor binding is the first ET Receptor Antagonist to show significant reduction of the risk of morbidity and mortality in PAH patients in a large-scale phase III study with a long-term outcome. Here we present a review of the available clinical pharmacokinetic, pharmacodynamic, pharmacokinetic/pharmacodynamic relationship, and drug–drug interaction data of macitentan in healthy subjects, patients with PAH, and in special populations.
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safety tolerability pharmacokinetics and pharmacodynamics of macitentan an Endothelin Receptor Antagonist in an ascending multiple dose study in healthy subjects
The Journal of Clinical Pharmacology, 2013Co-Authors: P. N. Sidharta, Paul L. M. Van Giersbergen, Jasper DingemanseAbstract:This multiple-ascending-dose study investigated safety, tolerability, pharmacokinetics, and pharmacodynamics, of macitentan, a new Endothelin Receptor Antagonist (ERA) with sustained Receptor binding and enhanced tissue penetration properties compared to other ERAs. Healthy male subjects (n = 32) received once daily oral doses of macitentan (1 - 30 mg) or placebo for 10 days. Administration of macitentan was safe and well tolerated. Macitentan had no effect on bile salts, suggesting an improved liver safety profile. The multiple-dose pharmacokinetics of macitentan were dose-proportional and were characterized by a median tmax and apparent elimination half-life varying from 6.0 to 8.5 and 14.3 to 18.5 hours, respectively, for the different doses and minimal accumulation. ACT-132577, a metabolite with lower potency than macitentan, had a half-life of about 48 hours and accumulated approximately 8.5-fold. Compared to placebo, administration of macitentan caused a dose-dependent increase in plasma ET-1 with maximum effects attained at 10 mg. A small dose-dependent increase in the 6β-hydroxycortisol/cortisol urinary excretion ratio was observed, although there were no statistically significant differences between treatments including placebo. Effects of macitentan on cytochrome P450 enzyme 3A4 should be further evaluated in dedicated studies. The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET-1-dependent pathologies.
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Pharmacokinetics of the novel dual Endothelin Receptor Antagonist macitentan in subjects with hepatic or renal impairment
Journal of clinical pharmacology, 2013Co-Authors: P. N. Sidharta, Nicolas Lindegger, Ivan Ulč, Jasper DingemanseAbstract:Macitentan is under development for the treatment of pulmonary arterial hypertension (PAH). Patients with PAH may suffer from comorbidities such as renal or hepatic impairment. Two prospective, single-center, open-label studies evaluated the pharmacokinetics of macitentan and its metabolites (pharmacologically active ACT-132577 and inactive ACT-373898) in healthy subjects and in subjects with mild, moderate, and severe hepatic impairment or severe renal function impairment (SRFI). After administering a single oral dose of 10 mg macitentan the pharmacokinetic parameters including area under the curve from zero to infinity (AUC∞) were derived from plasma concentration-time profiles. Exposure to macitentan and ACT-132577 was lower in hepatically impaired versus healthy subjects, with no correlation with the degree of hepatic impairment. Exposure to ACT-373898 was lower in subjects with moderate hepatic impairment only. Plasma concentration-time profiles for macitentan and ACT-132577 (active) were similar in healthy subjects and subjects with SRFI. AUC∞ of ACT-373898 (inactive) was 7.3-fold higher in subjects with SRFI versus healthy subjects. No safety concerns were raised in either study. Based on these observations, pharmacokinetic alterations of macitentan due to hepatic or renal function impairment are not considered clinically relevant and no dose adjustment is necessary in these patients.