Myeong Gyu Kim1, In-Wha Kim1, Boyoon Choi1, Nayoung Han1, Hwi-Yeol Yun2, Seonyang Park3, Jung Mi Oh4. 1. Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul, Korea. 2. Chungnam National University, College of Pharmacy, Seoul, Korea. 3. Seoul National University, College of Medicine, Seoul, Korea. 4. Seoul National University, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul, Korea jmoh@snu.ac.kr.
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.
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.