Pharmacogenetics to Predict Drug Interactions in Kidney Transplant Recipients

NCT01288521 | Completed Phase 4 Results DMC

• 1 other identifier: 200806718
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Solid organ transplant recipients would greatly benefit from pharmacogenetic evaluation since immunosuppressive drug regimens consist of multiple medications with narrow therapeutic ranges and toxic adverse event profiles. Tacrolimus is a potent immunosuppressive agent utilized for rejection prophylaxis. Intensive pharmacokinetic monitoring must be performed following organ transplantation to ensure therapeutic drug concentrations due to its highly variable pharmacokinetics profile and narrow therapeutic index. Tacrolimus is a substrate for CYP450 3A and for the membrane transporter p-glycoprotein (Pgp). Polymorphisms in the gene encoding for CYP3A5 have been extensively studied and have been found to influence the dosing of tacrolimus. The effect of ABCB1 gene polymorphisms (which encodes for Pgp) upon tacrolimus pharmacokinetics has been more difficult to establish. This study will determine if haplotypes derived from three frequent polymorphisms in the ABCB1 gene (C1236T, G2677T, C3435T) can predict the degree of drug interaction between tacrolimus (CYP3A5/Pgp substrate) and ketoconazole (CYP3A5/Pgp inhibitor) in patients who are CYP3A5 nonexpressors. This prospective pharmacokinetic and pharmacogenomic study will enroll 20 stable renal transplant recipients with the CYP3A5 \*3/\*3 genotype and grouped by ABCB1 haplotype (CGC vs TTT). Pharmacokinetics of tacrolimus will be assessed on 2 occasions with and without ketoconazole coadministration separated by 1 week. The order of study occasions will be randomized in a crossover design. The results of this study may identify a genomic marker for predicting drug-drug interactions. Knowing this information a priori will aid clinicians in modifying drug dosing and alleviate patients of the burden of significant drug toxicities.

Conditions

Kidney Transplantation

Keywords

kidney transplantation; tacrolimus; P-glycoprotein; ABCB1; genotyping

Outcome Measures

Primary Outcomes (1)

• Tacrolimus Bioavailability (F)

  Tac bioavailability alone vs. Tac bioavailability with Keto. To determine F we took the ratio of area under the curve of the oral dose divided by the area under the curve of the IV dose. F was determined by fitting a model that considered the plasma concentration of tac with IV vs. oral dosing.

  baseline and 2 weeks

Study Arms (2)

Tacrolimus + Ketoconazole, Then Tacrolimus alone

EXPERIMENTAL

Participants first received tacrolimus in combination with with ketoconazole. After a 1-2 week washout they received tacrolimus alone.

Drug: Tacrolimus + Ketoconazole, Then Tacrolimus alone

Tacrolimus alone, Then Tacrolimus + Ketoconazole

EXPERIMENTAL

The participants first received tacrolimus alone. After a 1-2 week washout period they received tacrolimus in combination with ketoconazole.

Drug: Tacrolimus alone, Then Tacrolimus + Ketoconazole

Interventions

Tacrolimus + Ketoconazole, Then Tacrolimus alone DRUG

Pharmacokinetic profiling of tacrolimus (AUC0-24h) in subjects receiving tacrolimus + ketoconazole 200 mg every 12 hours x 3 doses.

Also known as: Tacrolimus, Ketoconazole

Tacrolimus + Ketoconazole, Then Tacrolimus alone

Tacrolimus alone, Then Tacrolimus + Ketoconazole DRUG

Pharmacokinetic profiling of subjects on a stable dose of tacrolimus (AUC 0-24h)

Also known as: Tacrolimus, Ketoconazole

Tacrolimus alone, Then Tacrolimus + Ketoconazole

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Kidney transplant recipient
• \> 6 months posttransplant
• Serum creatinine \< 1.6 mg/dL
• Currently taking a stable dose of tacrolims

You may not qualify if:

• On medications known to interact with tacrolimus or ketoconazole
• Multi-organ transplant recipient
• Serum creatinine \>1.5 mg/dL

Sponsors & Collaborators

• Sony Tuteja: lead
• American College of Clinical Pharmacy: collaborator

Study Sites (1)

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

MeSH Terms

Interventions

Tacrolimus; Ketoconazole

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Early termination leading to small numbers of subjects analyzed.

Results Point of Contact

• Title: Sony Tuteja, Pharmd
• Organization: University of Iowa

sony.tuteja@gmail.com

215-573-7834

Study Officials

• Sony Tuteja, PharmD

  University of Iowa

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate

Study Record Dates

• First Submitted: February 9, 2010
• First Posted: February 2, 2011
• Study Start: October 1, 2008
• Primary Completion: June 1, 2011
• Study Completion: September 1, 2011
• Last Updated: March 9, 2018
• Results First Posted: March 9, 2018

Record last verified: 2018-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)