Non-interaction Study Between Pregabalin and Tramadol, Administered Individually or Combination, in Healthy Subjects

Study Overview
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Brief Summary
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The study was carried out in the Clinical Unit and Analytical Unit of the Department of Pharmacology and Toxicology of the Faculty of Medicine of the Universidad Autónoma de Nuevo León, with the aim of comparing the bioavailability (maximum concentration and area under the curve) of an oral formulation containing Pregabalin 150 mg/Tramadol 50 mg in combination with the two oral formulations Pregabalin 150 mg or Tramadol 50 mg administered as a single dose, in healthy subjects under fasting conditions.

Detailed Description
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The study design was crossover, 3 x 6 x 3, prospective and longitudinal, at a single dose of the combination Pregabalin 150 mg/Tramadol 50 mg administered orally versus each component administered individually, with three treatments, three periods, six sequences and one elimination period (wash out) of 7 days in 30 healthy subjects, under fasting conditions. The objective of the study was to characterize the pharmacokinetic parameters, maximum plasma concentration (Cmax), area under the curve (AUC), time to achieve Cmax (tmax), elimination constant (Ke), and elimination half life (t1/2) of Pregabalin and Tramadol after single oral dose administration, in combination: Pregabalin 150 mg/Tramadol 50 mg, tablets (Laboratorios Silanes S.A. de C.V.) versus each component individually managed, as well as to establish the frequency and type of events presented after the administration of a single dose of the formulations.

Official Title
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Pharmacokinetic Non-interaction Study Between Pregabalin 150 mg and Tramadol 50 mg, Administered Individually or in Combination, Single Dose in Healthy Subjects of Both Genders Under Fasting Conditions

Conditions
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Healthy

Intervention / Treatment
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* Drug: Fixed dose combination Pregabalin 150 mg / Tramadol 50 mg
* Drug: Pregabalin 150mg
* Drug: Tramadol 50 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subjects must have been accepted by the COFEPRIS 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 Criteria. Research subjects who presents alterations in the vital signs recorded during the selection. Subjects who have consumed grapefruit or cranberry juice in the 10 hours prior to the study. Research subject with alterations of the vital signs recorded during the selection.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Pregabalin/ Tramadol Fixed dose<br>Pharmaceutical Form: Tablet Dosage: 150 mg / 50 mg Administration way: oral | Drug: Fixed dose combination Pregabalin 150 mg / Tramadol 50 mg<br>* Pregabalin/Tramadol (Laboratorios Silanes S.A. de C.V.), Pharmaceutical Form: Tablet Dosage: 150 mg / 50 mg Administration way: oral<br>* Other names: P/T;|
| Active Comparator: Group B: Pregabalin (Lyrica®)<br>Pharmaceutical Form: Capsule Dosage: 150 mg Administration way: oral | Drug: Pregabalin 150mg<br>* From Pfizer S.a. de C.V. Pharmaceutical Form: Capsule Dosage: 150 mg Administration way: oral<br>* Other names: Preg (Lyrica®);|
| Active Comparator: Group C: Tramadol (Tradol®)<br>Pharmaceutical Form: Tablet Dosage: 50 mg Administration way: oral | Drug: Tramadol 50 mg<br>* From Grünenthal de México, S.A. de C.V. Pharmaceutical Form: Capsule Dosage: 50 mg Administration way: oral<br>* Other names: Tram (Tradol®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration following the treatment (Cmax) | Evaluate the pharmacokinetics profile of the fixed dose Pregabalin/Tramadol, employing the maximum observed concentration following the treatment (Cmax), obtained graphically, from the plasma concentration profile with respect to time. | Baseline, 0.16, 0.33, 0.50, 1.00, 1.50, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 10.0, 14.0, 24.0 and 36.0 hours. | 
| The area under the curve from time zero to the last measurable concentration (AUC 0-t) | Evaluate the fixed dose pharmacokinetics profile of Pregabalin/Tramadol, employing the area under the curve from time zero to the last measurable concentration (AUC 0-t) using the linear trapezoidal method. | Baseline, 0.16, 0.33, 0.50, 1.00, 1.50, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 10.0, 14.0, 24.0 and 36.0 hours. | 
| The area under the curve from time zero to infinity calculated (AUC 0-inf) | Evaluate the fixed dose pharmacokinetics profile of Pregabalin/Tramadol, employing the area under the curve from time zero to infinity calculated (AUC 0-inf). | Baseline, 0.16, 0.33, 0.50, 1.00, 1.50, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 10.0, 14.0, 24.0 and 36.0 hours. | 
| Time of the maximum measured concentration (Tmax) | Evaluate the fixed dose pharmacokinetics profile of Pregabalin/Tramadol, employing time of the maximum measured concentration (tmax), Obtained graphically, from the plasma concentration profile with respect to time. | Baseline, 0.16, 0.33, 0.50, 1.00, 1.50, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 10.0, 14.0, 24.0 and 36.0 hours. | 
| Elimination rate (Ke) | Evaluate the fixed dose pharmacokinetics profile of Pregabalin/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, 0.16, 0.33, 0.50, 1.00, 1.50, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 10.0, 14.0, 24.0 and 36.0 hours. | 
| Half time elimination (t1/2) | Evaluate the pharmacokinetics profile of the fixed dose Pregabalina/Tramadol, employing the half time elimination (t1/2) by the quotient of Ln(2)Ke. | Baseline, 0.16, 0.33, 0.50, 1.00, 1.50, 2.0, 2.5, 3.0, 3.5, 4.0, 6.0, 10.0, 14.0, 24.0 and 36.0 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of occurrence of adverse events | The percentage of frequency of appearance of each adverse event was evaluated. | 6 and 19 days | 
| Adverse events | Any adverse event were classified by severity, treatment and its relationship with the study drug was evaluated. | 6 and 19 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pharmacokinetic, Bioavailability, Fixed dose combination, Pregabalin, Tramadol, Acute Pain