Population Pharmacokinetics of Cyclosporine in Hematopoietic Stem Cell Transplant Patients: Consideration of Genetic Polymorphisms. (June 2015)

• Record Type: Journal Article
• Authors: Kim, Myeong Gyu; Kim, In-Wha; Choi, Boyoon; Han, Nayoung; Yun, Hwi-Yeol; Park, Seonyang; Oh, Jung Mi
• Is Part Of: Annals of pharmacotherapy. Volume 49:Number 6(2015:Jun.)
• Page Start: 622
• Page End: 630
• Publication Date: 2015-06
• Subjects: pharmacometrics -- pharmacokinetics -- cyclosporine -- pharmacogenetics and pharmacogenomics -- transplantation; Chemotherapy -- Periodicals; Pharmacology -- Periodicals; 615.5805
• DOI: 10.1177/1060028015577798
• Languages: English
• ISSNs: 1060-0280

Abstract

Background: Cyclosporine (CsA), which is used for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplant (allo-HSCT), has a narrow therapeutic range and large interindividual and intraindividual pharmacokinetic variability. Nevertheless, population pharmacokinetic (PopPK) studies of CsA in allo-HSCT are scarce.Objective: The goal of our study was to build a PopPK model of CsA in allo-HSCT in consideration of demographic, clinical, and genetic polymorphisms data.Methods: A total of 34 adult allo-HSCT patients who received CsA were enrolled prospectively. Demographic, clinical, and CYP3A5 *1/*3, CYP2C19 *1/*2/*3, ABCB1 3435C>T, 1236C>T, 2677G>T/A, ABCC2 -24C>T, 1249G>A, VDR Bsml, Apal polymorphisms data were collected. A PopPK modeling was conducted with NONMEM program.Results: A 1-compartment model with a 2-transit absorption compartment model was developed. After the stepwise covariate model building process, weight was incorporated into clearance (CL) as a power function model with the exponent value of 0.419. The final typical estimate of CL was 21.2 L/h; volume of distribution was 430 L; logit-transformed bioavailability was 1.49 (bioavailability: 81%); and transit compartment rate was 2.87/h. None of the genetic polymorphisms in CYP3A5, CYP2C19, ABCB1, ABCC2, and VDR were significant covariates in the pharmacokinetics of CsA.Conclusions: In our study, it was observed that weight had a significant effect on CL. Genetic polymorphisms did not affect CsA pharmacokinetics. Prospective studies with a larger number of participants is needed to validate the results of this study.