Drug Interaction Between Colchicine and Calcineurin Inhibitors in Renal Graft Recipients (COLCHINCAL)

An Open Non Randomized Comparative Study Exploring Drug Interaction Between Colchicine and Calcineurin Inhibitors in 2 Groups (Ciclosporin Group and Tacrolimus Group) of Renal Graft Recipients

Ciclosporin inhibits P-glycoprotein should increase colchicine bioavailability whereas tacrolimus should not influence colchicine disposition.

This is a prospective, controlled, open labeled study performed in renal graft recipients comparing colchicine single dose (1mg) pharmacokinetics in 14 patients treated with tacrolimus and 14 patients treated with cyclosporin.

Study Overview

• Status: Completed
• Conditions: Renal Replacement Therapies
• Intervention / Treatment: Drug: cyclosporine+colchicine; Drug: tacrolimus

Detailed Description

• Renal transplantation >= one year
• eGFR (MDRD) > 30ml/min
• hemoglobin >= 11g/dl
• treatment with tacrolimus or cyclosporine
• no previous muscular disease
• no drugs interfering with P-glycoprotein or CYP3A activity or expression outcomes
• colchicine AUC, Cmax, T1/2
• ABCB1C3435T, CYP3A5 and SLCO1B1 genotypes

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Le Kremlin Bicêtre, France, 94275
    • Assistance Publique - Hôpitaux de Paris : BICETRE Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with renal graft since at least 1 year
• Patients treated with ciclosporin or tacrolimus
• Are at least 18 years old.
• Glomerular filtration rate above 30 ml / min calculated using the MDRD formula
• Among the 14 patients receiving ciclosporin:
• The genotype is not a criterion for inclusion
• Among the 14 patients with tacrolimus treatment:
• 7 genotype ABCB1 3435CC, 7 genotype ABCB1 3435TT
• Recent (1 month) residual concentration of tacrolimus between 5-10ng/ml
• Recent (1 month) residual concentration of ciclosporin between 100-200ng/ml
• For women : a negative pregnancy test (serum beta hCG)
• Realization of a medical examination.
• Informed consent and writing form.

Exclusion Criteria:

• Abnormal transaminases (AST and ALT above the ULN Laboratory).
• Underlying Liver Disease (steatosis, cirrhosis, chronic hepatitis, the virus of hepatitis C or B).
• Previous history of muscle disease (drug related especially the statin type).
• Leukopenia (WBC <3000/mm3).
• Hemoglobin <11g/dl.
• Patient treated by erythropoetin (whatever its hemoglobin value).
• Abnormal CPK (greater than the ULN Laboratory).
• Prior intolerance to colchicine.
• Regular intake of the following medications associated with rhabdomyolyses: antipsychotics, cholesterol lowering agents (statins or fibrates), zidovudine, antidepressants (selective inhibitor of serotonin reuptake) and lithium.
• Patient (e) can not refrain from consuming grapefruit juice.
• Patient (e) taking a tea based on St John's wort.
• Taking drugs inducers of P-gp or CYP3A4 (rifabutin, rifampin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine, protease inhibitors, griseofulvin).
• Taking drugs inhibitors of P-gp or CYP3A4 (quinidine, macrolide antibiotics, azole antifungals, protease inhibitors, amiodarone, diltiazem, verapamil).
• Chronic diarrhea.
• ABCB1 Genotype 3435CT for patients in the tacrolimus group.
• Participation in another concurrent trial.
• Patient (e) exclusion period of another trial.
• Patient (e) having reached the maximum annual amount of compensation provided by law.
• No affiliation to French social security scheme or without CMU.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cyclosporine; The first group is composed of 14 renal graft recipients under cyclosporine	Drug: cyclosporine+colchicine; the 14 patients of the 1st group are under cyclosporine and One pill of colchimax 1mg will be taken by all the patients at Day 3.; Other Names: Colchicine; Colchimax
Active Comparator: Tacrolimus; The second group is composed of 14 renal graft recipients under tacrolimus	Drug: tacrolimus; the 14 patients of the second group are under tacrolimus and One pill of colchimax 1mg will be taken by all the patients at Day 3.; Other Names: Colchicine; Colchimax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Area under the curve of plasma concentration of colchicine over time 0-∞	4 weeks

Secondary Outcome Measures

Outcome Measure	Time Frame
Half-life of colchicine (T1/2).	4 weeks
AUC0-3h colchicine to focus the analysis on the absorption phase (argument in favor of an interaction-dependent P-gp)	4 weeks
Cmax observed colchicine.	4 weeks
Residual tacrolimus or cyclosporine concentrations	4 weeks
ABCB1 genotype at position 3435 (rs 1045642) or 3435 cc, 3435TT, heterozygotes could not be included in the tacrolimus group.	4 weeks
ABCB1 Haplotypes composed of 3 SNPs: C3435T, G2677T / A and C1236T.	4 weeks
CYP3A5 Genotype: search for the allele * 1 (rs 776746): 3 possible genotypes CYP3A5 * 3 / * 3 - CYP3A5 * 3 / * 1 - CYP3A5 * 1 / * 1.	4 weeks
GFR calculated by MDRD formula.	4 weeks
BMI	4 weeks
Drug related (azathioprine, mycophenolic acid, diuretics, ACE inhibitors, ARAII)	4 weeks

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France
• Investigators: Principal Investigator: Antoine Jacquet, MD, Nephrology Department of BICETRE Hospital

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (Actual): January 1, 2012
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: July 9, 2010
• First Submitted That Met QC Criteria: July 9, 2010
• First Posted (Estimate): July 12, 2010

Study Record Updates

• Last Update Posted (Estimate): April 11, 2013
• Last Update Submitted That Met QC Criteria: April 10, 2013
• Last Verified: April 1, 2013

More Information

Terms related to this study

• Keywords: drug interaction; renal transplant; tacrolimus; cyclosporine; colchicine; CYP3A5; renal transplantation; renal graft; ABCB1; SLCO1B1
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Dermatologic Agents; Antifungal Agents; Gout Suppressants; Calcineurin Inhibitors; Colchicine; Tacrolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: P081105