Clinical trial NCT01160276: Drug Interaction Between Colchicine and Calcineurin Inhibitors in Renal Graft Recipients
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Replacement Therapies
Keywords: renal graft
colchicine
drug interaction
cyclosporine
tacrolimus
renal transplantation
renal transplant
ABCB1
CYP3A5
SLCO1B1
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
First posted: 2010-07-12
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility 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.

Primary outcomes:
measure: Area under the curve of plasma concentration of colchicine over time 0-∞
timeFrame: 4 weeks
Secondary outcomes:
measure: Half-life of colchicine (T1/2).
timeFrame: 4 weeks
measure: AUC0-3h colchicine to focus the analysis on the absorption phase (argument in favor of an interaction-dependent P-gp)
timeFrame: 4 weeks
measure: Cmax observed colchicine.
timeFrame: 4 weeks
measure: Residual tacrolimus or cyclosporine concentrations
timeFrame: 4 weeks
measure: ABCB1 genotype at position 3435 (rs 1045642) or 3435 cc, 3435TT, heterozygotes could not be included in the tacrolimus group.
timeFrame: 4 weeks
measure: ABCB1 Haplotypes composed of 3 SNPs: C3435T, G2677T / A and C1236T.
timeFrame: 4 weeks
measure: CYP3A5 Genotype: search for the allele * 1 (rs 776746): 3 possible genotypes CYP3A5 * 3 / * 3 - CYP3A5 * 3 / * 1 - CYP3A5 * 1 / * 1.
timeFrame: 4 weeks
measure: GFR calculated by MDRD formula.
timeFrame: 4 weeks
measure: BMI
timeFrame: 4 weeks
measure: Drug related (azathioprine, mycophenolic acid, diuretics, ACE inhibitors, ARAII)
timeFrame: 4 weeks
Other outcomes:
Locations:
city: Le Kremlin Bicêtre
country: France
facility: Assistance publique - Hôpitaux de Paris : Bicêtre Hospital
Study officials:
affiliation: Nephrology Department of BICETRE Hospital
name: Antoine Jacquet, MD
role: PRINCIPAL_INVESTIGATOR
References: