Renal Replacement Therapies
Conditions
Keywords
renal graft, colchicine, drug interaction, cyclosporine, tacrolimus, renal transplantation, renal transplant, ABCB1, CYP3A5, SLCO1B1
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
Interventions
DRUGcyclosporine+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.
DRUGtacrolimus
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.
Sponsors
Institut National de la Santé Et de la Recherche Médicale, France
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Area under the curve of plasma concentration of colchicine over time 0-∞ | 4 weeks |
Secondary
| Measure | Time frame |
|---|---|
| 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 |
| Half-life of colchicine (T1/2). | 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 |
| ABCB1 Haplotypes composed of 3 SNPs: C3435T, G2677T / A and C1236T. | 4 weeks |
Countries
France
Outcome results
None listed