NESP Mechanism of Action

Long-Acting Erythropoiesis Stimulating Agent.
Pharmacology: NESP exerts an erythropoietic effect by acting on erythroid progenitor cells directly.
Erythropoietic Action: When intravenously administered to healthy rats and mice, NESP showed an erythropoietic effect (increasing the hemoglobin concentration and the reticulocyte count) more sustained than that of epoetin alfa. Moreover, when intravenously or subcutaneously administered to rats with renal anemia, NESP brought about a marked improvement in anemia. In partially nephrectomized rats, NESP showed an effect of improving anemia equivalent to that of epoetin alfa in a lower administration frequency.
Mechanism of Action: By binding with erythropoietin receptors, NESP acted on human hematopoietic progenitor cells to promote colony formation of late erythroid progenitor cells (CFU-E) and early erythroid progenitor cells (BFU-E) in a concentration-dependent manner (in vitro).
Clinical Studies: Double-blind comparative studies (in patients receiving hemodialysis): NESP or epoetin alfa was intravenously administered to 121 patients with renal anemia receiving hemodialysis (61 patients treated with NESP, 60 patients treated with epoetin alfa) for 28 weeks to examine the equivalence. As a result, once weekly administration of NESP proved to be equivalent to 2-3 times weekly administration of epoetin alfa in efficacy. (See Figure 1.)

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Long-term administration studies (in patients receiving hemodialysis): NESP was intravenously administered to 513 patients with renal anemia receiving hemodialysis at a dose adjusted appropriately in the range of 10-120 μg in a frequency of once weekly or once every two weeks for a long-term period. As a result, the hemoglobin concentration remained at around 11.0 g/dL during the treatment in both of the frequencies. (See Figure 2.)

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Comparability studies (in patients with chronic kidney disease not on dialysis): NESP or epoetin alfa was subcutaneously administered to 100 renal anemia patients with chronic kidney disease not on dialysis (50 patients received NESP and 50 patients received epoetin alfa) for 26-28 weeks to evaluate comparability. As a result, once every two weeks or once every four weeks administration of NESP proved to be equivalent to once weekly or once every two weeks administration of epoetin alfa in efficacy. (See Figure 3.)

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Long-term administration studies (in patients with chronic kidney disease not on dialysis): NESP was subcutaneously administered to 161 renal anemia patients with chronic kidney disease not on dialysis in a frequency of once every two weeks or once every four weeks for 46-48 weeks. Dose was adjusted in 60, 90, 120 or 180 μg. As a result, after starting administration of NESP, the hemoglobin concentration increased, and after 14 weeks and thereafter the hemoglobin concentration remained at around 12.0 g/dL. (See Figure 4.)

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General clinical studies (in patients receiving peritoneal dialysis): NESP was intravenously or subcutaneously administered to 146 patients receiving peritoneal dialysis in a frequency of once every two weeks or once every four weeks for 26-28 weeks. Dose was adjusted in 30, 60, 90, 120 or 180 μg. As a result, after starting administration of NESP, the hemoglobin concentration increased, and after 14 weeks and thereafter the hemoglobin concentration remained at around 12.0 g/dL. (See Figure 5.)

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Multinational clinical study (in patients with myelodysplastic syndrome): NESP was subcutaneously administered to 52 patients with myelodysplastic syndromes (including 31 Japanese patients) who were in the low or intermediate-1 risk categories under IPSS and transfusion-dependent ^{note 1)} with the serum erythropoietin concentration of 500 mIU (international units)/mL or lower at a dose of 60, 120, or 240 μg once weekly for 48 weeks ^{note 2)}. The efficacy of NESP was assessed at 16 weeks after the initiation of NESP administration ^{note 3)}. In the 50 patients included in efficacy evaluation, major erythroid response ^{note 4)} or minor erythroid response ^{note 5)} was observed in 11 of 17 patients (64.7%) of the 60 μg group, 8 of 18 patients (44.4%) of the 120 μg group, and 10 of 15 patients (66.7%) of the 240 μg group.
^{Note 1)} Defined as the longest transfusion-free interval of shorter than 56 days in the past 112 days (excluding transfusions performed when the hemoglobin concentration was higher than 9.0 g/dL).
^{Note 2)} If patients did not respond to NESP at 16 weeks after the initiation of administration, administration of NESP was discontinued in the 240 μg group, and the dose was increased in the other groups.
^{Note 3)} The target hemoglobin concentration was set at 10.0 g/dL by reference to the Guidelines for use of blood products, revised version (in Japanese) (Blood and Blood Products Division, PFSB, MHLW, 2005). To maintain the hemoglobin within the target range of 9.0 to 11.0 g/dL, administration of NESP was suspended if the hemoglobin concentration exceeded 11.0 g/dL.
^{Note 4)} Defined as transfusion independence for at least 56 consecutive days during the NESP administration period, and the maximum hemoglobin concentration during the transfusion-free period of at least 1.0 g/dL higher than that at the initiation of administration.
^{Note 5)} Defined as 50% decrease or more in transfusion requirement in 56 consecutive days during the NESP administration period in comparison with during the 56-day period before the initiation of administration.
Pharmacokinetics: Chronic Kidney Disease (Adults): Single administration: Intravenous administration: Following a single intravenous administration of NESP at a dose of 10-180 μg to patients with renal anemia receiving hemodialysis, the serum concentration increased almost dose proportionally and its time-course changes showed biphasic elimination. The pharmacokinetic parameters are shown as follows. AUC also increased almost in proportion to the dose. (See Figure 6 and Table 2.)

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Subcutaneous administration: Following a single subcutaneous administration of NESP at a dose of 20-180 μg to patients with chronic kidney disease not on dialysis, the serum concentration increased almost dose proportionally. The pharmacokinetic parameters are shown as follows. AUC also increased almost in proportion to the dose. (See Figure 7 and Table 3.)

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Repeated administration: Following repeated intravenous administration of NESP at a dose of 10-60 μg to patients with renal anemia receiving hemodialysis for 28 weeks, no change was found in the pharmacokinetics at the final administration when compared to the initial administration. Following repeated intravenous administration of NESP at a dose of 10-180 μg to patients with renal anemia receiving dialysis, no major change was found in the serum trough concentration. Following repeated subcutaneous administration of NESP at a dose of 15-180 μg to patients with peritoneal dialysis and patients with chronic kidney disease not on dialysis, no major change was found in the serum trough concentration.
Myelodysplastic syndrome: Single administration (Japanese and Korean patients): Following repeated subcutaneous administration of NESP at doses of 60-240 μg to patients with myelodysplastic syndrome for 16 weeks, the time course of serum concentrations and pharmacokinetic parameters at the initial administration were as follows. C_max and AUC_0-t did not increase in proportion to the dose. (See Figure 8 and Table 4.)

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Repeated administration (Japanese and Korean patients): Following repeated subcutaneous administration of NESP at doses of 60 to 240 μg to patients with myelodysplastic syndromes for 16 weeks, the serum trough concentration was not dose-proportional and showed no remarkable changes over the dose range tested throughout the administration period.