TY - JOUR
T1 - Population Pharmacokinetics of Cyclosporine in Hematopoietic Stem Cell Transplant Patients
T2 - Consideration of Genetic Polymorphisms
AU - Kim, Myeong Gyu
AU - Kim, In Wha
AU - Choi, Boyoon
AU - Han, Nayoung
AU - Yun, Hwi Yeol
AU - Park, Seonyang
AU - Oh, Jung Mi
N1 - Publisher Copyright:
© The Author(s) 2015
PY - 2015/6/8
Y1 - 2015/6/8
N2 - 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.
AB - 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.
KW - cyclosporine
KW - pharmacogenetics and pharmacogenomics
KW - pharmacokinetics
KW - pharmacometrics
KW - transplantation
UR - http://www.scopus.com/inward/record.url?scp=84930609029&partnerID=8YFLogxK
U2 - 10.1177/1060028015577798
DO - 10.1177/1060028015577798
M3 - Article
C2 - 25818517
AN - SCOPUS:84930609029
SN - 1060-0280
VL - 49
SP - 622
EP - 630
JO - Annals of Pharmacotherapy
JF - Annals of Pharmacotherapy
IS - 6
ER -