Semi-mechanistic Pharmacokinetic/Pharmacodynamic model of three pegylated rHuEPO and ior®EPOCIM in New Zealand rabbits.
Eur J Pharm Sci
; 120: 123-132, 2018 Jul 30.
Article
em En
| MEDLINE
| ID: mdl-29729414
ABSTRACT
Marketed formulations of erythropoietin (EPO) ior®EPOCIM, MIRCERA® and two newly developed pegylated-EPO analogues (PEG-EPO 32 and 40â¯kDa) formulations were intravenously administered to New Zealand rabbits. A semi-mechanistic Pharmacokinetic/Pharmacodynamic (PK/PD) model describing in a simultaneous and integrated form the time course of reticulocytes, red blood cells and hemoglobin was built to account for the time course of hematopoiesis stimulation after erythropoietin administration. Data analysis was performed based on the population approach with the software NONMEM version 7.3. Erythropoietin disposition of each of the administered formulations was best described with a two compartment model and linear elimination. Different formulations show different clearance and apparent volume of distribution of the central compartment but share estimates of inter-compartmental clearance and apparent peripheral volume of distribution. A semi-mechanistic model including cell proliferation, maturation, and homeostatic regulation provided a good description of the data regardless the type of erythropoietin formulation administered. The system-, and drug-related parameters showed consistency and differed across formulations, respectively. A single IV administration of PEG-EPO 32 and 40â¯kDa formulations in New Zealand rabbits achieves a median change of 27% and 22% on RET levels, and of 47% and 63% on RBC and HGB levels, respectively compared to MIRCERA®. The administration of new branched PEG-chains formulations improves PK and PD properties of EPO, in terms of increasing elimination half-lives and pharmacological activity on RET, RBC and HGB compared to commercially available formulations (ior®EPOCIM and MIRCERA®).
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Polietilenoglicóis
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Eritropoetina
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Hematínicos
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Hematopoese
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Modelos Biológicos
Limite:
Animals
Idioma:
En
Revista:
Eur J Pharm Sci
Ano de publicação:
2018
Tipo de documento:
Article