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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Renal Replacement Therapies	Drug: cyclosporine+colchicine; Drug: tacrolimus	Phase 1

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	17 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	May 2010
Actual Primary Completion Date :	January 2012
Actual Study Completion Date :	January 2012

Arms and Interventions

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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

Outcome Measures

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Primary Outcome Measures :

1. Area under the curve of plasma concentration of colchicine over time 0-∞ [ Time Frame: 4 weeks ]

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Locations

France
Assistance publique - Hôpitaux de Paris : Bicêtre Hospital
Le Kremlin Bicêtre, France, 94275

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Institut National de la Santé Et de la Recherche Médicale, France

Investigators

Principal Investigator:	Antoine Jacquet, MD	Nephrology Department of BICETRE Hospital

More Information

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Responsible Party:	Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:	NCT01160276 History of Changes
Other Study ID Numbers:	P081105
First Posted:	July 12, 2010
Last Update Posted:	April 11, 2013
Last Verified:	April 2013

Keywords provided by Assistance Publique - Hôpitaux de Paris:

renal graft; colchicine; drug interaction; cyclosporine; tacrolimus	renal transplantation; renal transplant; ABCB1; CYP3A5; SLCO1B1

Additional relevant MeSH terms:

Tacrolimus; Cyclosporins; Cyclosporine; Calcineurin Inhibitors; Colchicine; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action	Antifungal Agents; Anti-Infective Agents; Dermatologic Agents; Antirheumatic Agents; Gout Suppressants; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents