Cheung W K, Goon B L, Guilfoyle M C, Wacholtz M C
Department of Drug Metabolism, R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869-0602, USA.
Clin Pharmacol Ther. 1998 Oct;64(4):412-23. doi: 10.1016/S0009-9236(98)90072-8.
To understand the pharmacokinetic and pharmacodynamic properties of recombinant human erythropoietin (epoetin alfa) and to continue to optimize dosing regimens by determining whether administration of single high doses of epoetin alfa is as effective as repeated administration.
Epoetin alfa was administered as single subcutaneous doses of 300, 450, 600, 900, 1200, 1350, 1800, and 2400 IU/kg and in multiple subcutaneous dose regimens: 150 IU/kg 3 times a week for 4 weeks and 600 IU/kg once per week for 4 weeks in 2 open-label, randomized placebo-controlled studies in healthy volunteers.
The absorption rate of epoetin alfa after subcutaneous administration was independent of dose, whereas clearance was dose-dependent in that it decreased with increasing dose. There was a linear relationship between response measured as percentage of reticulocytes area under the curve (AUC) and erythropoietin AUC for single doses up to 1800 IU/kg. Beyond the 1800 IU/kg dose, there was a saturation of response. The mean percentage of reticulocytes after single-dose regimens began to increase by days 3 to 4, reached their maximum at days 8 to 11, and returned to baseline values by day 22. In contrast, the mean percentage of reticulocytes after both multiple-dose regimens were maintained above baseline values through day 22 as both regimens stimulated modest but sustained increases in percentage of reticulocytes (1% to 2%). The mean percentage of reticulocytes AUC for 600 IU/kg epoetin alfa given once a week for 4 weeks was apparently greater than the mean percentage of reticulocytes AUC for 150 IU/kg 3 times a week for 4 weeks. Although daily oral iron supplementation was given, mean serum ferritin levels declined by approximately 75% through day 22 in subjects treated with multiple doses of epoetin alfa.
These findings show that the pharmacologic response to epoetin alfa is a function of dose and dosing regimen. Repeated administration of epoetin alfa was more effective in stimulating a reticulocyte response than single-dose administration of the same total amount of epoetin alfa.
了解重组人促红细胞生成素（阿法依泊汀）的药代动力学和药效学特性，并通过确定单次高剂量阿法依泊汀给药是否与重复给药一样有效，继续优化给药方案。
在两项针对健康志愿者的开放标签、随机、安慰剂对照研究中，阿法依泊汀分别以300、450、600、900、1200、1350、1800和2400 IU/kg的单次皮下剂量给药，并采用多次皮下给药方案：每周3次，每次150 IU/kg，共4周；以及每周1次，每次600 IU/kg，共4周。
皮下注射后阿法依泊汀的吸收速率与剂量无关，而清除率与剂量有关，即随着剂量增加而降低。对于单次剂量高达1800 IU/kg的情况，以网织红细胞曲线下面积（AUC）百分比衡量的反应与促红细胞生成素AUC之间存在线性关系。超过1800 IU/kg剂量后，反应出现饱和。单次给药方案后网织红细胞的平均百分比在第3至4天开始增加，在第8至11天达到最大值，并在第22天恢复到基线值。相比之下，两种多次给药方案后网织红细胞的平均百分比在第22天之前均维持在基线值以上，因为两种方案均刺激网织红细胞百分比适度但持续增加（1%至2%）。每周1次，每次600 IU/kg，共4周的阿法依泊汀给药方案的网织红细胞AUC平均百分比明显大于每周3次，每次150 IU/kg，共4周的给药方案。尽管给予了每日口服铁补充剂，但在接受多次剂量阿法依泊汀治疗的受试者中，到第22天平均血清铁蛋白水平下降了约75%。
这些发现表明，对阿法依泊汀的药理反应是剂量和给药方案的函数。重复给予阿法依泊汀在刺激网织红细胞反应方面比给予相同总量的阿法依泊汀单次给药更有效。
