Effect of Itraconazole and Ticlopidine on the Pharmacokinetics and Pharmacodynamics of Oral Tramadol - Full Text View

Purpose

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.

Condition	Intervention	Phase
Pharmacokinetics Pharmacodynamics	Drug: Placebo Drug: Ticlopidine Drug: Ticlopidine and itraconazole	Phase 4

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics/Dynamics Study Intervention Model: Crossover Assignment Masking: Single Blind (Subject) Primary Purpose: Basic Science

Resource links provided by NLM:

Drug Information available for: Ticlopidine hydrochloride Ticlopidine Itraconazole

U.S. FDA Resources

Further study details as provided by Turku University Hospital:

Primary Outcome Measures:

Concentration of tramadol and its metabolites in plasma [ Time Frame: 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48 hours after administration of tramadol ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Metabolites of tramadol in urine [ Time Frame: 0-12 and 12-24 hour fractions after administration of tramadol ] [ Designated as safety issue: No ]
Urine will be collected for 24 hours and M1 and M2 metabolites of tramadol are quantified from 0-12h and 12-24h fractions
Serotonin concentrations [ Time Frame: 0, 4 and 8 hours after tramadol administration ] [ Designated as safety issue: No ]
Serotonin concentrations will be analyzed with chromatographical methods from the blood samples drawn 0, 4 and 8 hours after tramadol administration
Pharmacodynamic effects [ Time Frame: 1, 2, 3, 4, 5, 6, 8, 10, 12 hours after administration of tramadol ] [ Designated as safety issue: No ]
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
Analgesia [ Time Frame: 1, 2, 3, 4, 5, 6, 8, 10, 12 hours after the administration of tramadol ] [ Designated as safety issue: No ]
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.

Enrollment:	12
Study Start Date:	September 2010
Study Completion Date:	December 2010
Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: Placebo	Drug: Placebo The subjects will be given orally placebo twice a day for 5 days prior to the study.
Active Comparator: Ticlopidine	Drug: Ticlopidine The subjects will be given orally ticlopidine 250mg twice a day for 5 days prior to the study.
Active Comparator: Ticlopidine and itraconazole	Drug: Ticlopidine and itraconazole 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.

Eligibility

Ages Eligible for Study:	18 Years to 40 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01214941

Locations

Finland
Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University and Turku University Hospital
Turku, Finland, 20521

Sponsors and Collaborators

Turku University Hospital

Investigators

Principal Investigator:

Klaus T Olkkola, MD, PhD, Prof

Turku University Hospital and Turku University

More Information

No publications provided

Responsible Party:	Klaus T Olkkola, MD, Prof, Turku University Hospital
ClinicalTrials.gov Identifier:	NCT01214941 History of Changes
Other Study ID Numbers:	54/180/2010, 2010-020617-82
Study First Received:	October 4, 2010
Last Updated:	April 12, 2011
Health Authority:	Finland: Finnish Medicines Agency

Additional relevant MeSH terms:

Ticlopidine
Itraconazole
Hydroxyitraconazole
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Cardiovascular Agents
Therapeutic Uses
Hematologic Agents
Platelet Aggregation Inhibitors

Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Antifungal Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on May 21, 2013