Pharmacodynamics Of rHuEPO

Erythropoietic responses to rHuEPO are generally measured by changes in reticu-locyte count, Hb concentration, and hematocrit (65). In an early study of healthy volunteers (65), the mean peak reticulocyte response occurred 4-5 d after a single intravenous dose of rHuEPO. In another study assessing multiple iv doses, 25 patients on hemodialysis received rHuEPO three times weekly at doses of 15, 50,150, or 500 U/kg or placebo (111). Hematocrit values increased in a striking, dose-dependent fashion, with increases apparent in most of the dose groups within the first week of administration.

A similar but more prolonged response was seen with subcutaneous dosing; administration of rHuEPO in ascending, single doses to healthy volunteers produced prompt increases in the number of circulating reticulocytes (112). The magnitude of the response was proportional to the EPO AUC until the next to the highest dose was administered (a single dose of 1800 U/kg), whereupon saturation of the response was noted. In a multidose study, Cheung et al. (112) randomized 36 healthy volunteers to receive sc either 40,000 U of rHuEPO once weekly or 150 U/kg three times weekly for 4 wk. Increases in Hb concentration, number of RBCs, and percent reticulocytes were maintained throughout the dosing period.

The in vivo activity of rHuEPO also depends on another pharmacodynamic factor, the minimum effective concentration (MEC). The intravenous administration of rHuEPO requires approx 30% more drug than the subcutaneous administration (113) despite the markedly higher peak plasma levels and bioavailability of the intravenous dose. It appears that serum rHuEPO concentrations must be maintained above a critical threshold (i.e., the MEC) for effective erythropoiesis, and increased time above the critical threshold results in increased biologic response. Maintenance of this threshold concentration is best achieved through slower absorption and more prolonged elimination (20,44,110). The increased in vivo activity of darbepoetin alfa (56,59) is caused by its ability to maintain the MEC over an extended period (110).

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