Population pharmacokinetics of darbepoetin alfa in haemodialysis and peritoneal dialysis patients after intravenous administration.
OBJECTIVE
To characterize the pharmacokinetics of darbepoetin alfa and covariate relationships in haemodialysis (HD) and peritoneal dialysis (PD) patients.


METHODS
Data were collected from 131 (63 HD and 68 PD) patients who received darbepoetin alfa intravenously. A total of 917 serum concentrations were available. The data were analysed by nonlinear mixed effect modelling using NONMEM with a model including endogenous erythropoietin production. In addition, the final model was evaluated using bootstrap resampling.


RESULTS
The selected basic model was a two-compartment model with a combination of additive and the constant coefficient of variation error models. The significant covariates were weight (WT) for clearance (CL) and the volume of central compartment (V(1)), and the dialysis technique (DIA) for V(1). The typical values of CL and V(1) were 0.0807 l h(-1) and 2.51 l, respectively. V(1) in PD patients was 17% higher than in HD patients. With the introduction of WT in CL and WT and DIA in V(1), interindividual variability decreased from 27.1% to 20.6% in CL and from 29.1% to 21.8% in V(1). The mean parameter estimates from the bootstrap datasets were similar to those from the original dataset. Evaluation by bootstrapping showed that the final model was stable.


CONCLUSIONS
The results of the present analysis suggest no dosage regimen change is warranted for darbepoetin alfa in HD and PD patients over the range of distribution of covariates included in this study.
Takama
Hirotaka
H
Product Development Department, Pharmaceutical Division, Kirin Brewery Company Ltd, Tokyo, Japan. takamah@kirin.co.jp
Tanaka
Hideji
H
Nakashima
Daisuke
D
Ogata
Hiroyasu
H
Uchida
Eiji
E
Akizawa
Tadao
T
Koshikawa
Shozo
S
D000328:Adult; D000368:Aged; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D006397:Hematinics / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010530:Peritoneal Dialysis; D006435:Renal Dialysis
D006397:Hematinics; D004921:Erythropoietin; D000068256:Darbepoetin alfa