Population pharmacokinetic characteristics of sirolimus in healthy Chinese subjects and renal transplant patients.
OBJECTIVE
To identify the factors affecting the pharmacokinetics (PKs) of sirolimus in healthy Chinese subjects and renal transplant patients.


METHODS
A population PK model of sirolimus was constructed using dense data from 22 healthy volunteers and sparse data from 105 renal transplant patients.


RESULTS
The data were well described by a two-compartment model with first-order absorption. The estimates of absorption rate constant (Ka), clearance (CL/F), and central volume of distribution (V2/F) were 0.24 h(-1), 8.81 L/h, and 676 L, respectively. The CL/F in renal transplant patients was 45.5% lower than that in healthy subjects. Based on the final model, CL/F decreased significantly with increasing cyclosporine (CsA) daily dose and age. A decrease of 7.3% in CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in CL/F for every 20-year increase in age was observed. Moreover, V2/F increased significantly with increasing serum creatinine in our study. However, the range of serum creatinine concentration and the interindividual variability for V2/F are large.


CONCLUSIONS
This is the first study to characterize the population PKs of sirolimus using a two-compartment model in healthy Chinese subjects and renal transplant patients. A decrease of 7.3% in the sirolimus CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in the sirolimus CL/F for every 20-year increase in age was observed, which allowed us to better optimize sirolimus dosing regimens in Chinese renal transplant patients.
Miao
M
Wang
Bao-ling
BL
Duan
Yin-jin
YJ
Yuan
Xia
X
Su
Hang
H
Zheng
Fu-sheng
FS
Wang
He
H
Sun
D000328:Adult; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D020123:Sirolimus / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D020123:Sirolimus