A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia.
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Scholz M, Ackermann M, Engel C, Emmrich F, Loeffler M, Kamprad M
A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia.
Cell Prolif. 2009 Dec;42(6):813-22. doi: 10.1111/j.1365-2184.2009.00638.x. Epub 2009 Aug 17.
- PubMed ID
- 19689472 [ View in PubMed]
- Abstract
OBJECTIVES: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre-select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G-CSF derivatives filgrastim and pegfilgrastim in mice. METHODS: Healthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation. RESULTS: Predictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results. CONCLUSION: Dynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Filgrastim Neutrophil elastase Protein Humans UnknownSubstrateDetails