Drug Interaction Between Colchicine and Calcineurin Inhibitors in Renal Graft Recipients

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.

• 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

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.