Absolute oral bioavailability of selexipag, a novel oral prostacyclin IP receptor agonist.

PURPOSE: The aim of this single-center, open-label study was to assess the absolute bioavailability of an oral (tablet) versus intravenous (i.v.) formulation of selexipag in healthy subjects. METHODS: A pilot phase in three healthy male subjects, which preceded the main study, consisted of a single 20-minute i.v. infusion of 50 µg selexipag. Its objectives were to ensure the safety of the i.v. formulation and to select the i.v. dose for the main study. The main study had a randomized, two-way crossover design in 16 healthy male subjects. Subjects received a single oral dose of 400 µg selexipag and a single 80-minute i.v. infusion of 200 µg selexipag. RESULTS: Three subjects in the pilot and 15 in the main phase completed the study as planned, whereas one subject of the main study withdrew the consent. A geometric mean total body clearance (95% confidence interval (CI)) of 17.9 L/h (15.0-21.5) and a volume of distribution of 11.7 L (10.6-13.0) were determined. The absolute oral bioavailability of selexipag (90% CI) was 49.4% (42.6-57.2). Selexipag was well-tolerated; no adverse event (AE) occurred during the pilot phase, and the main observed AEs were headache, nausea, and vomiting. CONCLUSION: A single i.v. administration of selexipag in healthy subjects was safe and well-tolerated. The bioavailability of selexipag after oral administration is approximately 50%.

First-in-humans study of the safety, tolerability, and pharmacokinetics of ACT-451840, a new chemical entity with antimalarial activity.

Emerging resistance to antimalarial agents raises the need for new drugs. ACT-451840 is a new compound with potent activity against sensitive and resistant Plasmodium falciparum strains. This was a first-in-humans single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of ACT-451840 across doses of 10, 50, 200, and 500 mg in healthy male subjects. In the 200- and 500-mg dose groups, the effect of food was investigated, and antimalarial activity was assessed using an ex vivo bioassay with P. falciparum. No (serious) adverse events leading to discontinuation were reported. At the highest dose level, the peak drug concentration (Cmax) and the area under the plasma concentration-time curve from zero to infinity of ACT-451840 under fasted conditions reached 11.9 ng/ml and 100.6 ng·h/ml, respectively, and these were approximately 13-fold higher under fed conditions. Food did not affect the half-life (approximately 34 h) of the drug, while the Cmax was attained 2.0 and 3.5 h postdose under fasted and fed conditions, respectively. The plasma concentrations estimated by the bioassay were approximately 4-fold higher than those measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Several potentially active metabolites were also identified. ACT-451840 was well tolerated across all doses. Exposure to ACT-451840 significantly increased with food. The bioassay indicated the presence of circulating active metabolites. (This study has been registered at ClinicalTrials.gov under registration no. NCT02186002.).

Multiple-dose up-titration study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in healthy subjects.

OBJECTIVE: The objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of selexipag, an orally available selective prostacyclin receptor agonist, in development for pulmonary arterial hypertension in healthy subjects. METHODS: This was a double-blind, placebo-controlled, randomised, multiple-ascending-dose, up-titration study. Male subjects received increasing oral doses of selexipag (400-1,800 µg; n = 12) or placebo (n = 4) twice daily for 3 days each, using incremental steps of 200 µg between each dose level. Standard safety and tolerability data were collected. Blood samples were taken to assess the pharmacokinetics of selexipag and its active metabolite ACT-333679 and possible effects on platelet aggregation. RESULTS: Dose levels of selexipag up to 1,600 µg were well tolerated and this dose was identified as the maximum tolerated dose. Plasma exposure to ACT-333679 was approximately 4 times higher than that to selexipag. Steady-state conditions for both compounds were reached on day 3 of each dose level, and no accumulation of selexipag or ACT-333679 was observed. Based on the area under the curve and the maximum plasma concentration, the pharmacokinetics of selexipag and ACT-333679 were dose proportional. At the highest dose level, the geometric mean terminal half-life of selexipag and ACT-333679 was 1.4 and 8.7 h, respectively. The observed effects on platelet aggregation were variable without obvious drug- or dose-dependent pattern. CONCLUSIONS: Oral administration of increasing doses of selexipag was well tolerated. The present results support the conduct of future clinical trials.

Clinical pharmacology, efficacy, and safety of selexipag for the treatment of pulmonary arterial hypertension.

INTRODUCTION: Selexipag is the first oral, non-prostanoid, selective prostacyclin receptor (IP receptor) agonist, approved for the long-term treatment of pulmonary arterial hypertension (PAH) in adult patients. Areas covered: This article reviews the clinical pharmacology, efficacy, and safety of selexipag in the treatment of PAH. Expert opinion: Selexipag is the first oral drug that selectively targets the prostacyclin pathway, and has evidence of long-term efficacy and safety. In the global phase 3 study GRIPHON (NCT01106014) in PAH patients, selexipag significantly reduced the risk of the primary composite outcome of morbidity/mortality (M/M). The adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, nausea, jaw pain, and diarrhea. Importantly, selexipag was efficacious and safe irrespective of whether or not patients were already receiving other PAH therapies. With selexipag approval, triple oral combination therapy addressing three important pathways is available for patients with PAH. Selexipag has one major metabolite, ACT-333679, which is also a selective IP receptor agonist, with 37-fold higher potency than selexipag. Pharmacokinetic properties of ACT-333679 permit twice-daily dosing of selexipag, providing a more convenient treatment compared to prostacyclin or its analogs. For patients with moderate hepatic impairment a once-daily regimen is recommended.

Lack of Pharmacokinetic Interactions Between Macitentan and a Combined Oral Contraceptive in Healthy Female Subjects.

Macitentan, a dual endothelin receptor antagonist used in pulmonary arterial hypertension, induces cytochrome P450 (CYP) 3A at supratherapeutic concentrations in vitro. Most combined oral hormonal contraceptives (OCs) are CYP3A substrates and their efficacy can be affected by CYP3A inducers. This randomized crossover study assessed possible pharmacokinetic (PK) interactions between macitentan and an OC containing ethinyl estradiol and norethindrone (or norethisterone). Twenty-six healthy women received a single oral dose of OC alone (reference) and concomitantly with 10 mg macitentan at steady state (test). No PK interaction was concluded if the 90% confidence intervals (CIs) of geometric mean ratios (GMRs; test/reference) of the peak plasma concentration (Cmax ) and the exposure from 0 to infinity (AUC0 - ∞ ) to the OC components were within the equivalence limits of 0.8 to 1.25. Cmax and AUC0-∞ of the OC were within the equivalence limits. For ethinyl estradiol, GMRs (90%CIs) of Cmax and AUC0-∞ were 0.92 (0.85-0.99) and 0.95 (0.90-0.99). For norethindrone, these values were 1.02 (0.95-1.09) and 1.04 (0.98-1.09), respectively. Overall, study treatments were well tolerated. No major changes from baseline in safety parameters were reported in either treatment. Macitentan does not affect the PK of OCs.