A Clinical Study to Assess the Effect of Clopidogrel on the Pharmacokinetics of Selexipag and Its Active Metabolite in Healthy Male Subjects

A Single-center, Open-label, Two-treatment, One-sequence, Cross-over Study to Investigate the Effect of Clopidogrel on the Pharmacokinetics of Selexipag and Its Active Metabolite, ACT-333679, in Healthy Male Subjects

The purpose of this study is to evaluate the effect of clopidogrel on the pharmacokinetics of selexipag and its active metabolite (ACT-333679) in healthy male adults (by determining the blood concentrations of selexipag and its metabolite). Also, the safety of selexipag when administered alone or with clopidogrel will be assessed.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Selexipag; Drug: Clopidogrel

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Merksem, Belgium, 2170
    • Clinical Pharmacology Unit (CPU)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Signed informed consent in the local language prior to any study-mandated procedure.
• Healty male subjects aged between 18 and 45 years (inclusive) at screening.
• Body mass index from 18.0 to 28.0 kg/m2 (inclusive) at screening.
• Systolic blood pressure (SBP) 100-145 mmHg, diastolic blood pressure (DBP) 50-90 mmHg, and pulse rate 45-90 bpm (inclusive).

Exclusion Criteria:

• Any contraindication included in the SmPC of selexipag or clopidogrel treatment.
• History or clinical evidence of any disease and/or existence of any surgical or medical condition, which might interfere with the absorption, distribution, metabolism or excretion of the study treatments.
• History or clinical evidence of any disorder of hemostasis, hemorrhagic diathesis, nose or gingival bleeding, hemophilia, thrombotic thrombocytopenic purpura, presence of any lesions with a propensity to bleed (particularly gastrointestinal and intraocular), history of bleeding complications after surgical procedures such as tooth extraction
• Previous history of stroke, fainting, collapse, syncope, orthostatic hypotension,vasovagal reactions, head injury.
• Excessive caffeine consumption
• Nicotine consumption within 3 months prior to screening, and inability to refrain from nicotine consumption during the course of the study
• Previous treatment with any prescribed medications (including vaccines) or over the counter (OTC) medications (including herbal medicines such as St John's Wort, homeopathic preparations, vitamins, and minerals) within 2 weeks prior to first selexipag administration.
• Subjects with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
• Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequential treatment arm; Subjects receive 1 tablet of selexipag twice daily from Day 1 to Day 9 and 1 tablet in the morning of Day 10. In the morning of Day 4 and 1 hour before the administration of selexipag, they receive 4 tablets of clopidogrel. Then from Day 5 to Day 10, 1 hour before the morning administration of selexipag, they receive 1 tablet of clopidogrel .	Drug: Selexipag; Each film-coated tablet contains 200 microgram (mcg) of selexipag (oral use); Other Names: ACT-293987; Drug: Clopidogrel; Each film-coated tablet containing 75 mg of clopidogrel (oral use)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area under the plasma concentration-time profile of selexipag and ACT-333679 during a dose interval (AUC-tau)	AUC-tau for selexipag and ACT-333679 is calculated on the basis of the actual blood sampling time points drawn during the 12-hour interval after the morning administration of selexipag administered either alone (Day 3) or concomitantly with clopidogrel (Day 4 and Day 10)	Blood samples at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dose on Day 3, Day 4 and Day 10
Maximal plasma concentration of selexipag and ACT-333679 (Cmax)	Cmax is directly derived from the individual plasma concentration-time curves for selexipag and ACT-333679, following administration of selexipag alone (Day 3) or concomitantly with clopidogrel (Day 4 and Day 10)	Blood samples at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dose on Day 3, Day 4 and Day 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trough plasma concentration of selexipag and ACT-333679 (Ctrough)	Ctrough is the concentration of selexipag and ACT-333679 directly measured in the blood samples collected prior to the morning and evening administrations of selexipag	Blood samples from Day 1 to Day 9 before the morning and evening administrations of selexipag and on Day 10 before the morning administration of selexipag
Time to reach Cmax (tmax)	tmax is the time to reach the maximal plasma concentration of selexipag and ACT-333679 and it is directly derived from the individual plasma concentration-time curves for selexipag and ACT-333679, following administration of selexipag alone (Day 3) or concomitantly with clopidogrel (Day 4 and Day 10)	Blood samples at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10 and 12 hours post-dose on Day 3, Day 4 and Day 10
Number of participants with any treatment-emergent adverse events (TEAEs) including serious adverse events	A treatment-emergent adverse event is any adverse event temporally associated with the use of a study treatment, whether or not considered related to the study treatment	From the first selexipag administration on Day 1 up to Day 18 (about 1 week after the last administration of selexipag)

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Director: Shirin Bruderer, Actelion

Publications and helpful links

General Publications

• Axelsen LN, Poggesi I, Rasschaert F, Perez Ruixo JJ, Bruderer S. Clopidogrel, a CYP2C8 inhibitor, causes a clinically relevant increase in the systemic exposure to the active metabolite of selexipag in healthy subjects. Br J Clin Pharmacol. 2021 Jan;87(1):119-128. doi: 10.1111/bcp.14365. Epub 2020 Jun 5.

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2018
• Primary Completion (Actual): May 10, 2018
• Study Completion (Actual): May 18, 2018

Study Registration Dates

• First Submitted: April 6, 2018
• First Submitted That Met QC Criteria: April 6, 2018
• First Posted (Actual): April 12, 2018

Study Record Updates

• Last Update Posted (Actual): June 1, 2018
• Last Update Submitted That Met QC Criteria: May 31, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: clopidogrel; selexipag
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel; Selexipag
• Other Study ID Numbers: AC-065-117

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No