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Drug Interaction Between Colchicine and Calcineurin Inhibitors in Renal Graft Recipients

Information source: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Renal Replacement Therapies

Intervention: cyclosporine+colchicine (Drug); tacrolimus (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Assistance Publique - Hôpitaux de Paris

Official(s) and/or principal investigator(s):
Antoine Jacquet, MD, Principal Investigator, Affiliation: Nephrology Department of BICETRE Hospital

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.

Clinical Details

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 design: Allocation: Non-Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Area under the curve of plasma concentration of colchicine over time 0-∞

Secondary outcome:

Half-life of colchicine (T1/2).

AUC0-3h colchicine to focus the analysis on the absorption phase (argument in favor of an interaction-dependent P-gp)

Cmax observed colchicine.

Residual tacrolimus or cyclosporine concentrations

ABCB1 genotype at position 3435 (rs 1045642) or 3435 cc, 3435TT, heterozygotes could not be included in the tacrolimus group.

ABCB1 Haplotypes composed of 3 SNPs: C3435T, G2677T / A and C1236T.

CYP3A5 Genotype: search for the allele * 1 (rs 776746): 3 possible genotypes CYP3A5 * 3 / * 3 - CYP3A5 * 3 / * 1 - CYP3A5 * 1 / * 1.

GFR calculated by MDRD formula.

BMI

Drug related (azathioprine, mycophenolic acid, diuretics, ACE inhibitors, ARAII)

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

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Locations and Contacts

Assistance publique - HĂŽpitaux de Paris : BicĂȘtre Hospital, Le Kremlin BicĂȘtre 94275, France
Additional Information

Starting date: May 2010
Last updated: April 10, 2013

Page last updated: August 23, 2015

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