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Title: Patients With Chronic Kidney Disease on Darbepoetin Therapy Do Not Require Dose-Adjustment for Weight: Presented at ACCP

"Patients With Chronic Kidney Disease on Darbepoetin Therapy Do Not Require Dose-Adjustment for Weight: Presented at ACCP"

By Crina Frincu-Mallos, PhD PHILADELPHIA -- September 22, 2008 -- In patients with chronic kidney disease (CKD) receiving darbepoetin alfa (KRN321), it is not necessary to adjust the dose according to the patient's weight, researchers reported here at the American College of Clinical Pharmacology (ACCP) 37th Annual Meeting. Darbepoetin alfa, a novel molecule that stimulates erythropoiesis, is currently being tested in patients with CKD. In this patient population, its terminal half-life is 3 times that of recombinant human erythropoietin. Kazuki Kawakami, Product Development Division, Kirin Pharma Company Ltd., Tokyo, Japan, presented the data in a poster session on September 14. The researchers sought to characterise the pharmacokinetics (PK) of darbepoetin alfa, as well as to assess potential covariate relationships in patients with CKD. Darbepoetin alfa was administered subcutaneously in a single dose to 64 peritoneal dialysis and nondialysis patients with CKD. A total of 989 serum samples provided by these patients were analysed using nonlinear, mixed-effect modelling, with a model including endogenous erythropoietin production, the researchers explained in their poster presentation. "The selected basic model was a 1-compartment model with a combination of additive and constant coefficient of variation error models," said Kawakami. Body weight was used as a significant covariate for apparent clearance (CL/f) and apparent volume of central compartment (V[₁/f).

With the introduction of body weight in CL/f and V₁/f, the investigators noted a decrease in CL/f from 35.9% to 25.9%, paralleled by a decrease in V₁/f from 49.2% to 42%.

Mean values for CL/f, V₁/f, and the absorption rate constant (K_a) were 0.160 L/h, 13.9 L, and 0.0376 hr^-1, respectively.

Evaluation by bootstrapping indicated that the final model was stable, said Kawakami.

Based on these data, the investigators concluded that body weight was the significant covariate for CL/f and V₁/f.

"However, dosage adjustment by weight is not necessary for subcutaneous administration of darbepoetin alfa in CKD patients," he added.

[Presentation title: Population Pharmacokinetics of Darbepoetin Alfa in Peritoneal Dialysis and Non-Dialysis Patients With Chronic Kidney Disease After Single Subcutaneous Administration. Abstract 10]

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