Drug Interaction Between Colchicine and Calcineurin Inhibitors in Renal Graft Recipients

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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

Conditions
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Renal Replacement Therapies

Intervention / Treatment
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* Drug: cyclosporine+colchicine
* Drug: tacrolimus


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cyclosporine<br>The first group is composed of 14 renal graft recipients under cyclosporine | Drug: cyclosporine+colchicine<br>* 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.<br>* Other names: Colchimax;|
| Active Comparator: Tacrolimus<br>The second group is composed of 14 renal graft recipients under tacrolimus | Drug: tacrolimus<br>* 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.<br>* Other names: Colchimax;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal graft, colchicine, drug interaction, cyclosporine, tacrolimus, renal transplantation, renal transplant, ABCB1, CYP3A5, SLCO1B1