Gledys Reynaldo1, Leyanis Rodríguez1, Roberto Menéndez2, Joaquín Solazábal3, Daniel Amaro3, María de Los A Becquer4, Yamila Colom5, Haydee Gil5, Juan C Polo1, Gilberto Castañeda6, Braulio Jiménez-Vélez7, Jorge Duconge8, Eduardo M Fernández-Sánchez1,4. 1. Department of Pharmacy, Institute of Pharmacy & Foods, University of Havana, 222 St. and 23 Av. La Coronela, La Lisa, 13600, Havana, Cuba. 2. Center of Neurosciences of Cuba, 190 St between 25 and 27, Cubanacan, Playa, 11600, Havana, Cuba. 3. Center of Molecular Immunology, 216 St. and 15 St. Atabey, Playa. 11600, Havana, Cuba. 4. Center for Research and Biological Evaluation, Institute of Pharmacy & Foods, University of Havana, 222 St. and 23 Av. La Coronela, La Lisa, 13600, Havana, Cuba. 5. National Institute of Oncology and Radiobiology (INOR), 29 St. and F, Vedado, Plaza de la Revolución, 10400, Havana, Cuba. 6. Department of Pharmacology, CINVESTAV-IPN, Av. IPN N0. 2508, Col. San Pedro Zacatenco, 07360, Delegación Gustavo A Madero, Mexico City, Mexico. 7. University of Puerto Rico Medical Sciences Campus, Department of Biochemistry, School of Medicine, PO Box 365067, 00936-5067, San Juan, Puerto Rico. 8. University of Puerto Rico Medical Sciences Campus, Department of Pharmaceutical Sciences, School of Pharmacy, PO Box 365067, 00936-5067, San Juan, Puerto Rico.
Abstract
CONTEXT: The recombinant human erythropoietin (rHuEPO) stimulates the erythropoiesis process. Because this glycoprotein has a short half-life, it needs to be administrated two to three times a week. One of the technics to solve this issue is the PEGgilation. AIMS: To evaluate the pharmacokinetics (PK) and pharmacodynamics of two new branched PEGylated erythropoietins (i.e., an asymmetric 32 kDa-PEG2-rHuEPO and a symmetric 40 kDa-PEG2-rHuEPO molecule) compared to non-PEGylated ior®EPOCIM and MIRCERA®. METHODS: Serum concentrations of both PEGylated and non-PEGylated erythropoietins were measured at various time points in order to determine PK parameters using non-compartmental analysis approach. The reticulocyte (%), erythrocyte count and hemoglobin levels were ascertained in order to compare the effect of these molecules after administrating a single intravenous dose (10 μg/kg) of each product in male New Zealand rabbits. RESULTS: Both branched PEGylated erythropoietin forms exhibited half-lives that were significantly longer than ior®EPOCIM (p<0.05), but not statistically different to MIRCERA®. The mean elimination half-life increased from 4 h (ior®EPOCIM) to 131 h for the 32 kDa-PEG2-rHuEPO and 119 h for the 40 kDa-PEG2-rHuEPO. Conversely, MIRCERA® exhibits a half-life of 64 h. Both PEGylated erythropoietin products significantly enhanced the stimulating effect on reticulocytes and erythrocytes formation, as well as on hemoglobin levels, when compared to ior®EPOCIM treatment up to 42 days post-dose. CONCLUSIONS: The PEGylation strategy employed in this study is an effective method to modify the pharmacokinetics and pharmacodynamics of rHuEPO molecule achieving higher half-lives and, therefore, longer in vivo bioactivity. Both of the branched PEGylated-EPO forms tested are promising candidates for human testing.
CONTEXT: The recombinant human erythropoietin (rHuEPO) stimulates the erythropoiesis process. Because this glycoprotein has a short half-life, it needs to be administrated two to three times a week. One of the technics to solve this issue is the PEGgilation. AIMS: To evaluate the pharmacokinetics (PK) and pharmacodynamics of two new branched PEGylated erythropoietins (i.e., an asymmetric 32 kDa-PEG2-rHuEPO and a symmetric 40 kDa-PEG2-rHuEPO molecule) compared to non-PEGylated ior®EPOCIM and MIRCERA®. METHODS: Serum concentrations of both PEGylated and non-PEGylated erythropoietins were measured at various time points in order to determine PK parameters using non-compartmental analysis approach. The reticulocyte (%), erythrocyte count and hemoglobin levels were ascertained in order to compare the effect of these molecules after administrating a single intravenous dose (10 μg/kg) of each product in male New Zealand rabbits. RESULTS: Both branched PEGylated erythropoietin forms exhibited half-lives that were significantly longer than ior®EPOCIM (p<0.05), but not statistically different to MIRCERA®. The mean elimination half-life increased from 4 h (ior®EPOCIM) to 131 h for the 32 kDa-PEG2-rHuEPO and 119 h for the 40 kDa-PEG2-rHuEPO. Conversely, MIRCERA® exhibits a half-life of 64 h. Both PEGylated erythropoietin products significantly enhanced the stimulating effect on reticulocytes and erythrocytes formation, as well as on hemoglobin levels, when compared to ior®EPOCIM treatment up to 42 days post-dose. CONCLUSIONS: The PEGylation strategy employed in this study is an effective method to modify the pharmacokinetics and pharmacodynamics of rHuEPO molecule achieving higher half-lives and, therefore, longer in vivo bioactivity. Both of the branched PEGylated-EPO forms tested are promising candidates for human testing.
Authors: Iain C Macdougall; Richard Robson; Sylvie Opatrna; Xavier Liogier; Anne Pannier; Paul Jordan; Frank C Dougherty; Bruno Reigner Journal: Clin J Am Soc Nephrol Date: 2006-09-13 Impact factor: 8.237
Authors: K K Flaharty; J Caro; A Erslev; J J Whalen; E M Morris; T D Bjornsson; P H Vlasses Journal: Clin Pharmacol Ther Date: 1990-05 Impact factor: 6.875