Pharmacokinetic Interaction Between Ibuprofen and Acetaminophen Oral Suspension

Study Overview
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Brief Summary
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This study was carried out in the Clinical and Analytical Unit of the Pharmacology and Toxicology Department of the Faculty of Medicine of the Autonomous University of Nuevo León, in order to compare the bioavailability (Cmax, AUC) of an oral formulation containing Ibuprofen 100 mg/Acetaminophen 125 mg in combination with the two oral formulations Ibuprofen 100 mg or Acetaminophen 125 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, open, prospective and longitudinal, at a single dose, of the combination of Ibuprofen 100 mg/Acetaminophen 125 mg/5 mL suspension, administered orally versus each component administered individually Ibuprofen 100 mg/5 mL or Acetaminophen 125 mg/3.9 mL, with an elimitation period (washout) of 1 week. In order to compare the pharmacokinetic profile (Cmax and AUC0-t) of the Ibuprofen/Acetaminophen combination 100 mg/125 mg/5 mL, versus each component administered individually, in 42 healthy subjects, of both genders, under fasting conditions, to establish the interaction of drugs in combination. As well as, to characterize the pharmacokinetic parameters, Cmax and AUC0-t, AUC0-∞, Tmax, Ke, and T1/2 and to establish the frequency and type of adverse events with the two formulations.

Official Title
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Study of no Pharmacokinetic Interaction Between Ibuprofen 100 mg and Acetaminophen 125 mg, Suspension Administered Individually or in Combination, Single Dose in Healthy Subjects, Both Genders Under Fasting Conditions

Conditions
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Healthy

Intervention / Treatment
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* Drug: A1: Ibuprofen/Acetaminophen Fixed dose combination oral suspension (Laboratorios Silanes S.A. de C.V.)
* Drug: A2: Ibuprofen (Advil®, Pfizer S.A. de C.V.)
* Drug: A3: Acetaminophen (Tylenol®, from Janssen-Cilag, S.A. de C.V.)


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.

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: Ibuprofen/ Acetaminophen oral suspension in fixed dose<br>Pharmaceutical Form: Oral Suspension Formula: Ibuprofen 100 mg/ Acetaminophen 125 mg/ 5 mL Dosage: 5 mL Administration way: oral | Drug: A1: Ibuprofen/Acetaminophen Fixed dose combination oral suspension (Laboratorios Silanes S.A. de C.V.)<br>* Formula : 100 mg/ 125 mg /5mL Pharmaceutical Form: Oral suspension Dosage: 5mL (100 mg/125mg) Administration way: oral<br>* Other names: IBU/ACETA SUSP;|
| Active Comparator: Group B: Ibuprofen oral suspension<br>Pharmaceutical Form: Oral Suspension Formula: Ibuprofen 2 g/100 mL Dosage: 5 mL (100 mg of ibuprofen) Administration way: oral | Drug: A2: Ibuprofen (Advil®, Pfizer S.A. de C.V.)<br>* Pharmaceutical Form: oral suspension Formula: 2 g/100 mL Dosage: 5 mL(100 mg of Ibuprofen) Administration way: oral<br>* Other names: IBU SUSP;|
| Active Comparator: Group C: Acetaminophen oral suspension<br>Pharmaceutical Form: Oral Suspension Formula: Acetaminophen 3.2 g/100 mL Dosage: 3.9 mL (125 mg of acetaminophen) Administration way: oral | Drug: A3: Acetaminophen (Tylenol®, from Janssen-Cilag, S.A. de C.V.)<br>* Pharmaceutical Form: oral suspension Formula: 3.2 g/100 mL Dosage: 3.9 mL (125 mg) Administration way: oral<br>* Other names: ACETA SUSP;|

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 Ibuprofen/Acetaminophen oral suspension, 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, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12,0 and 14.0 hours. | 
| The area under the curve from time zero to the last measurable concentration (AUC 0-t) | Evaluate the fixed dose pharmacokinetics profile of Ibuprofen/Acetaminophen oral suspension, 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, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12,0 and 14.0 hours. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The area under the curve from time zero to infinity calculated (AUC 0-inf) | Evaluate the fixed dose pharmacokinetics profile of ibuprofen/Acetaminophen oral suspension, employing the area under the curve from time zero to infinity calculated (AUC 0-inf) | Baseline, 0.16, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12,0 and 14.0 hours. | 
| Time of the maximum measured concentration (Tmax) | Evaluate the fixed dose pharmacokinetics profile of ibuprofen/Acetaminophen oral suspension, 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, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12,0 and 14.0 hours. | 
| Elimination rate (Ke) | Evaluate the fixed dose pharmacokinetics profile of ibuprofen/Acetaminophen oral suspension, 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, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12,0 and 14.0 hours. | 
| Half time elimination (T1/2) | Evaluate the pharmacokinetics profile of the fixed dose ibuprofen/Acetaminophen oral suspension, employing the half time elimination (T1/2) by the quotient of Ln(2)Ke. | Baseline, 0.16, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12,0 and 14.0 hours. | 
| Frequency of occurrence of adverse events | The percentage of frequency of appearance of each adverse event was evaluated. | 1, 8 and 16 days | 
| Adverse events | Any adverse event was classified by severity, treatment and its relationship with the study drug evaluated. | 1, 8 and 16 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 (FDC), Ibuprofen, Acetaminophen, Oral suspension, Pain