Potential Pharmacokinetic Interaction Between Selexipag and Midazolam in Healthy Male Subjects

A Single-center, Open-label, Randomized, Two-treatment Crossover Study to Investigate the Effect of Selexipag on the Pharmacokinetics of Midazolam and Its Metabolite 1-hydroxymidazolam in Healthy Male Subjects

The primary purpose of this study is to evaluate the effect of repeated doses of selexipag on the pharmacokinetics of a single oral dose of midazolam (i.e., how long and how much midazolam is present in the blood)

Study Overview

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

Detailed Description

In order to exclude an inductive effect of selexipag in the gastrointestinal tract, this study aims at investigating the effect of selexipag on the PK of midazolam, a sensitive substrate of both hepatic and intestinal cytochrome P450 3A4 (CYP3A4).

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Gieres, France, 38610
    • Investigator site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Key Inclusion Criteria:

• Signed informed consent form
• Age from 18 to 45 years (inclusive) at screening
• Body mass index (BMI) from 18.0 to 28.0 kg/m2 (inclusive) at screening
• Healthy on the basis of physical examination, cardiovascular assessments and laboratory tests

Key Exclusion Criteria:

• Any contraindication to the study treatments
• History or clinical evidence of any disease or medical / surgical condition or treatment, which may put the subject at risk of participation in the study or may interfere with the absorption, distribution, metabolism or excretion of the study treatments
• 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

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequence AB; Subjects participate in two study periods: During the first period, they receive a single oral dose of midazolam on Day 1. During the second period, they receive oral selexipag alone from Day 1 to Day 11 and selexipag + midazolam on Day 12. There is a washout period of 14 to 21 days between the two periods.	Drug: Midazolam; Single oral dose of 7.5 mg midazolam (tablet); Drug: Selexipag; Oral administration of selexipag (200 µg film-coated tablet) for 12 consecutive days (with a titration scheme from 400 to 1600 μg b.i.d. ); Other Names: ACT-293987
Experimental: Sequence BA; Subjects participate in two study periods: During the first period, they receive oral selexipag alone from Day 1 to Day 11 and selexipag + midazolam on Day 12. During the second period, they receive a single oral dose of midazolam on Day 1. There is a washout period of 14 to 21 days between the two periods.	Drug: Midazolam; Single oral dose of 7.5 mg midazolam (tablet); Drug: Selexipag; Oral administration of selexipag (200 µg film-coated tablet) for 12 consecutive days (with a titration scheme from 400 to 1600 μg b.i.d. ); Other Names: ACT-293987

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of midazolam following administration of midazolam alone and in combination with selexipag	Cmax is the maximum observed plasma concentration and is directly derived from the individual plasma concentration time curves of midazolam	From pre-dose up to 24 hours after midazolam admisnitration for each treatment period
AUC(0-inf) of midazolam following administration of midazolam alone and in combination with selexipag	AUC(0-inf) is the area under the plasma concentration-time curves of midazolam, calculated from time 0 (pre-dose) to the extrapolated infinite time	From pre-dose up to 24 hours after midazolam admisnitration for each treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of 1-hydroxymidazolam following administration of midazolam alone and in combination with selexipag		From pre-dose up to 24 hours after midazolam admisnitration
AUC(0-inf) of 1-hydroxymidazolam following administration of midazolam alone and in combination with selexipag		From pre-dose up to 24 hours after midazolam admisnitration
tmax of midazolam and 1-hydroxymidazolam following administration of midazolam alone and in combination with selexipag	tmax is the time to reach Cmax of midazolam and its metabolite (1-hydroxymidazolam), respectively	From pre-dose up to 24 hours after midazolam admisnitration
t½ of midazolam and 1-hydroxymidazolam following administration of midazolam alone and in combination with selexipag.	t½ is the terminla half-life of midazolam and its metabolite (1-hydroxymidazolam), and corresponds to the period of time required for the concentration levels of midazolam and its metabolite to be reduced by one-half, respectively	From pre-dose up to 24 hours after midazolam admisnitration
Trough concentration of selexipag and its metabolite ACT-333679 at steady-state	Trough concentrations are measured before morning administration of selexipag	Days 1, 4, 7, 10,12 and 13

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of treatment-emergent adverse events and serious adverse events	A treatment-emergent AE is any AE temporally associated with the use of a study treatment, whether or not considered related to the study treatment	Up to 39 days (from Day 1 of Period 1 to end of study of Period 2)

Collaborators and Investigators

• Sponsor: Actelion
• Investigators: Study Director: Pierre-Eric JUIF, PhD, Actelion

Study record dates

Study Major Dates

• Study Start: July 1, 2016
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: June 2, 2016
• First Submitted That Met QC Criteria: June 2, 2016
• First Posted (Estimate): June 7, 2016

Study Record Updates

• Last Update Posted (Estimate): October 13, 2016
• Last Update Submitted That Met QC Criteria: October 12, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: midazolam; pharmacokinetics; selexipag
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Central Nervous System Depressants; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Selexipag
• Other Study ID Numbers: AC-065-114; 2016-000856-83 (EudraCT Number)