Xiaoyan Qiu1, Weiwei Qin2, Junjun Mao3, Luyang Xu3, Ming Zhang4, Mingkang Zhong3. 1. Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040, China. xyqiu@fudan.edu.cn. 2. Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040, China. wwqin@fudan.edu.cn. 3. Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040, China. 4. Department of Nephrology, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai, 200040, China.
Abstract
AIM: The pharmacokinetic (PK) properties of cyclosporine (CsA) in renal transplant recipients are patient- and time-dependent. Knowledge of this time-related variability is necessary to maintain or achieve CsA target exposure. Here, we aimed to identify factors explaining variabilities in CsA PK properties and characterize time-varying clearance (CL/F) by performing a comprehensive analysis of CsA PK factors using population PK (popPK) modeling of long-term follow-up data from our institution. METHODS: In total, 3674 whole-blood CsA concentrations from 183 patients who underwent initial renal transplantation were analyzed using nonlinear mixed-effects modeling. The effects of potential covariates were selected according to a previous study and well-accepted theoretical mechanisms. Model-informed individualized therapeutic regimens were also evaluated. RESULTS: A two-compartment model adequately described the data and the estimated mean CsA CL/F was 32.6 L h-1 (relative standard error: 5%). Allometrically scaled body size, hematocrit (HCT) level, CGC haplotype carrier status, and postoperative time may contribute to CsA PK variability. The CsA bioavailability in patients receiving a prednisolone dose (PD) of 80 mg was 20.6% lower than that in patients receiving 20 mg. A significant decrease (52.6%) in CL/F was observed as the HCT increased from 10.5% to 60.5%. The CL/F of the non-CGC haplotype carrier was 14.4% lower than that of the CGC haplotype carrier at 3 months post operation. CONCLUSIONS: By monitoring body size, HCT, PD, and CGC haplotype, changes in CsA CL/F over time could be predicted. Such information could be used to optimize CsA therapy. CsA dose adjustments should be considered in different postoperative periods.
AIM: The pharmacokinetic (PK) properties of cyclosporine (CsA) in renal transplant recipients are patient- and time-dependent. Knowledge of this time-related variability is necessary to maintain or achieve CsA target exposure. Here, we aimed to identify factors explaining variabilities in CsA PK properties and characterize time-varying clearance (CL/F) by performing a comprehensive analysis of CsA PK factors using population PK (popPK) modeling of long-term follow-up data from our institution. METHODS: In total, 3674 whole-blood CsA concentrations from 183 patients who underwent initial renal transplantation were analyzed using nonlinear mixed-effects modeling. The effects of potential covariates were selected according to a previous study and well-accepted theoretical mechanisms. Model-informed individualized therapeutic regimens were also evaluated. RESULTS: A two-compartment model adequately described the data and the estimated mean CsA CL/F was 32.6 L h-1 (relative standard error: 5%). Allometrically scaled body size, hematocrit (HCT) level, CGC haplotype carrier status, and postoperative time may contribute to CsA PK variability. The CsA bioavailability in patients receiving a prednisolone dose (PD) of 80 mg was 20.6% lower than that in patients receiving 20 mg. A significant decrease (52.6%) in CL/F was observed as the HCT increased from 10.5% to 60.5%. The CL/F of the non-CGC haplotype carrier was 14.4% lower than that of the CGC haplotype carrier at 3 months post operation. CONCLUSIONS: By monitoring body size, HCT, PD, and CGC haplotype, changes in CsA CL/F over time could be predicted. Such information could be used to optimize CsA therapy. CsA dose adjustments should be considered in different postoperative periods.
Authors: Yang Dai; Kazunori Iwanaga; Yvonne S Lin; Mary F Hebert; Connie L Davis; Weili Huang; Evan D Kharasch; Kenneth E Thummel Journal: Biochem Pharmacol Date: 2004-11-01 Impact factor: 5.858
Authors: R Venkataramanan; T E Starzl; S Yang; G J Burckart; R J Ptachcinski; B W Shaw; S Iwatsuki; D H Van Thiel; A Sanghvi; H Seltman Journal: Transplant Proc Date: 1985-02 Impact factor: 1.066
Authors: H-U Meier-Kriesche; S Li; R W G Gruessner; J J Fung; R T Bustami; M L Barr; A B Leichtman Journal: Am J Transplant Date: 2006 Impact factor: 8.086