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Jasper Dingemanse - One of the best experts on this subject based on the ideXlab platform.

  • Biocomparison Study of Adult and Paediatric Dose Strengths of the Prostacyclin Receptor Agonist Selexipag
    European Journal of Drug Metabolism and Pharmacokinetics, 2018
    Co-Authors: Margaux Boehler, Shirin Bruderer, Jasper Dingemanse
    Abstract:

    Background and objectives Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of Selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200 µg Selexipag (Treatment A) vs. 4 paediatric tablets of 50 µg (Treatment B) in healthy adult male subjects. Methods This was an open-label, randomized, two-treatment, two-period, crossover biocomparison study. Bioequivalence criteria were explored and safety variables (vital signs, electrocardiogram, and laboratory parameters) were assessed. Results The exploratory analysis showed that the 90% confidence intervals of geometric mean ratio (Treatment B/Treatment A) for maximum plasma concentration ( C _max), area under the plasma concentration–time curve from zero to infinity (AUC_0–∞) of ACT-333679, as well as AUC_0–∞ of Selexipag, were within the bioequivalence interval (0.80, 1.25). In addition, no relevant difference in C _max for Selexipag between the two treatments can be concluded. Single oral dose administration of 200 µg Selexipag as one tablet of 200 µg or four tablets of 50 µg was well tolerated. Conclusions Pharmacokinetic characteristics of Selexipag and its metabolite ACT-333679 following administration of one adult tablet of 200 µg Selexipag and four paediatric tablets of 50 µg Selexipag were comparable. Trial registration ClinicalTrials.gov identifier: NCT02745860.

  • biocomparison study of adult and paediatric dose strengths of the prostacyclin receptor agonist Selexipag
    European Journal of Drug Metabolism and Pharmacokinetics, 2018
    Co-Authors: Margaux Boehler, Shirin Bruderer, Jasper Dingemanse
    Abstract:

    Background and objectives Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of Selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200 µg Selexipag (Treatment A) vs. 4 paediatric tablets of 50 µg (Treatment B) in healthy adult male subjects.

  • effect of gemfibrozil and rifampicin on the pharmacokinetics of Selexipag and its active metabolite in healthy subjects
    British Journal of Clinical Pharmacology, 2017
    Co-Authors: Shirin Bruderer, Margaux Boehler, Atef Halabi, Marc Petersensylla, Tatiana Remeňova, Jasper Dingemanse
    Abstract:

    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 (Cmax) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration–time curve from zero to infinity (AUC0–∞) 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 Cmax 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 Cmax 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.

  • A pharmacokinetic drug–drug interaction study between Selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects
    European Journal of Clinical Pharmacology, 2017
    Co-Authors: Pierreeric Juif, Shirin Bruderer, Margaux Boehler, Yves Donazzolo, Jasper Dingemanse
    Abstract:

    Purpose In vitro data showed that Selexipag and its active metabolite (ACT-333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration ( C _max) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of Selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4. Methods This study was conducted according to an open-label, randomized, two-way crossover design. A total of 20 subjects received a single oral dose of 7.5 mg midazolam alone (treatment A) or on top of steady-state Selexipag (treatment B). Selexipag was administered twice daily using an up-titration scheme consisting of three steps: 400, 600, 1000, and 1600 μg with increments every fourth day. A 24-h pharmacokinetic profile was performed following midazolam administration, and bioequivalence criteria were investigated on an exploratory basis. Results The C _max of midazolam and 1-hydroxymidazolam was decreased by approximately 20 and 14%, respectively, following treatment B compared to A. The time to reach C _max for midazolam and 1-hydroxymidazolam was similar between treatments. The terminal half-life was reduced in treatment B compared to A for both midazolam (16%) and 1-hydroxymidazolam (20%). Exposure (area under the curve) to midazolam and 1-hydroxymidazolam was similar between treatments, and the 90% confidence intervals of geometric mean ratios were within the bioequivalence interval. Treatment with midazolam, Selexipag, and the combination was safe and well tolerated. Conclusion Exposure to midazolam and 1-hydroxymidazolam was not affected by treatment with Selexipag.

  • population modeling of Selexipag pharmacokinetics and clinical response parameters in patients with pulmonary arterial hypertension
    CPT: Pharmacometrics & Systems Pharmacology, 2017
    Co-Authors: Andreas Krause, Shirin Bruderer, Noemie Hurst, M Machacek, Dominik Lott, Jasper Dingemanse
    Abstract:

    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.

Vallerie V Mclaughlin - One of the best experts on this subject based on the ideXlab platform.

  • Risk assessment in pulmonary arterial hypertension: Insights from the GRIPHON study.
    Journal of Heart and Lung Transplantation, 2020
    Co-Authors: Olivier Sitbon, Sean Gaine, Richard N Channick, Vallerie V Mclaughlin, Kelly M Chin, Lilla Di Scala, Hossein Ardeschir Ghofrani, Irene M Lang, Raymond L. Benza, R Preiss
    Abstract:

    BACKGROUND: Approaches to risk assessment in pulmonary arterial hypertension (PAH) include the noninvasive French risk assessment approach (number of low-risk criteria based on the European Society of Cardiology and European Respiratory Society guidelines) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) 2.0 risk calculator. The prognostic and predictive value of these methods for morbidity/mortality was evaluated in the predominantly prevalent population of GRIPHON, the largest randomized controlled trial in PAH. METHODS: GRIPHON randomized 1,156 patients with PAH to Selexipag or placebo. Post-hoc analyses were performed on the primary composite end-point of morbidity/mortality by the number of low-risk criteria (World Health Organization functional class I-II; 6-minute walk distance >440 m; N-terminal pro-brain natriuretic peptide

  • Results of an Expert Consensus Survey on the Treatment of Pulmonary Arterial Hypertension With Oral Prostacyclin Pathway Agents.
    Chest, 2019
    Co-Authors: Vallerie V Mclaughlin, Sean Gaine, Richard N Channick, Ioana R Preston, Harrison W Farber, Nazzareno Galie, Teresa De Marco, Richard A. Krasuski, Rogério Souza, J Gerry Coghlan
    Abstract:

    Background Treatment of pulmonary arterial hypertension (PAH) has evolved substantially over the past two decades and varies according to etiology, functional class (FC), hemodynamic parameters, and other clinical factors. Current guidelines do not provide definitive recommendations regarding the use of oral prostacyclin pathway agents (PPAs) in PAH. To provide guidance on the use of these agents, an expert panel was convened to develop consensus statements for the initiation of oral PPAs in adults with PAH. Methods A systematic literature search was conducted using MEDLINE. The established RAND/University of California Los Angeles appropriateness method, which incorporates the Delphi method and the nominal group technique, was used to create consensus statements. Idiopathic, heritable, repaired congenital heart defect, and drug- or toxin-induced PAH (IPAH+) was considered as one etiologic grouping. The process was focused on the use of oral treprostinil or Selexipag in patients with IPAH+ or connective tissue disease-associated PAH and FC II or III symptoms receiving background dual endothelin receptor antagonist/phosphodiesterase type 5 inhibitor therapy. Results The panel developed 14 consensus statements regarding the appropriate use of oral PPAs in the target population. The panel identified 13 clinical scenarios in which Selexipag may be considered as a treatment option. Conclusions The paucity of clinical evidence overall, and particularly from randomized trials in this setting, creates a gap in knowledge. These consensus statements are intended to aid physicians in navigating treatment options and using oral PPAs in the most appropriate manner in patients with PAH.

  • P3671Selexipag dosing and titration in the first 500 patients enrolled in SPHERE (Selexipag: tHe UsErs dRug rEgistry)
    European Heart Journal, 2019
    Co-Authors: Vallerie V Mclaughlin, Kelly M Chin, Harrison W Farber, Anna R. Hemnes, Kristin B. Highland, Carol Zhao, V Narayan, M. Shah, Murali M. Chakinala
    Abstract:

    Abstract Introduction SPHERE is an ongoing US-based, multicentre, prospective, registry collecting data on use of the oral selective IP prostacyclin receptor agonist Selexipag in real-world settings. Here, we report Selexipag dosing and titration in the first 500 patients. Methods SPHERE, initiated in November 2016, will enrol 800 patients newly initiated on or already treated with Selexipag at enrolment who have a documented titration regimen. Patients are followed for up to 18 months. Patients were considered “newly initiated” on Selexipag if they were enrolled in SPHERE ≤60 days after starting Selexipag and were considered “previously initiated” if they enrolled >60 days after starting Selexipag. The highest dose is the maximum dose reached during up-titration within 6 months since initiation. Selexipag “maintenance dose” is defined as the first dose received for ≥14 days without interruption or change; “titration speed” is defined as the highest dose reached within the first 6 months after initiation divided by the time (in weeks) to reach it. Results The data cut-off for this analysis was December 20, 2018. Most patients had Group 1 pulmonary hypertension (PH) (95.4%), which was primarily idiopathic (49.6%) or connective tissue disease associated (26.0%). At Selexipag initiation 49.8% of patients had functional class III symptoms. At the time of Selexipag initiation, 19.2% of patients were on PH therapy containing a prostacyclin pathway agent (PPA) (8.5% with a parenteral PPA). The median maintenance dose of Selexipag was 1200 μg BID (IQR: 800–1600 μg BID) and the median time to reach it was 8.1 wks (IQR: 5.3–11.0 wks). Low (≤400 μg BID), medium (600–1000 μg BID), and high (≥1200 μg BID) maintenance doses were attained by 15.1%, 30.8%, and 49.5% of patients, respectively (and in 23.2%, 31.2%, and 36.2%, respectively, in GRIPHON). The median titration speed was 175 μg BID/wk (IQR: 110.5–195.3 μg BID/wk), slower than the protocol-outlined 200 μg BID/wk in GRIPHON. In SPHERE, most patients titrated at speeds <200 μg BID/wk, regardless of whether they were newly (175 μg BID/wk; IQR 118.6, 195.3) or previously (175 μg BID/wk; IQR 109.8, 195.3) initiated. As expected, more patients discontinued due to adverse events in the newly (29.0%) versus previously (14.1%) initiated groups. The most common adverse events leading to Selexipag discontinuation were worsening pulmonary hypertension (2.2%), headache (2.0%), myalgia (1.4%), and nausea (1.0%). Conclusion The median maintenance Selexipag dose in SPHERE was 1200 μg BID. While the median titration speed was 175 μg BID/wk, there was marked variation and the vast majority of patients titrated slower than 200 μg BID/wk. No new safety signals were observed. Acknowledgement/Funding Actelion Pharmaceuticals US, Inc.

  • 4973Efficacy and safety of Selexipag in pulmonary arterial hypertension (PAH) patients with and without significant cardiovascular (CV) comorbidities
    European Heart Journal, 2019
    Co-Authors: Stephan Rosenkranz, N Galie, Sean Gaine, Richard N Channick, Marius M Hoeper, Vallerie V Mclaughlin, Hossein Ardeschir Ghofrani, K Chin, B Jenner, R Preiss
    Abstract:

    Abstract Introduction Many PAH patients today have a number of CV comorbidities, yet data on the efficacy and safety of therapies in such patients remain scarce. Most recent PAH clinical trials also include patients with comorbidities. Purpose To assess the long-term efficacy and safety of the oral, selective IP prostacyclin receptor agonist, Selexipag, in PAH patients with and without significant CV comorbidities using post hoc analysis of GRIPHON data. Methods GRIPHON enrolled 1156 PAH patients randomised 1:1 to placebo:Selexipag. The present analysis includes patients with right heart catheterisation within 1 year of randomisation who were categorised as with or without CV comorbidities. Patients with CV comorbidities were defined as having ≥3 of the following: body mass index (BMI) >30 kg/m2, history of essential hypertension, diabetes mellitus, or historical evidence of significant coronary artery disease; if PAWP/LVEDP was >12 but <15 mmHg, pulmonary vascular resistance (PVR) had to be >500 dyn.sec/cm5; if PAWP/LVEDP was <12, then PVR had to be >300 dyn.sec/cm5. Selexipag effect on time to first morbidity/mortality (M/M) event up to end of treatment was assessed for both subgroups. Baseline (BL) adjusted treatment hazard ratios with 95% CIs were calculated using Cox models. Model building involved stepwise backward elimination of BL covariates. Results 752 PAH patients could be categorised based on these criteria (99 with CV comorbidities, 653 without). At BL, patients with CV comorbidities were older (median [range] 60 [28–80] vs 46 [18–78] yrs), had higher BMI (mean [SD] 33.3 [7.23] vs 26.0 [5.64] kg/m2) and lower 6-minute walk distance (mean [SD] 319 [95.7] vs 354 [79.3] m) vs those without. A greater proportion were from Western Europe/Australia/North America (60.6% vs 38.9%) and in WHO functional class III (69.7% vs 49.9%). At BL, 82.8% of patients with CV comorbidities were receiving PAH therapies vs 75.7% of those without. As expected, at BL a higher proportion of patients with CV comorbidities (vs without) had previous/concomitant cardiac disease (62.6% vs 43.0%), metabolism/nutrition disorders (75.8% vs 31.2%), respiratory/thoracic/mediastinal disorders (59.6% vs 37.5%) and vascular disorders (76.8% vs 37.4%). Selexipag reduced the risk of M/M events vs placebo in both subgroups (Figure), with no evidence of an inconsistent treatment effect (interaction p-value=0.1544). Adverse events leading to treatment discontinuation were reported in 35.4% (25.9% Selexipag, 46.7% placebo) of patients with CV comorbidities and 35.0% (32.0% Selexipag, 38.0% placebo) of those without. Common prostacyclin associated side effects observed with Selexipag (headache, diarrhoea, nausea) were reported at a similar incidence in both subgroups. Conclusions Selexipag had a beneficial effect on long-term outcome in PAH patients both with and without CV comorbidities. Safety in both groups was consistent with the known profile of Selexipag. Acknowledgement/Funding Actelion Pharmaceuticals Ltd

  • Selexipag treatment for pulmonary arterial hypertension associated with congenital heart disease after defect correction insights from the randomised controlled griphon study
    European Journal of Heart Failure, 2019
    Co-Authors: Maurice Beghetti, Sean Gaine, Richard N Channick, Marius M Hoeper, Vallerie V Mclaughlin, Kelly M Chin, Lilla Di Scala, Hossein Ardeschir Ghofrani, Irene M Lang, R Preiss
    Abstract:

    AIMS:Patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) after defect correction have a poor prognosis compared with other CHD-PAH patients. Therefore, it is important that these patients are treated as early and effectively as possible. Evidence supporting the use of PAH therapies in patients with corrected CHD-PAH from randomised controlled trials is limited. The purpose of these analyses was to characterise the corrected CHD-PAH patients from the GRIPHON study and examine the response to Selexipag. METHODS AND RESULTS:Out of the 110 patients diagnosed with corrected CHD-PAH, 55 had atrial septal defects, 38 had ventricular septal defects, 14 had persistent ducti arteriosus, and 3 had defects not further specified. Hazard ratios (HR) and 95% confidence intervals (CI) for the primary composite endpoint were calculated using Cox proportional hazard models. Compared with the non-CHD patients from GRIPHON, patients with corrected CHD-PAH were slightly younger, with a greater proportion being treatment-naive and in World Health Organization functional class I/II. The rate of the primary composite endpoint of morbidity/mortality was lower in patients with corrected CHD-PAH who were treated with Selexipag compared with those treated with placebo (HR 0.58; 95% CI 0.25, 1.37). The most common adverse events were those known to be related to Selexipag. CONCLUSIONS:These post-hoc analyses of GRIPHON provide valuable information about a large population of patients with corrected CHD-PAH, and suggest that Selexipag may delay disease progression and was well-tolerated in patients with corrected CHD-PAH.

Martine Clozel - One of the best experts on this subject based on the ideXlab platform.

  • selective prostacyclin receptor agonist Selexipag in contrast to prostacyclin analogs does not evoke paradoxical vasoconstriction of the rat femoral artery
    Journal of Pharmacology and Experimental Therapeutics, 2018
    Co-Authors: Keith Morrison, Roland Ernst, Franck Haag, Marc Iglarz, Martine Clozel
    Abstract:

    Selexipag [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide] is a selective nonprostanoid prostacyclin (PGI2) receptor (IP receptor) agonist that is approved for the treatment of pulmonary arterial hypertension (PAH). In contrast to Selexipag, PGI2 analogs used in the clinic are nonselective agonists at prostanoid receptors and can also activate contractile prostaglandin E receptor 3 (EP3) receptors. Leg pain is a common side effect in patients receiving treatment with PGI2 analogs and peripheral vasoconstriction can be responsible for side effects related to muscular ischemia. This study tested the hypothesis that PGI2 analogs could cause paradoxical vasoconstriction of the femoral artery via EP3 receptor activation but that only vasorelaxation would be observed in response to Selexipag and its active metabolite ACT-333679 [{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid]. Selexipag and ACT-333679 relaxed rings of the isolated rat femoral artery contracted with either prostaglandin F2α (PGF2α) or the α1 adrenoceptor (α1AR) agonist phenylephrine. ACT-333679 also inhibited contraction of the femoral artery to sympathetic nerve stimulation. In contrast, PGI2 analogs (iloprost, beraprost, and treprostinil) caused additional contraction of arterial rings precontracted with phenylephrine, which was reverted to relaxation by antagonism of EP3 receptors. Treprostinil augmented contraction of the femoral artery to sympathetic nerve stimulation in an EP3 receptor–dependent manner. Mechanistically, concomitant EP3 and α1AR receptor activation synergistically constricted femoral arteries. It is concluded that Selexipag and ACT-333679 are vasorelaxants of the rat femoral artery and, unlike PGI2 analogs, do not cause paradoxical vasoconstriction via activation of EP3 receptors. EP3 receptor–mediated vasoconstriction may contribute to the well documented peripheral muscle pain reported in patients with PAH receiving PGI2 analogs. Leg pain may be less in patients treated with Selexipag.

  • Selexipag active metabolite act 333679 displays strong anticontractile and antiremodeling effects but low β arrestin recruitment and desensitization potential
    Journal of Pharmacology and Experimental Therapeutics, 2017
    Co-Authors: John Gatfield, Carmela Gnerre, Keith Morrison, Daniel Wanner, Patrick Hess, Martine Clozel, Marc Iglarz, Katalin Menyhart, Lucile Monnier, Oliver Nayler
    Abstract:

    Prostacyclin (PGI2) receptor (IP receptor) agonists, which are indicated for the treatment of pulmonary arterial hypertension (PAH), increase cytosolic cAMP levels and thereby inhibit pulmonary vasoconstriction, pulmonary arterial smooth muscle cell (PASMC) proliferation, and extracellular matrix synthesis. Selexipag (Uptravi, 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide) is the first nonprostanoid IP receptor agonist, it is available orally and was recently approved for the treatment of PAH. In this study we show that the active metabolite of Selexipag and the main contributor to clinical efficacy ACT-333679 (previously known as MRE-269) behaved as a full agonist in multiple PAH-relevant receptor-distal—or downstream—cellular assays with a maximal efficacy (Emax) comparable to that of the prototypic PGI2 analog iloprost. In PASMC, ACT-333679 potently induced cellular relaxation (EC50 4.3 nM) and inhibited cell proliferation (IC50 4.0 nM) as well as extracellular matrix synthesis (IC50 8.3 nM). In contrast, ACT-333679 displayed partial agonism in receptor-proximal—or upstream—cAMP accumulation assays (Emax 56%) when compared with iloprost and the PGI2 analogs beraprost and treprostinil (Emax ∼100%). Partial agonism of ACT-333679 also resulted in limited β-arrestin recruitment (Emax 40%) and lack of sustained IP receptor internalization, whereas all tested PGI2 analogs behaved as full agonists in these desensitization-related assays. In line with these in vitro findings, Selexipag, but not treprostinil, displayed sustained efficacy in rat models of pulmonary and systemic hypertension. Thus, the partial agonism of ACT-333679 allows for full efficacy in amplified receptor-distal PAH-relevant readouts while causing limited activity in desensitization-related receptor-proximal readouts.

  • abstract 13829 the active metabolite of Selexipag relaxes rat pulmonary artery via selective activation of ip prostacyclin receptors
    Circulation, 2015
    Co-Authors: Keith Morrison, Roland Ernst, Franck Haag, Martine Clozel
    Abstract:

    Introduction: Selexipag is a selective IP prostacyclin receptor agonist in development for the treatment of pulmonary arterial hypertension. Preclinical studies demonstrate that Selexipag and its active metabolite ACT-333679 relax rat extralobar pulmonary artery (EPA) ex vivo . It has been reported that the IP receptor antagonist CAY10441 does not inhibit relaxation to ACT-333679. Hypothesis: We hypothesized that relaxation of rat EPA to ACT-333679 could be inhibited by antagonism of IP receptors using a modified protocol. Methods: Rings of rat EPA were prepared using standard techniques. Relaxation to ACT-333679 was measured in EPA pre-contracted with PGF 2 α (10 μM). The effect of CAY10441, BWA868C and PF04418948 (selective antagonists of relaxant IP, DP 1 and EP 2 receptors, respectively) on relaxation to ACT-333679 was measured using 2 protocols: (1) EPA was incubated with each receptor antagonist prior to addition of increasing concentrations of ACT-333679; (2) each receptor antagonist was added after stabilization of relaxation to ACT-333679 (1 μM). Results: ACT-333679 relaxed EPA in a concentration-dependent manner (Figure 1A; control pEC 50 5.8 ± 0.1). CAY10441 (1 μM) did not inhibit relaxation to ACT-333679 when added prior to ACT-333679 (pEC 50 5.6 ± 0.1; not statistically significant vs control). However, CAY10441 (0.1-10 μM) reversed relaxation of EPA when added after sub-maximal relaxation to ACT-333679 (1 μM) was reached (relaxation 48.8 ± 9.8% of PGF 2 α contraction) (Figure 1B). BWA868C and PF04418948 did not inhibit relaxation of EPA when added before or after ACT-333679. Conclusion: Relaxation of EPA to ACT-333679 is inhibited by antagonism of IP receptors, but not DP 1 or EP 2 receptors. IP receptor activation by ACT-333679 is first required to observe the inhibitory effect of CAY10441 on vasorelaxation. ACT-333679 relaxes rat EPA via selective activation of IP prostacyclin receptors.

  • repeated oral administration of the selective prostacyclin receptor agonist Selexipag does not cause tachyphylaxis in spontaneously hypertensive rats
    Journal of the American College of Cardiology, 2015
    Co-Authors: Keith Morrison, Carmela Gnerre, Daniel Wanner, John Gatfield, Patrick Hess, Martine Clozel
    Abstract:

    Selexipag, an orally available, selective prostacyclin (PGI2) receptor (IP receptor) agonist, significantly decreased pulmonary vascular resistance in patients with pulmonary arterial hypertension (PAH) in a phase 2 clinical trial. Selexipag is structurally different from PGI2. Reduced clinical

  • differential effects of Selexipag and prostacyclin analogs in rat pulmonary artery
    Journal of Pharmacology and Experimental Therapeutics, 2012
    Co-Authors: Keith Morrison, Roland Ernst, Rolf Studer, Franck Haag, Katalin Kauser, Martine Clozel
    Abstract:

    ACT-333679 is the main metabolite of the selective prostacyclin (PGI2) receptor (IP receptor) agonist Selexipag. The goal of this study was to determine the influence of IP receptor selectivity on vasorelaxant efficacy of ACT-333679 and the PGI2 analog treprostinil in pulmonary artery under conditions associated with PAH. Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and MCT-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either ET-1 or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of EP3 receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP3 receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH compared to control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP3 receptor antagonist DBTSA. Antagonism of EP3 receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist Selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.

Shirin Bruderer - One of the best experts on this subject based on the ideXlab platform.

  • biocomparison study of adult and paediatric dose strengths of the prostacyclin receptor agonist Selexipag
    European Journal of Drug Metabolism and Pharmacokinetics, 2018
    Co-Authors: Margaux Boehler, Shirin Bruderer, Jasper Dingemanse
    Abstract:

    Background and objectives Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of Selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200 µg Selexipag (Treatment A) vs. 4 paediatric tablets of 50 µg (Treatment B) in healthy adult male subjects.

  • Biocomparison Study of Adult and Paediatric Dose Strengths of the Prostacyclin Receptor Agonist Selexipag
    European Journal of Drug Metabolism and Pharmacokinetics, 2018
    Co-Authors: Margaux Boehler, Shirin Bruderer, Jasper Dingemanse
    Abstract:

    Background and objectives Selexipag is an oral, non-prostanoid, selective prostacyclin receptor agonist recently marketed for the treatment of pulmonary arterial hypertension (PAH) in adults. Selexipag may also be an effective treatment in children with PAH. The aim of this study was to compare the pharmacokinetics of Selexipag and its active metabolite ACT-333679 following single oral administration of one tablet of 200 µg Selexipag (Treatment A) vs. 4 paediatric tablets of 50 µg (Treatment B) in healthy adult male subjects. Methods This was an open-label, randomized, two-treatment, two-period, crossover biocomparison study. Bioequivalence criteria were explored and safety variables (vital signs, electrocardiogram, and laboratory parameters) were assessed. Results The exploratory analysis showed that the 90% confidence intervals of geometric mean ratio (Treatment B/Treatment A) for maximum plasma concentration ( C _max), area under the plasma concentration–time curve from zero to infinity (AUC_0–∞) of ACT-333679, as well as AUC_0–∞ of Selexipag, were within the bioequivalence interval (0.80, 1.25). In addition, no relevant difference in C _max for Selexipag between the two treatments can be concluded. Single oral dose administration of 200 µg Selexipag as one tablet of 200 µg or four tablets of 50 µg was well tolerated. Conclusions Pharmacokinetic characteristics of Selexipag and its metabolite ACT-333679 following administration of one adult tablet of 200 µg Selexipag and four paediatric tablets of 50 µg Selexipag were comparable. Trial registration ClinicalTrials.gov identifier: NCT02745860.

  • effect of gemfibrozil and rifampicin on the pharmacokinetics of Selexipag and its active metabolite in healthy subjects
    British Journal of Clinical Pharmacology, 2017
    Co-Authors: Shirin Bruderer, Margaux Boehler, Atef Halabi, Marc Petersensylla, Tatiana Remeňova, Jasper Dingemanse
    Abstract:

    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 (Cmax) 3.6-fold [90% confidence interval (CI) 3.1, 4.3] and the area under the plasma concentration–time curve from zero to infinity (AUC0–∞) 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 Cmax 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 Cmax 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.

  • A pharmacokinetic drug–drug interaction study between Selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects
    European Journal of Clinical Pharmacology, 2017
    Co-Authors: Pierreeric Juif, Shirin Bruderer, Margaux Boehler, Yves Donazzolo, Jasper Dingemanse
    Abstract:

    Purpose In vitro data showed that Selexipag and its active metabolite (ACT-333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration ( C _max) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of Selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4. Methods This study was conducted according to an open-label, randomized, two-way crossover design. A total of 20 subjects received a single oral dose of 7.5 mg midazolam alone (treatment A) or on top of steady-state Selexipag (treatment B). Selexipag was administered twice daily using an up-titration scheme consisting of three steps: 400, 600, 1000, and 1600 μg with increments every fourth day. A 24-h pharmacokinetic profile was performed following midazolam administration, and bioequivalence criteria were investigated on an exploratory basis. Results The C _max of midazolam and 1-hydroxymidazolam was decreased by approximately 20 and 14%, respectively, following treatment B compared to A. The time to reach C _max for midazolam and 1-hydroxymidazolam was similar between treatments. The terminal half-life was reduced in treatment B compared to A for both midazolam (16%) and 1-hydroxymidazolam (20%). Exposure (area under the curve) to midazolam and 1-hydroxymidazolam was similar between treatments, and the 90% confidence intervals of geometric mean ratios were within the bioequivalence interval. Treatment with midazolam, Selexipag, and the combination was safe and well tolerated. Conclusion Exposure to midazolam and 1-hydroxymidazolam was not affected by treatment with Selexipag.

  • population modeling of Selexipag pharmacokinetics and clinical response parameters in patients with pulmonary arterial hypertension
    CPT: Pharmacometrics & Systems Pharmacology, 2017
    Co-Authors: Andreas Krause, Shirin Bruderer, Noemie Hurst, M Machacek, Dominik Lott, Jasper Dingemanse
    Abstract:

    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.

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  • 4973Efficacy and safety of Selexipag in pulmonary arterial hypertension (PAH) patients with and without significant cardiovascular (CV) comorbidities
    European Heart Journal, 2019
    Co-Authors: Stephan Rosenkranz, N Galie, Sean Gaine, Richard N Channick, Marius M Hoeper, Vallerie V Mclaughlin, Hossein Ardeschir Ghofrani, K Chin, B Jenner, R Preiss
    Abstract:

    Abstract Introduction Many PAH patients today have a number of CV comorbidities, yet data on the efficacy and safety of therapies in such patients remain scarce. Most recent PAH clinical trials also include patients with comorbidities. Purpose To assess the long-term efficacy and safety of the oral, selective IP prostacyclin receptor agonist, Selexipag, in PAH patients with and without significant CV comorbidities using post hoc analysis of GRIPHON data. Methods GRIPHON enrolled 1156 PAH patients randomised 1:1 to placebo:Selexipag. The present analysis includes patients with right heart catheterisation within 1 year of randomisation who were categorised as with or without CV comorbidities. Patients with CV comorbidities were defined as having ≥3 of the following: body mass index (BMI) >30 kg/m2, history of essential hypertension, diabetes mellitus, or historical evidence of significant coronary artery disease; if PAWP/LVEDP was >12 but <15 mmHg, pulmonary vascular resistance (PVR) had to be >500 dyn.sec/cm5; if PAWP/LVEDP was <12, then PVR had to be >300 dyn.sec/cm5. Selexipag effect on time to first morbidity/mortality (M/M) event up to end of treatment was assessed for both subgroups. Baseline (BL) adjusted treatment hazard ratios with 95% CIs were calculated using Cox models. Model building involved stepwise backward elimination of BL covariates. Results 752 PAH patients could be categorised based on these criteria (99 with CV comorbidities, 653 without). At BL, patients with CV comorbidities were older (median [range] 60 [28–80] vs 46 [18–78] yrs), had higher BMI (mean [SD] 33.3 [7.23] vs 26.0 [5.64] kg/m2) and lower 6-minute walk distance (mean [SD] 319 [95.7] vs 354 [79.3] m) vs those without. A greater proportion were from Western Europe/Australia/North America (60.6% vs 38.9%) and in WHO functional class III (69.7% vs 49.9%). At BL, 82.8% of patients with CV comorbidities were receiving PAH therapies vs 75.7% of those without. As expected, at BL a higher proportion of patients with CV comorbidities (vs without) had previous/concomitant cardiac disease (62.6% vs 43.0%), metabolism/nutrition disorders (75.8% vs 31.2%), respiratory/thoracic/mediastinal disorders (59.6% vs 37.5%) and vascular disorders (76.8% vs 37.4%). Selexipag reduced the risk of M/M events vs placebo in both subgroups (Figure), with no evidence of an inconsistent treatment effect (interaction p-value=0.1544). Adverse events leading to treatment discontinuation were reported in 35.4% (25.9% Selexipag, 46.7% placebo) of patients with CV comorbidities and 35.0% (32.0% Selexipag, 38.0% placebo) of those without. Common prostacyclin associated side effects observed with Selexipag (headache, diarrhoea, nausea) were reported at a similar incidence in both subgroups. Conclusions Selexipag had a beneficial effect on long-term outcome in PAH patients both with and without CV comorbidities. Safety in both groups was consistent with the known profile of Selexipag. Acknowledgement/Funding Actelion Pharmaceuticals Ltd

  • Selexipag treatment for pulmonary arterial hypertension associated with congenital heart disease after defect correction insights from the randomised controlled griphon study
    European Journal of Heart Failure, 2019
    Co-Authors: Maurice Beghetti, Sean Gaine, Richard N Channick, Marius M Hoeper, Vallerie V Mclaughlin, Kelly M Chin, Lilla Di Scala, Hossein Ardeschir Ghofrani, Irene M Lang, R Preiss
    Abstract:

    AIMS:Patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) after defect correction have a poor prognosis compared with other CHD-PAH patients. Therefore, it is important that these patients are treated as early and effectively as possible. Evidence supporting the use of PAH therapies in patients with corrected CHD-PAH from randomised controlled trials is limited. The purpose of these analyses was to characterise the corrected CHD-PAH patients from the GRIPHON study and examine the response to Selexipag. METHODS AND RESULTS:Out of the 110 patients diagnosed with corrected CHD-PAH, 55 had atrial septal defects, 38 had ventricular septal defects, 14 had persistent ducti arteriosus, and 3 had defects not further specified. Hazard ratios (HR) and 95% confidence intervals (CI) for the primary composite endpoint were calculated using Cox proportional hazard models. Compared with the non-CHD patients from GRIPHON, patients with corrected CHD-PAH were slightly younger, with a greater proportion being treatment-naive and in World Health Organization functional class I/II. The rate of the primary composite endpoint of morbidity/mortality was lower in patients with corrected CHD-PAH who were treated with Selexipag compared with those treated with placebo (HR 0.58; 95% CI 0.25, 1.37). The most common adverse events were those known to be related to Selexipag. CONCLUSIONS:These post-hoc analyses of GRIPHON provide valuable information about a large population of patients with corrected CHD-PAH, and suggest that Selexipag may delay disease progression and was well-tolerated in patients with corrected CHD-PAH.

  • s122 long term survival and safety with Selexipag in patients with pulmonary arterial hypertension results from the griphon study and its open label extension
    Thorax, 2018
    Co-Authors: J G Coghlan, N Galie, Sean Gaine, Richard N Channick, Ha Ghofrani, Marius M Hoeper, I M Lang, Vallerie V Mclaughlin, R Preiss, Lewis J Rubin
    Abstract:

    Introduction Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis. In the event-driven GRIPHON study, Selexipag significantly reduced the risk of a composite primary endpoint event of morbidity/mortality compared with placebo. Purpose The long-term safety, tolerability and survival for patients treated with Selexipag in the GRIPHON double-blind (DB) study and its open-label extension (OLE) are presented. Methods All patients that received Selexipag in the GRIPHON DB study and/or the OLE were included. Patients were followed for adverse events (AEs) and survival from Selexipag initiation until the end of treatment (up to 30 days after Selexipag discontinuation for survival), or until the cut-off date (20 December 2017). Results At the cut-off date, 953 patients had received Selexipag during the DB study and/or the OLE. Of the 574 patients randomised to DB Selexipag, 330 entered the OLE and continued to receive Selexipag (of these, 67 had experienced a morbidity event). A further 379 patients switched from placebo to Selexipag in the OLE (160 of whom had experienced a morbidity event). At Selexipag initiation, the majority of patients were Conclusion These analyses are based on a large and comprehensive cohort of PAH patients and provide 5 year survival data (survival rate 72.9%). These analyses also support the known safety and tolerability profile of Selexipag. Please refer to page A265 for declarations of interest related to this abstract.

  • Targeting the Prostacyclin Pathway with Selexipag in Patients with Pulmonary Arterial Hypertension Receiving Double Combination Therapy: Insights from the Randomized Controlled GRIPHON Study
    American Journal of Cardiovascular Drugs, 2018
    Co-Authors: J Gerry Coghlan, Marius M Hoeper, Lilla Di Scala, Nazzareno Galie, Hossein Ardeschir Ghofrani, Irene M Lang, Kelly Chin, Richard Channick, Vallerie Mclaughlin, R Preiss
    Abstract:

    Background In pulmonary arterial hypertension (PAH), combination therapy is an important treatment strategy. Although randomized controlled trial data are available to support the combination of two therapies, data regarding triple combination therapy are few. Objective The phase III GRIPHON trial enrolled 1156 patients with PAH, including 376 receiving background double combination therapy. We evaluated the efficacy and safety of Selexipag as a third agent in these patients and further analyzed this subgroup according to symptom burden at baseline as indicated by World Health Organization (WHO) functional class (FC). Methods In this post hoc analysis, hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using Cox proportional-hazard models to determine response to Selexipag versus placebo on the composite primary endpoint of morbidity/mortality. Baseline characteristics and adverse events were summarized descriptively. Results Of 376 patients receiving background endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE-5i) therapy, 115 had WHO FC II symptoms and 255 had WHO FC III symptoms at baseline. The impact on the primary endpoint of adding Selexipag versus placebo to double combination therapy was consistent with the effect in the overall population (HR 0.63; 95% CI 0.44–0.90) as well as in patients with WHO FC II and III symptoms. Compared with the overall population, discontinuations due to an adverse event were higher when Selexipag was added to background double combination therapy; no safety concerns were identified. Conclusion The addition of Selexipag to background double combination therapy with an ERA and PDE-5i provides an incremental benefit similar to that seen in the overall population, including in patients with WHO FC II or III symptoms at baseline. ClinicalTrials.gov Identifier NCT01106014.

  • targeting the prostacyclin pathway with Selexipag in patients with pulmonary arterial hypertension receiving double combination therapy insights from the randomized controlled griphon study
    American Journal of Cardiovascular Drugs, 2018
    Co-Authors: Gerry Coghlan, Richard N Channick, Marius M Hoeper, Kelly M Chin, Lilla Di Scala, Nazzareno Galie, Hossein Ardeschir Ghofrani, Irene M Lang, Vallerie V Mclaughlin
    Abstract:

    In pulmonary arterial hypertension (PAH), combination therapy is an important treatment strategy. Although randomized controlled trial data are available to support the combination of two therapies, data regarding triple combination therapy are few. The phase III GRIPHON trial enrolled 1156 patients with PAH, including 376 receiving background double combination therapy. We evaluated the efficacy and safety of Selexipag as a third agent in these patients and further analyzed this subgroup according to symptom burden at baseline as indicated by World Health Organization (WHO) functional class (FC). In this post hoc analysis, hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using Cox proportional-hazard models to determine response to Selexipag versus placebo on the composite primary endpoint of morbidity/mortality. Baseline characteristics and adverse events were summarized descriptively. Of 376 patients receiving background endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE-5i) therapy, 115 had WHO FC II symptoms and 255 had WHO FC III symptoms at baseline. The impact on the primary endpoint of adding Selexipag versus placebo to double combination therapy was consistent with the effect in the overall population (HR 0.63; 95% CI 0.44–0.90) as well as in patients with WHO FC II and III symptoms. Compared with the overall population, discontinuations due to an adverse event were higher when Selexipag was added to background double combination therapy; no safety concerns were identified. The addition of Selexipag to background double combination therapy with an ERA and PDE-5i provides an incremental benefit similar to that seen in the overall population, including in patients with WHO FC II or III symptoms at baseline. NCT01106014.