Renal Transplant Clinical Trial
Official title:
Influence of MDR-1 CYP3A4 and CYP3A5 Genotypes/Haplotypes on Sirolimus Pharmacokinetics and Pharmacodynamics in Patients With Renal Transplantation
This study will evaluate the effects of certain genes (MDR-1, CYP3A4, and CYP3A5) on
metabolism of the drug sirolimus, an immune-suppressing drug given to transplant recipients
to prevent organ rejection. Individual differences in metabolism and excretion of sirolimus
affect the patient's response to treatment.
Patients who have undergone kidney transplantation at the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) Transplant Branch and have received sirolimus treatment
will be enrolled in this study.
DNA (genetic material) will be extracted from blood samples collected from transplant
recipients to determine their MDR-1, CYP3A4, and CYP3A5 genotypes. Patient demographic
information and data on sirolimus metabolism and excretion will be collected from the medical
information system, NIDDK transplant database, and the patients' medical records. The data
will be compared among patients with different genotypes (genetic constitution of an
individual) and haplotypes (set of genes that code for different proteins but are inherited
as a unit) to determine the effect of these gene variations on sirolimus metabolism.
Information from this study may be applied to developing better dosing strategies, and thus,
treatment outcomes for transplant patients receiving sirolimus.
The immunosuppressant sirolimus is a substrate for the drug efflux pump p-glycoprotein
(Pgp) and the hepatic and intestinal drug metabolizing enzyme cytochrome P450 3A4/5
(CYP3A4/5). Single nucleotide polymorphisms (SNPs) in the multi-drug resistance (MDR)-1
gene which encodes for the Pgp, CYP3A4, and CYP3A5 genes have been shown to be associated
with altered metabolism of various drugs including the immunosuppressants cyclosporine and
tacrolimus. This protocol will evaluate the effects of MDR-1, CYP3A4, and CYP3A5
gentotypes/haplotypes on the pharmacokinetics and pharmacodynamics of sirolimus in patients
with renal transplantation. All patients who had kidney transplantation at the National
Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Transplant Branch,
participated in one of the NIDDK therapeutic protocols, and have received sirolimus will be
enrolled in this study. Selected MDR-1, CYP3A4, and CYP3A5 SNPs will be determined by
polymerase chain reaction based methods using existing patient blood samples. Demographic,
pharmacokinetic, and pharmacodynamic data will be collected from the medical information
system, NIDDK transplant database, and medical records of these patients. Population
pharmacokinetic parameters and pharmacodynamic measurements will then be compared among
patients with different MDR-1, CYP3A4, and CYP3A5 genotypes/haplotypes. Results from this
study will help to understand the effects of pharmacogenetics on sirolimus pharmacokinetics
and pharmacodynamics, and will provide information for rationalizing sirolimus dosing in
patients with renal transplantation.
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