Drug Interaction Between Colchicine and Calcineurin Inhibitors in Renal Graft Recipients
Phase 1
Completed
- Conditions
- Renal Replacement Therapies
- Interventions
- Drug: tacrolimusDrug: cyclosporine+colchicine
- Registration Number
- NCT01160276
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- 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.
- 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 17
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.
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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.
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Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Tacrolimus tacrolimus The second group is composed of 14 renal graft recipients under tacrolimus Cyclosporine cyclosporine+colchicine The first group is composed of 14 renal graft recipients under cyclosporine
- Primary Outcome Measures
Name Time Method Area under the curve of plasma concentration of colchicine over time 0-∞ 4 weeks
- Secondary Outcome Measures
Name Time Method Cmax observed colchicine. 4 weeks ABCB1 Haplotypes composed of 3 SNPs: C3435T, G2677T / A and C1236T. 4 weeks 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 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 Drug related (azathioprine, mycophenolic acid, diuretics, ACE inhibitors, ARAII) 4 weeks BMI 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
Trial Locations
- Locations (1)
Assistance publique - Hôpitaux de Paris : Bicêtre Hospital
🇫🇷Le Kremlin Bicêtre, France