Effect of Itraconazole and Ticlopidine on the Pharmacokinetics and Pharmacodynamics of Oral Tramadol

Study Overview
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Brief Summary
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Tramadol is an opioid analgesic, which is widely used in the treatment of acute and neuropathic pain. After oral administration, tramadol is rapidly and almost completely absorbed. Tramadol is extensively metabolised by O- and N-demethylation, which are catalysed by the liver CYP-450 enzymes. O-desmethyltramadol is an active metabolite and its formation is catalysed by CYP2D6. The formation of inactive metabolites is catalysed by CYP3A4 and 2B6. This study is aimed to investigate the possible interaction of oral tramadol with itraconazole and ticlopidine, which are inhibitors of CYP3A4 and 2B6. Twelve healthy male or female adult non-smoking volunteers aged 18-40 years with body weights within ±15% of the ideal weight for height are taken into the study. Primary endpoints of the study are plasma concentrations of tramadol and its metabolites.

Conditions
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Pharmacokinetics, Pharmacodynamics

Intervention / Treatment
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* Drug: Placebo
* Drug: Ticlopidine
* Drug: Ticlopidine and itraconazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy volunteers Age 18-40 Body weight within ±15% of the ideal weight for height Exclusion Criteria: A previous history of intolerance to the study drugs or to related compounds and additives Concomitant drug therapy of any kind for at least 14 days prior to the study Existing or recent significant disease History of hematological, endocrine, metabolic or gastrointestinal disease, including gut motility disorders History of asthma or any kind of drug allergy Previous or present alcoholism, drug abuse, psychological or other emotional problems that are likely to invalidate informed consent, or limit the ability of the subject to comply with the protocol requirements A positive test result for urine toxicology A yes answer to any one of the Abuse Questions Pregnancy or nursing Donation of blood for 4 weeks prior and during the study Special diet or life style conditions which would compromise the conditions of the study or interpretation of the results Participation in any other studies involving investigational or marketed drug products concomitantly or within one month prior to the entry into this study Smoking for one month before the start of the study and during the whole study period Any history of coagulation abnormality, also in first degree relatives

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* The subjects will be given orally placebo twice a day for 5 days prior to the study.<br>|
| Active Comparator: Ticlopidine<br> | Drug: Ticlopidine<br>* The subjects will be given orally ticlopidine 250mg twice a day for 5 days prior to the study.<br>|
| Active Comparator: Ticlopidine and itraconazole<br> | Drug: Ticlopidine and itraconazole<br>* The subjects will be given orally ticlopidine 250mg twice a day and itraconazole 200mg as a single daily dose for 5 days prior to the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of tramadol and its metabolites in plasma |  | 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours after administration of tramadol | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metabolites of tramadol in urine | Urine will be collected for 24 hours and M1 and M2 metabolites of tramadol are quantified from 0-12h and 12-24h fractions | 0-12 and 12-24 hour fractions after administration of tramadol | 
| Serotonin concentrations | Serotonin concentrations will be analyzed with chromatographical methods from the blood samples drawn 0, 4 and 8 hours after tramadol administration | 0, 4 and 8 hours after tramadol administration | 
| Pharmacodynamic effects | The psychomotor effects of tramadol will be assessed with the measurement of pupil size with Cogan's pupillometer, Maddox wing test and digit symbol substitution test | 1, 2, 3, 4, 5, 6, 8, 10, 12 hours after administration of tramadol | 
| Analgesia | The analgesic effect of tramadol will be evaluated using the cold pressor test. Briefly, the subject's hand is immersed into ice-cold water of + 4° C up to the wrist. The subject is told to keep his or her hand in the water and to report when the cold sensation becomes painful. Cold pain threshold is defined as the latency from the immersion of the hand to the subject's first report of pain. Cold pain intensity is assessed at 30 s intervals following immersion of the hand in cold water for up to 60s . A verbal numerical rating scale of 0-100 will be used. | 1, 2, 3, 4, 5, 6, 8, 10, 12 hours after the administration of tramadol |