Healthy
Conditions
Keywords
Healthy volunteers
Brief summary
The purposes of this study were: * To evaluate the plasma pharmacokinetic profile of tramadol and its principal metabolite, the O-desmethyltramadol, after a single oral administration of 100, 200 and 300 mg of tramadol as the Labopharm extended-release formulation prepared with Contramid. * To assess the dose linearity of tramadol and its principal metabolite, the O-desmethyltramadol, between 100 mg and 300 mg following a single dose administration of the Labopharm extended-release formulation prepared with Contramid under fasting conditions in young healthy volunteers.
Interventions
DRUGTramadol HCl
One single oral administration of Tramadol HCl 100 mg, 200 mg or 300 mg as per randomization schedule.
Sponsors
Labopharm Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Availability of subject for the entire study period and willingness to adhere to protocol requirements as evidenced by the informed consent form duly signed by the subject. * Males aged from 18 to 45 years inclusively and with Body Mass Index (BMI) between 18 and 30 kg/m2 inclusively. * Clinical laboratory values within 10% above or below the laboratory's stated normal range; if not within this range, the clinical investigator will decide if they were not clinically significant and recorded this fact on the Case Report Form (CRF). * Healthy according to the physical examination and laboratory results. * Normal cardiovascular function according to a 12-lead electrocardiogram (ECG). * Non-smoker or subjects smoking no more than 5 cigarettes per day (or equivalent) and able to abstain from smoking during inpatient phases of the study. * Subjects covered by Social Security in compliance with the recommendations of French Law relating to biomedical research. * Subjects with normal dietary requirements (neither vegetarian, nor on a diet).
Exclusion criteria
* History of hypersensitivity to tramadol or any other compounds. * Presence or significant history of gastrointestinal, liver or kidney disease, or any other conditions known to interfere with the absorption, distribution, metabolism or excretion of drugs. * Presence or significant history of cardiovascular, pulmonary, haematological, neoplasic, neurological, psychiatric, endocrine, immunological or dermatological disease. * Presence or significant history of glaucoma. * Supine pulse rate lower than 45 beats per minute (bpm) after 5 minutes at rest or higher than 100 bpm. * History of hypotensive episodes or a standing systolic blood pressure reading of \<100 mmHg or a diastolic reading of \<45 mmHg, measured on the screening day. * History of hypertensive episodes or a supine systolic blood pressure reading of \>145 mmHg or a diastolic reading of \>95 mmHg, measured on the screening day. * Presence of atrioventricular (AV) block assessed during pre-study evaluation or during the study. The lower limit considered for a first degree AV block was be a PR interval of 200 millisecond (msec). * Maintenance therapy with any drug, or history of drug dependency, alcohol abuse (\>3 units of alcohol per day), or serious psychological disease. * Subjects consuming large quantities of drinks containing xanthine bases (coffee, tea, chocolate or cola; more than 6 cups or glasses per day). * Any clinically significant illness in the previous 21 days before day 1 of this study. * Subjects who had undergone general anesthesia within 3 months prior to the present study. * Use of drugs known to affect liver enzymes (eg, inducers or inhibitors of Cytochrome P450) in the previous 30 days before day 1 of this study (eg, all barbiturates, corticosteroids, di & methyl-phenylhydantoin). * Use of any medication (including OTC preparations) in the previous 14 days before day 1 of this study. * Donation of 350 mL (or more) of blood in the previous 3 months or participation in another clinical trial in the previous 3 months before day 1 of this study. * Subjects undergoing dental care. * Positive urine drug screening. * Positive results to human immunodeficiency virus (HIV) 1 & 2 or hepatitis B surface antigen (HBsAg) or anti-HCV (hepatitis C virus) tests. * History of fainting upon blood sampling. * Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to limit the validity of the consent to participate in the study or to limit the ability to comply with the protocol requirements. * Subjects unable to abstain from intensive muscular effort or sport competitions during the week prior to the study and throughout the study itself. * Subjects who had forfeited his freedom by administrative or legal award or who were under guardianship. * Subjects who received the ceiling amount of 25,000 francs within the last 12 months or who reached this ceiling with the payment of this allowance for this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC(0-t) | 48 hours | Area under the plasma concentration versus time curve to the last measurable concentration. h = hours |
| AUC(0-inf) | 48 hours | Area under the plasma concentration versus time curve extrapolated to infinity. h = hours |
| Cmax | 48 hours | Maximum plasma concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax | 48 hours | Time to maximum plasma concentration |
| t1/2 | 48 hours | Apparent terminal elimination half-life |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1: Tramadol HCl 100mg * Single oral administration fasting conditions.
* Randomization schedule based on a Latin Square design. | 9 |
| 2: Tramadol HCl 200mg * Single oral administration fasting conditions.
* Randomization schedule based on a Latin Square design. | 9 |
| 3: Tramadol HCl 300mg * Single oral administration fasting conditions.
* Randomization schedule based on a Latin Square design. | 9 |
| Total | 27 |
Baseline characteristics
| Characteristic | 1: Tramadol HCl 100mg | 2: Tramadol HCl 200mg | 3: Tramadol HCl 300mg | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0.0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0.0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 9 Participants | 9 Participants | 27.0 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0.0 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 9 Participants | 27.0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 27 | 0 / 27 | 0 / 27 |
| serious Total, serious adverse events | 0 / 27 | 0 / 27 | 0 / 27 |
Outcome results
Primary
AUC(0-inf)
Area under the plasma concentration versus time curve extrapolated to infinity. h = hours
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: Tramadol HCl 100mg | AUC(0-inf) | 2108 ng.h/mL | Standard Deviation 731 |
| 2: Tramadol HCl 200mg | AUC(0-inf) | 4416 ng.h/mL | Standard Deviation 1192 |
| 3: Tramadol HCl 300mg | AUC(0-inf) | 6741 ng.h/mL | Standard Deviation 2156 |
Primary
AUC(0-t)
Area under the plasma concentration versus time curve to the last measurable concentration. h = hours
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: Tramadol HCl 100mg | AUC(0-t) | 2064 ng.h/mL | Standard Deviation 707 |
| 2: Tramadol HCl 200mg | AUC(0-t) | 4332 ng.h/mL | Standard Deviation 1149 |
| 3: Tramadol HCl 300mg | AUC(0-t) | 6568 ng.h/mL | Standard Deviation 2050 |
Primary
Cmax
Maximum plasma concentration.
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: Tramadol HCl 100mg | Cmax | 91 ng/mL | Standard Deviation 27 |
| 2: Tramadol HCl 200mg | Cmax | 197 ng/mL | Standard Deviation 58 |
| 3: Tramadol HCl 300mg | Cmax | 290 ng/mL | Standard Deviation 147 |
Secondary
t1/2
Apparent terminal elimination half-life
Time frame: 48 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1: Tramadol HCl 100mg | t1/2 | 6.1 hours | Standard Deviation 1.3 |
| 2: Tramadol HCl 200mg | t1/2 | 6.1 hours | Standard Deviation 1.3 |
| 3: Tramadol HCl 300mg | t1/2 | 6.3 hours | Standard Deviation 1.5 |
Secondary
Tmax
Time to maximum plasma concentration
Time frame: 48 hours
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1: Tramadol HCl 100mg | Tmax | 9 hours |
| 2: Tramadol HCl 200mg | Tmax | 5.5 hours |
| 3: Tramadol HCl 300mg | Tmax | 5 hours |