Estimation of rhG-CSF absorption kinetics after subcutaneous administration using a modified Wagner-Nelson method with a nonlinear elimination model

The clearance of recombinant human granulocyte-colony stimulating factor (r hG-CSF) is known to decrease with dose increase, and to be saturable. The a verage clearance after intravenous administration will be lower than that a fter subcutaneous administration. Therefore, the apparent absolute bioavail ability with subcutaneous administration calculated from the AUC ratio is e xpected to be an underestimate. The absorption pharmacokinetics after subcu taneous administration was examined using the results of the bioequivalency study between two rhG-CSF formulations with a dose of 2 mug/kg. The analys is was performed using a modified Wagner-Nelson method with the nonlinear e limination model. The apparent absolute bioavailability for subcutaneous ad ministration was 56.9 and 67.5% for each formulation, and the ratio between them was approximately 120%. The true absolute bioavailability was, howeve r, estimated to be 89.8 and 96.9%. respectively, and the ratio was approxim ately 108%. The absorption pattern was applied to other doses. and the pred icted clearance values for subcutaneous and intravenous administrations wer e then similar to the values for several doses reported in the literature. The underestimation of bioavailability was around 30%. and the amplificatio n of difference was 2.5 times, from 8 to 20%, because of the nonlinear phar macokinetics. The neutrophil increases for each formulation were identical, despite the different bioavailabilities. The reason for this is probably t hat the amount eliminated through the saturable process. which might indica te the amount consumed by the G-CSF receptor, was identical for each formul ation. (C) 2001 Elsevier Science B.V. All rights reserved.