A Study of Macitentan and Tadalafil as a Fixed Dose Combination and the Free Combination in Healthy Adult Participants

NCT04235270 | Completed Phase 1 FDA Drug

• 2 other identifiers: CR10873567896062PAH1006
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to demonstrate bioequivalence on the primary pharmacokinetic (PK) parameters of tadalafil administered as an fixed dose combination (FDC) (test) of macitentan/tadalafil (10 milligram \[mg\]/40 mg) and coadministered as a free combination (reference) of 10 mg macitentan (Opsumit) and 40 mg Canada-sourced tadalafil (Adcirca) in fasted conditions in healthy adult participants (Group 1) and to evaluate the effect of food on the primary PK parameters of macitentan and tadalafil administered as an FDC of macitentan/tadalafil (10 mg/40 mg) in healthy adult participants (Group 2).

Conditions

Healthy

Outcome Measures

Primary Outcomes (6)

• Group 1: Maximum Observed Plasma Analyte Concentration (Cmax) of Tadalafil

  Cmax is the maximum observed plasma analyte concentration.

  Up to 216 hours post dose (Up to Day 10)

• Group 1: Area Under the Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC [0-last]) of Tadalafil

  AUC(0-last) is the area under the plasma analyte concentration-time curve from time 0 to time of the last quantifiable (non-below quantification limit \[non-BQL\]) concentration, calculated by linear-linear trapezoidal summation.

  Up to 216 hours post dose (Up to Day 10)

• Group 1: Area Under the Concentration-time Curve from Time Zero to Infinity (AUC [0-infinity]) of Tadalafil

  AUC (0-infinity) is the area under the analyte concentration-time curve (AUC) from time zero to infinite time, calculated as the sum of AUC (0-last) and C(last)/lambda(z); wherein AUC (0-last) is area under the plasma concentration-time curve from time zero to last measurable concentration, C(last) is the last observed measurable (non-BQL) analyte concentration; and lambda(z) is apparent terminal elimination rate constant.

  Up to 216 hours post dose (Up to Day 10)

• Group 2: Maximum Observed Plasma Analyte Concentration (Cmax) of Tadalafil and Macitentan

  Cmax is the maximum observed plasma analyte concentration.

  Up to 216 hours post dose (Up to Day 10)

• Group 2: Area Under the Concentration-time Curve from Time Zero to the Last Quantifiable Concentration (AUC [0-last]) of Tadalafil and Macitentan

  AUC(0-last) is the area under the plasma analyte concentration-time curve from time 0 to time of the last quantifiable (non-below quantification limit \[non-BQL\]) concentration, calculated by linear-linear trapezoidal summation.

  Up to 216 hours post dose (Up to Day 10)

• Group 2: Area Under the Concentration-time Curve from Time Zero to Infinity (AUC [0-infinity]) of Tadalafil and Macitentan

  AUC (0-infinity) is the area under the analyte concentration-time curve (AUC) from time zero to infinite time, calculated as the sum of AUC (0-last) and C(last)/lambda(z); wherein AUC (0-last) is area under the plasma concentration-time curve from time zero to last measurable concentration, C(last) is the last observed measurable (non-BQL) analyte concentration; and lambda(z) is apparent terminal elimination rate constant.

  Up to 216 hours post dose (Up to Day 10)

Secondary Outcomes (8)

• Group 1 and Group 2: Time to Reach Maximum Observed Plasma Analyte Concentration (Tmax) of Tadalafil and Macitentan

  Up to 216 hours post dose (Up to Day 10)

• Group 1 and Group 2: Last Observed Measurable Plasma Analyte Concentration (Clast) of Tadalafil and Macitentan

  Up to 216 hours post dose (Up to Day 10)

• Group 1 and Group 2: Area Under the Plasma Analyte Concentration-time Curve from Time of 0 to 72 Hours Post Dosing (AUC[0-72h] of Tadalafil and Macitentan

  Up to 72 hours post dose

• Group 1 and Group 2: Apparent Terminal Elimination Half-life (t1/2) of Tadalafil and Macitentan

  Up to 216 hours post dose (Up to Day 10)

• Group 1 and Group 2: Apparent Terminal Elimination Rate Constant (Lambda[z]) of Tadalafil and Macitentan

  Up to 216 hours post dose (Up to Day 10)

Study Arms (2)

Group 1 (Bioequivalence Part)

EXPERIMENTAL

Participants will receive Treatment A (single oral dose of an fixed dose combination \[FDC\] of macitentan/tadalafil \[10 milligram \[mg\]/40 mg\] in fasted conditions \[test\]) or Treatment B (single oral dose of a free combination of 10 mg macitentan and 40 mg tadalafil in fasted conditions \[reference\]) on Day 1 of Treatment Period 1 followed by Treatment B or Treatment A on Day 1 of Treatment Period 2. Study drug intake in subsequent treatment periods will be separated by a washout period of at least 10 days.

Combination Product: FDC of Macitentan and Tadalafil; Drug: Macitentan; Drug: Tadalafil

Group 2 (Food-effect Part)

EXPERIMENTAL

Participants will receive Treatment C (single oral dose of an FDC of macitentan/tadalafil \[10 mg/40 mg\] in fed conditions \[test\]) or Treatment D (single oral dose of an FDC of macitentan/tadalafil (10 mg/40 mg) in fasted conditions \[reference\]) on Day 1 of Treatment Period 1 followed by Treatment D or Treatment C on Day 1 of Treatment Period 2. Study drug intake in subsequent treatment periods will be separated by a washout period of at least 10 days.

Combination Product: FDC of Macitentan and Tadalafil; Drug: Macitentan; Drug: Tadalafil

Interventions

FDC of Macitentan and Tadalafil COMBINATION_PRODUCT

Fixed dose combination (FDC) of 1 film-coated tablet containing 10 mg of macitentan and 40 mg of tadalafil will be administered orally.

Group 1 (Bioequivalence Part); Group 2 (Food-effect Part)

Macitentan DRUG

Macitentan 10 mg tablet will be administered orally as free combination.

Also known as: Opsumit

Group 1 (Bioequivalence Part); Group 2 (Food-effect Part)

Tadalafil DRUG

Tadalafil 40 mg tablet will be administered orally as free combination.

Also known as: Adcirca

Group 1 (Bioequivalence Part); Group 2 (Food-effect Part)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Body mass index (BMI; weight \[kilogram\]/height\^2 \[m\^2\]) between 18.5 and 30.0 kilogram per meter square (kg/m\^2), inclusive, and body weight not less than 50.0 kg at screening
• Healthy on the basis of physical examination, and medical and surgical history, performed at screening. If there are abnormalities, the participant may be included only if the investigator judges the abnormalities to be not clinically significant. This determination must be recorded in the participant's source documents and initialed by the investigator
• Healthy on the basis of clinical laboratory tests performed at screening. If the results of hematology, coagulation, or biochemistry assessments are outside the normal reference ranges, the participant may be included only if the investigator judges the abnormalities or deviations from normal to be not clinically significant. This determination must be recorded in the participant's source documents and initialed by the investigator
• Systolic blood pressure (SBP) between 100 and 145 millimeter of Mercury (mmHg), diastolic blood pressure (DBP) between 50 and 90 mmHg, and pulse rate between 45 and 99 beats per minute (bpm; inclusive), preferably measured on the right arm, after the participant is supine for at least 5 minutes, at screening
• lead electrocardiogram (ECG) without clinically relevant abnormalities, at the discretion of the investigator, measured after the participant is supine for at least 5 minutes, at screening

You may not qualify if:

• Female participant who is breastfeeding at screening and plans to breastfeed throughout the study
• Known allergy, hypersensitivity, or intolerance to any active substance or drugs of the same class, or any excipient of the drug formulation(s)
• 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 treatment(s) (appendectomy and herniotomy allowed, cholecystectomy not allowed)
• Any loss of vision in 1 or both eyes
• Known hereditary degenerative retinal disorders, including retinitis pigmentosa

Sponsors & Collaborators

• Janssen Research & Development, LLC: lead

Study Sites (1)

Celerion

Tempe, Arizona, 85283, United States

Location

Related Publications (1)

• Csonka D, Fishman V, Natarajan J, Stieltjes H, Armas D, Dishy V, Perez Ruixo JJ. Bioequivalence and food effect of a fixed-dose combination of macitentan and tadalafil: Adaptive design in the COVID-19 pandemic. Pharmacol Res Perspect. 2021 Oct;9(5):e00846. doi: 10.1002/prp2.846.

  PMID: 34624174 DERIVED

MeSH Terms

Interventions

Tadalafil; macitentan

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Study Officials

• Janssen Research & Development, LLC Clinical Trial

  Janssen Research & Development, LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 16, 2020
• First Posted: January 21, 2020
• Study Start: January 17, 2020
• Primary Completion: July 17, 2020
• Study Completion: July 17, 2020
• Last Updated: March 30, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share

Locations

US (1)