Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects

A pharmacokinetic and pharmacodynamic (PK/PD) model for recombinant human erythropoietin (Epoetin alfa) in healthy subjects was developed to describe the time profiles of changes in serum Epoetin alfa and the pharmacological responses of percent reticulocytes, total red blood cell counts, and hemoglobin after single and multiple subcutaneous administration of Epoetin alfa. Data used in the development of the model were obtained from a clinical study carried out in healthy volunteers in which Epoetin alfa was administered either as 150 IU/kg three-times-a-week (t.i.w.) or fixed 40,000 IU weekly (q.w.) doses for 4 weeks. A dual-absorption rate model (fast zero-order and slow first-order inputs) with linear disposition kinetics was used to characterize the pharmacokinetics of erythropoietin after subcutaneous administration. A new catenary cell production and lifespan loss model was used to fit the pharmacodynamic data yielding estimates of SC₅₀, S_max, and other pharmacodynamic parameters. Flip-flop kinetics was apparent in the pharmacokinetics as the absorption rate was slower (k_a = 0.7 day^-1) than the elimination rate (CL/V_d = 1.2-9.2 day^-1). In the pharmacodynamics, an SC₅₀ of 58 mIU/mL was estimated indicating that low serum erythropoietin concentrations were sufficient to produce pharmacological effects. The established PK/PD model predicts similar pharmacological responses of hemoglobin and total red blood cell counts for the 150 IU/kg t.i.w. and 40,000 IU q.w. regimens in healthy subjects.