Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed‐dose combination tablets versus the use of single‐component tablets in healthy subjects
The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐...
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| Published in | Pharmacology research & perspectives Vol. 12; no. 3; pp. e1202 - n/a |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
John Wiley & Sons, Inc
01.06.2024
John Wiley and Sons Inc Wiley |
| Subjects | |
| Online Access | Get full text |
| ISSN | 2052-1707 2052-1707 |
| DOI | 10.1002/prp2.1202 |
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| Abstract | The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐label, 3‐way crossover, single‐dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.
Arithmetic mean plasma concentration versus time profiles for macitentan, aprocitentan and tadalafil during the first 24 hours and 216 hours after administration of Treatment A (FDC, fasted), Treatment B (FDC, fed), and Treatment C (free combination, fasted). |
|---|---|
| AbstractList | The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐label, 3‐way crossover, single‐dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (
C
max
) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of
C
max
and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated. The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated. The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐label, 3‐way crossover, single‐dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated. Arithmetic mean plasma concentration versus time profiles for macitentan, aprocitentan and tadalafil during the first 24 hours and 216 hours after administration of Treatment A (FDC, fasted), Treatment B (FDC, fed), and Treatment C (free combination, fasted). Abstract The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐label, 3‐way crossover, single‐dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated. The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated. The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single-center, randomized, open-label, 3-way crossover, single-dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (C ) and area under the plasma analyte concentration-time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of C and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated. The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐label, 3‐way crossover, single‐dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration ( C max ) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of C max and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated. Arithmetic mean plasma concentration versus time profiles for macitentan, aprocitentan and tadalafil during the first 24 hours and 216 hours after administration of Treatment A (FDC, fasted), Treatment B (FDC, fed), and Treatment C (free combination, fasted). |
| Author | Goyal, Navin Natarajan, Jaya Csonka, Denes Chao, Daniel L. Ford, Jennifer Lynn Stieltjes, Hans Sabet, Ahad |
| AuthorAffiliation | 3 Janssen Research & Development Raritan New Jersey USA 2 ICON Salt Lake City Utah USA 1 Janssen Research & Development Spring House Pennsylvania USA 4 Janssen Research & Development Beerse Belgium 5 Actelion Pharmaceuticals, A Janssen Pharmaceutical Company of Johnson & Johnson Allschwil Switzerland |
| AuthorAffiliation_xml | – name: 4 Janssen Research & Development Beerse Belgium – name: 2 ICON Salt Lake City Utah USA – name: 5 Actelion Pharmaceuticals, A Janssen Pharmaceutical Company of Johnson & Johnson Allschwil Switzerland – name: 1 Janssen Research & Development Spring House Pennsylvania USA – name: 3 Janssen Research & Development Raritan New Jersey USA |
| Author_xml | – sequence: 1 givenname: Jennifer Lynn orcidid: 0000-0002-1740-5704 surname: Ford fullname: Ford, Jennifer Lynn organization: Janssen Research & Development – sequence: 2 givenname: Ahad orcidid: 0009-0004-7266-3310 surname: Sabet fullname: Sabet, Ahad organization: ICON – sequence: 3 givenname: Jaya orcidid: 0009-0009-4833-1750 surname: Natarajan fullname: Natarajan, Jaya organization: Janssen Research & Development – sequence: 4 givenname: Hans orcidid: 0009-0006-6913-7285 surname: Stieltjes fullname: Stieltjes, Hans organization: Janssen Research & Development – sequence: 5 givenname: Daniel L. orcidid: 0000-0001-9174-8118 surname: Chao fullname: Chao, Daniel L. organization: Janssen Research & Development – sequence: 6 givenname: Navin orcidid: 0000-0002-8521-0108 surname: Goyal fullname: Goyal, Navin organization: Janssen Research & Development – sequence: 7 givenname: Denes orcidid: 0000-0001-7797-2615 surname: Csonka fullname: Csonka, Denes email: dcsonka@its.jnj.com organization: Actelion Pharmaceuticals, A Janssen Pharmaceutical Company of Johnson & Johnson |
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| Cites_doi | 10.1016/j.jacc.2013.10.031 10.7326/0003-4819-115-5-343 10.1111/bcp.14347 10.1093/nar/gkx1121 10.1007/s40262-015-0255-5 10.1093/eurheartj/ehv317 10.1111/bph.16177 10.1007/s00228-011-1043-2 10.1111/j.1365-2125.2005.02553.x 10.1016/j.cjca.2019.11.041 10.1002/prp2.846 |
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| Copyright | 2024 Actelion Pharmaceuticals Ltd. published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd. 2024 Actelion Pharmaceuticals Ltd. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd. 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. |
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| Keywords | fixed‐dose combination tadalafil food effect macitentan pulmonary arterial hypertension bioequivalence |
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| References_xml | – volume: 115 start-page: 343 issue: 5 year: 1991 end-page: 349 article-title: Survival in patients with primary pulmonary hypertension. Results from a national prospective registry publication-title: Ann Intern Med – volume: 9 year: 2021 article-title: Bioequivalence and food effect of a fixed‐dose combination of macitentan and tadalafil: adaptive design in the COVID‐19 pandemic publication-title: Pharmacol Res Perspect – volume: 86 start-page: 2424 issue: 12 year: 2020 end-page: 2434 article-title: Bioequivalence of macitentan and tadalafil given as fixed‐dose combination or single‐component tablets in healthy subjects publication-title: Br J Clin Pharmacol – volume: 54 start-page: 457 year: 2015 end-page: 471 article-title: Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan publication-title: Clin Pharmacokinet – volume: 37 start-page: 67 issue: 1 year: 2016 end-page: 119 article-title: ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension publication-title: Eur Heart J – volume: 180 start-page: S23 issue: S2 year: 2023 end-page: S144 article-title: The concise guide to PHARMACOLOGY 2023/24: G protein‐coupled receptors publication-title: Br J Pharmacol – volume: 61 start-page: 280 issue: 3 year: 2006 end-page: 288 article-title: Tadalafil pharmacokinetics in healthy subjects publication-title: Br J Clin Pharmacol – volume: 36 start-page: 977 issue: 7 year: 2020 end-page: 992 article-title: Canadian cardiovascular society/Canadian thoracic society position statement on pulmonary hypertension publication-title: Can J Cardiol – volume: 46 start-page: D1091 issue: D1 year: 2018 end-page: D1106 article-title: The IUPHAR/BPS guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY publication-title: Nucleic Acids Res – year: 2010 – volume: 62 start-page: D60 issue: 25 Suppl year: 2013 end-page: D72 article-title: Updated treatment algorithm of pulmonary arterial hypertension publication-title: J Am Coll Cardiol – volume: 67 start-page: 977 issue: 10 year: 2011 end-page: 984 article-title: Macitentan: entry into‐humans study with a new endothelin receptor antagonist publication-title: Eur J Clin Pharmacol – ident: e_1_2_17_3_1 doi: 10.1016/j.jacc.2013.10.031 – ident: e_1_2_17_2_1 doi: 10.7326/0003-4819-115-5-343 – ident: e_1_2_17_12_1 – ident: e_1_2_17_10_1 doi: 10.1111/bcp.14347 – ident: e_1_2_17_6_1 – ident: e_1_2_17_13_1 doi: 10.1093/nar/gkx1121 – ident: e_1_2_17_17_1 doi: 10.1007/s40262-015-0255-5 – ident: e_1_2_17_8_1 doi: 10.1093/eurheartj/ehv317 – ident: e_1_2_17_7_1 – ident: e_1_2_17_4_1 – ident: e_1_2_17_14_1 doi: 10.1111/bph.16177 – ident: e_1_2_17_16_1 doi: 10.1007/s00228-011-1043-2 – ident: e_1_2_17_5_1 – ident: e_1_2_17_15_1 doi: 10.1111/j.1365-2125.2005.02553.x – ident: e_1_2_17_9_1 doi: 10.1016/j.cjca.2019.11.041 – ident: e_1_2_17_11_1 doi: 10.1002/prp2.846 |
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| Snippet | The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free... The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed-dose combination (FDC) of macitentan/tadalafil in a single tablet and the free... Abstract The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the... |
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| SubjectTerms | Administration, Oral Adolescent Adult Area Under Curve Bioequivalence Body mass index Brand names Chromatography Combination therapy Cross-Over Studies Drug Combinations Drug dosages Fainting Fasting FDA approval Female fixed‐dose combination food effect Food-Drug Interactions Genital diseases Healthy Volunteers Humans macitentan Male Middle Aged Original Pharmacokinetics Plasma pulmonary arterial hypertension Pulmonary hypertension Pyrimidines - administration & dosage Pyrimidines - blood Pyrimidines - pharmacokinetics Sulfonamides - administration & dosage Sulfonamides - blood Sulfonamides - pharmacokinetics Tablets tadalafil Tadalafil - administration & dosage Tadalafil - blood Tadalafil - pharmacokinetics Therapeutic Equivalency Young Adult |
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| Title | Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed‐dose combination tablets versus the use of single‐component tablets in healthy subjects |
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