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

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.

Study Overview

• Status: Completed
• Conditions: Pharmacokinetics; Pharmacodynamics
• Intervention / Treatment: Drug: Placebo; Drug: Ticlopidine; Drug: Ticlopidine and itraconazole

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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
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
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

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Investigators: Principal Investigator: Klaus T Olkkola, MD, PhD, Prof, Turku University Hospital and Turku University

Publications and helpful links

General Publications

• Hagelberg NM, Saarikoski T, Saari TI, Neuvonen M, Neuvonen PJ, Turpeinen M, Scheinin M, Laine K, Olkkola KT. Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction. Eur J Clin Pharmacol. 2013 Apr;69(4):867-75. doi: 10.1007/s00228-012-1433-0. Epub 2012 Oct 26.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (ACTUAL): December 1, 2010
• Study Completion (ACTUAL): December 1, 2010

Study Registration Dates

• First Submitted: October 4, 2010
• First Submitted That Met QC Criteria: October 4, 2010
• First Posted (ESTIMATE): October 5, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): April 13, 2011
• Last Update Submitted That Met QC Criteria: April 12, 2011
• Last Verified: October 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Itraconazole; Ticlopidine
• Other Study ID Numbers: 54/180/2010; 2010-020617-82 (EUDRACT_NUMBER)