Clinical pharmacokinetics of lyophilized recombinant human erythropoietin-alpha following single-dose subcutaneous administration in premature newborns.

ABSTRACT

OBJECTIVE: The aim of this study was to determine pharmacokinetic parameters after subcutaneous administration of a single dose (400 IU/kg) of lyophilized recombinant human erythropoietin-alpha (rhEPOalpha) to preterm newborns. The parameters determined were maximum concentration (C(max)), time to reach maximum concentration (T(max)), absorption half-life (t(l/2abs)), volume of distribution (Vd), elimination half-life (t(l/2el)), clearance (C(L)), constant of elimination (k(el)) and area under the 0-72 h curve (AUC(0-72). METHODS: The study group comprised 20 premature newborns (eight males and 12 females) delivered in the Teaching Hospital, University of São Paulo. The inclusion criteria were birth weight < 1500 g or gestational age < or = 34 weeks, and clinical and hemodynamic stability. Serum erythropoietin (EPO) concentration was determined before and 1, 4, 6, 12, 24,48 and 72 h after subcutaneous administration of 400 IU/kg rhEPOalpha, and the pharmacokinetic parameters were calculated. RESULTS: There was a significant difference in serum EPO concentration between t72 and t0 (p = 0.001). Mean values (range) of the pharmacokinetic parameters were as follows C(max), 739.8 (188.0-1390.0) mIU/ml; T(max), 7.7 (4.0-12.0) h; t(l/2abs), 2.9 (0.8-4.8) h, V(d), 0.705 (0.23-1.73) 1/kg; t(l/2e1), 14.9 (8.7-36.1) h; C(L), 0.032 (0.014-0.066) 1/h; k(el), 0.0475 (0.0200-0.0700); and AUC(0-72), 19058.2 (7648.0-34701.5) mIU/ml per h. The Spearman test showed no correlation between the pharmacokinetic parameters analyzed and the characteristics of the population studied. CONCLUSIONS: Studies evaluating the effectiveness of therapy with recombinant human erythropoietin in premature newborns have used various doses, administered at intervals between 24 and 48 h. The kinetics of absorption measured in our study supports the use of 400 IU/kg within an interval of no less than 72 h, together with therapeutic control of the drug and evaluation of the erythropoietic response.