Comparative Bioavailability Study Between Etoricoxib and Tramadol, Administered Individually or in Combination

Comparative Bioavailability Study Between Etoricoxib 90 mg and Tramadol 50 mg, Administered Individually or in Combination, Single Dose in Healthy Subjects of Both Genders Under Fasting Conditions

Study carried out in the Clinical and Analytical Unit of the Department of Pharmacology and Toxicology of the Faculty of Medicine of the Autonomous University of Nuevo León, with the objective of comparing the bioavailability (Cmax, AUC) of an oral formulation containing Etoricoxib 90 mg / Tramadol 50 mg in combination with that of two oral formulations, Etoricoxib 90 mg or Tramadol 50 mg, administered as a single dose, in healthy subjects under fasting conditions.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: A1: Etoricoxib / Tramadol Fixed dose combination; Drug: A2: Etoricoxib; Drug: A3: Tramadol

Detailed Description

The study design was a crossover, 3 x 6 x 3, open-label, prospective and longitudinal, truncated, single-dose combination of Etoricoxib 90 mg / Tramadol 50 mg administered orally versus each component administered individually, with three treatments, three periods. , six sequences with an elimination period (washout) of 14 days and with a total of 42 healthy subjects, of both genders, under fasting conditions. Among the objectives were the characterization of the pharmacokinetic parameters, Cmax, AUC 0-72, Tmax, Ke and T1/2 of Etoricoxib and Tramadol after oral administration in a single dose, in combination: sachet with granules equivalent to Etoricoxib 90 mg/ Tramadol 50 mg manufactured by Laboratorios Silanes, S.A. of C.V. versus each component administered individually: Etoricoxib 90 mg tablet (Arcoxia®) manufactured by Schering Plough S.A de C.V. and Tramadol 50 mg capsule (Tradol®) made by Grunenthal GMBH (private company).

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• Mexico
  • Mexico City, Mexico, 11000
    • Laboratorio Silanes, S.A. de C.V.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The subjects must have been accepted by the COFEPRIS (Federal Commission for the Protection against Sanitary Risks) research subjects registration database.
• Subjects without a subordinate relationship with the researchers.
• Subjects who have given informed consent in writing.
• Subjects of both genders, aged between 18 and 55 years, Mexicans. - -Subjects with no background of hypersensitivity or allergies to the drug under study or related drugs.
• Body mass index between 18 and 27 kg/m2.
• Healthy subjects, according to the results of the complete clinical history, electrocardiogram and the integration of the results of the clinical analyses, carried out in certified clinical laboratories, without alterations that require a medical intervention as a consequence.
• Subjects with negative results for immunological tests (Anti-HIV, Anti-hepatitis B and C, VDRL).
• Subjects with negative results in drug abuse screening tests: tetrahydrocannabinoids, cocaine and amphetamines.
• Negative (qualitative) pregnancy test for women of childbearing potential without Bilateral tubal obstruction or hysterectomy.
• In the case of women of childbearing age, they must have a birth control method, including barrier methods, non-hormonal intrauterine device, or bilateral tubal obstruction.

Exclusion Criteria:

• Subjects with recent history or physical examination evidence of gastrointestinal, renal, hepatic, endocrine, respiratory, cardiovascular, dermatological, or hematological disease that could affect the pharmacokinetic study of the product in research.
• Subjects who have been exposed to drugs known as liver enzyme inducers or inhibitors or who have taken drugs potentially toxic within 30 days before the start of the study.
• Subjects who have received any medication during the 7 days before the start of the study.
• Subjects who have been hospitalized for any problem during the three months before the start of the study.
• Subjects who have been rejected by the registry database of research subjects of COFEPRIS, for having participated in a clinical study within the three months prior to the start of the study.
• Subjects who have received investigational drugs within the previous 60 days th the start of the study.
• Subjects allergic to the study drug or related drugs.
• Subjects who have ingested alcohol or drinks containing xanthines (coffee, tea, cocoa, chocolate, cola) or who have eaten charcoal-grilled food or grapefruit juice , at least 10 hours before the start of the study or who have smoked tobacco 24 hours before to the start of the internment period.
• Subjects who have donated or lost 450 mL or more of blood within the previous 60 days of the beginning of the study.
• Subjects with a history of drug and/or alcohol abuse according to the DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders) Criteria.
• Research subjects who presents alterations in the vital signs recorded during the selection.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Etoricoxib/Tramadol FDC; Pharmaceutical Form: Sachet with granules to dilute in 100 mL of water Formula: Each sachet contains Etoricoxib 90 mg / Tramadol 50 mg Dosage: 100 mL Administration way: oral	Drug: A1: Etoricoxib / Tramadol Fixed dose combination; Sachet with granules (Laboratorios Silanes S.A. de C.V.). Formula : 90 mg/ 50 mg Pharmaceutical Form: Sachet with granules Dosage: 100 mL (90 mg/ 50mg) Administration way: oral; Other Names: E/T
Active Comparator: Group B: Etoricoxib; Pharmaceutical Form: Tablet Formula: Tablet containing Etoricoxib 90 mg Dosage: 1 tablet of 90 mg Administration way: oral	Drug: A2: Etoricoxib; Arcoxia®, Schering Plough S.A. de C.V. A2: Pharmaceutical Form: Tablet Formula: 90 mg Dosage: 1 tablet of 90 mg Administration way: oral; Other Names: Arcoxia®
Active Comparator: Group C: Tramadol; Pharmaceutical Form: Capsule Formula: Each capsule contains 50mg of Tramadol Dosage:1 capsule of 50 mg Administration way: oral	Drug: A3: Tramadol; Tradol®, from Grünenthal GMBH. Pharmaceutical Form: Capsule Formula: Each capsule contains 50 mg Dosage: 1 capsule of 50 mg Administration way: oral; Other Names: Tradol®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum observed concentration following the treatment (Cmax)	Evaluate the pharmacokinetics profile of the fixed dose Etoricoxib/Tramadol, employing the maximum observed concentration following the treatment (Cmax), obtained graphically, from the plasma concentration profile with respect to time.	Baseline, 0.25, 0.50, 0.75, 1.00, 1.50, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12,0, 15.0, 24.0, 30.0, 36.0, 48.0 and 72.0 hours.
The area under the curve from time zero to the last measurable concentration (AUC 0-t)	Evaluate the fixed dose pharmacokinetics profile of Etoricoxib/Tramadol, employing the area under the curve from time zero to the last measurable concentration (AUC 0-t) using the linear trapezoidal method.	Baseline, 0.25, 0.50, 0.75, 1.00, 1.50, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12,0, 15.0, 24.0, 30.0, 36.0, 48.0 and 72.0 hours.
The area under the curve from time zero to infinity calculated (AUC 0-inf),	Evaluate the fixed dose pharmacokinetics profile of Etoricoxib/Tramadol, employing the area under the curve from time zero to infinity calculated (AUC 0-inf).	Baseline, 0.25, 0.50, 0.75, 1.00, 1.50, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12,0, 15.0, 24.0, 30.0, 36.0, 48.0 and 72.0 hours.
Time of the maximum measured concentration (Tmax).	Evaluate the fixed dose pharmacokinetics profile of Etoricoxib/Tramadol, employing time of the maximum measured concentration (tmax), Obtained graphically, from the plasma concentration profile with respect to time.	Baseline, 0.25, 0.50, 0.75, 1.00, 1.50, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12,0, 15.0, 24.0, 30.0, 36.0, 48.0 and 72.0 hours.
Elimination rate (Ke)	Evaluate the fixed dose pharmacokinetics profile of Etoricoxib/Tramadol, employing the elimination rate (Ke), estimated from the terminal linear portion of the plasma concentration profile with respect to time (on a semi-log scale)	Baseline, 0.25, 0.50, 0.75, 1.00, 1.50, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12,0, 15.0, 24.0, 30.0, 36.0, 48.0 and 72.0 hours.
Half time elimination (t1/2)	Evaluate the pharmacokinetics profile of the fixed dose Etoricoxib/Tramadol, employing the half time elimination (t1/2) by the quotient of Ln(2)Ke.	Baseline, 0.25, 0.50, 0.75, 1.00, 1.50, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12,0, 15.0, 24.0, 30.0, 36.0, 48.0 and 72.0 hours.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the frequency of occurrence of adverse events	The percentage of frequency of appearance of each adverse event was evaluated.	1, 15 and 29 days
Adverse Events	Any adverse event were classified by severity, treatment and its relationship with the study drug was evaluated.	1, 15 and 29 days

Collaborators and Investigators

• Sponsor: Laboratorios Silanes S.A. de C.V.
• Investigators: Principal Investigator: Lourdes Garza Ocaña, M.D, Department of Pharmacology and Toxicology of the Faculty of Medicine of the U.A.N.L

Publications and helpful links

General Publications

• Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987 Dec;15(6):657-80. doi: 10.1007/BF01068419.
• Rosenthal R. An application of the Kolmogorov-Smirnov test for normality with estimated mean and variance. Psychol Rep. 1968 Apr;22(2):570. doi: 10.2466/pr0.1968.22.2.570. No abstract available.
• Hauck WW, Anderson S. A new statistical procedure for testing equivalence in two-group comparative bioavailability trials. J Pharmacokinet Biopharm. 1984 Feb;12(1):83-91. doi: 10.1007/BF01063612.
• Shohag MH, Islam MS, Ahmed MU, Joti JJ, Islam MS, Hasanuzzaman M, Hasnat A. Pharmacokinetic and bioequivalence study of etoricoxib tablet in healthy Bangladeshi volunteers. Arzneimittelforschung. 2011;61(11):617-21. doi: 10.1055/s-0031-1300564.
• Agrawal NG, Porras AG, Matthews CZ, Rose MJ, Woolf EJ, Musser BJ, Dynder AL, Mazina KE, Lasseter KC, Hunt TL, Schwartz JI, McCrea JB, Gottesdiener KM. Single- and multiple-dose pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, in man. J Clin Pharmacol. 2003 Mar;43(3):268-76. doi: 10.1177/0091270003251122.
• Silva Mde F, Schramm SG, Kano EK, Mori Koono EE, Porta V, dos Reis Serra CH. Bioequivalence evaluation of single doses of two tramadol formulations: a randomized, open-label, two-period crossover study in healthy Brazilian volunteers. Clin Ther. 2010 Apr;32(4):758-65. doi: 10.1016/j.clinthera.2010.03.016.

Study record dates

Study Major Dates

• Study Start (Actual): August 3, 2020
• Primary Completion (Actual): September 7, 2020
• Study Completion (Actual): November 30, 2020

Study Registration Dates

• First Submitted: September 6, 2022
• First Submitted That Met QC Criteria: September 6, 2022
• First Posted (Actual): September 8, 2022

Study Record Updates

• Last Update Posted (Actual): September 9, 2022
• Last Update Submitted That Met QC Criteria: September 7, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Pain; Bioavailability; Pharmacokinetic; Etoricoxib; Tramadol; Fixed-dose combination (FDC)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Analgesics, Opioid; Narcotics; Cyclooxygenase 2 Inhibitors; Tramadol; Etoricoxib
• Other Study ID Numbers: BD ET-Sil No. 112-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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