The pharmacokinetics (PK) of continuous erythropoietin receptor activator (CERA), a PEGylated erythropoietin (EPO) derivative, was studied in sheep after bone marrow (BM) busulfan ablation by using a receptor-based recirculation model and tracer interaction method (TIM) experiments. The nontracer CERA component of the TIM was analyzed using a noncompartmental approach. In contrast to EPO elimination that is linear after the BM ablation, CERA elimination remains nonlinear. After busulfan treatment, initial EPO receptors (EPOR) normalized production rate constant, EPOR degradation rate constant, and CERA-EPOR complex internalization rate constant decreased (p < 0.01), whereas no change in CERA/EPOR equilibrium dissociation constant was detected (p > 0.05). After BM ablation, noncompartmental analysis showed that CERA-PK parameters underwent 1) a decrease in plasma clearance (p < 0.01); 2) a concomitant increase in elimination half-life and mean residence time; and 3) no significant change in volume of distribution, distribution half-life, or distributional clearance (p > 0.05). These results suggest that CERA elimination is mediated through saturable hematopoietic and nonhematopoietic EPOR pathways, with possible contribution of another EPOR-independent pathway(s). Compared with the nonhematopoietic EPOR population, the hematopoietic receptors have similar affinity to CERA but are significantly more involved in CERA's in vivo elimination. The saturable nature of the nonerythropoietic, non-BM pathway(s) for CERA in contrast to EPO predicts two fundamental differences: 1) an increasing fraction of CERA is used for erythropoiesis for increasing concentrations; and 2) the clearance of CERA becomes more limited for increasing concentrations. Taken together, these differences favor a more efficacious and prolonged action for CERA.
Footnotes
This work was supported by a grant from Roche Penzberg Germany from September 2004 until December 2006.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.036236.
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ABBREVIATIONS:
- CERA
- continuous erythropoietin receptor activator
- BM
- bone marrow
- CL
- CERA total clearance
- CLd
- distribution clearance
- EPO
- erythropoietin
- EPOR
- erythropoietin receptor
- ESA
- erythropoiesis-stimulating agent
- CV
- coefficient of variation
- HLS
- heart-lung segment
- MRT
- mean residence time
- MSE%
- mean percent standard error
- NESP
- novel erythropoiesis-stimulating protein
- NTM
- nontarget mediated
- PEG
- polyethylene glycol
- PK
- pharmacokinetic
- PBPK
- physiologically based PK
- QE
- quasi-equilibrium
- RIA
- radioimmunoassay
- t1/2(α)
- distribution half-life
- t1/2(β)
- CERA elimination half-life
- tcold
- time of injection of unlabeled CERA
- TIM
- tracer interaction method
- TM
- target-mediated
- TMDD
- target-mediated drug disposition
- Vd
- initial volume of distribution
- Vss
- steady-state volume of distribution
- AUC
- area under the curve
- ksyn/R0
- EPOR-normalized production rate constant
- kdeg
- EPOR degradation rate constant
- kint
- CERA-EPOR complex internalization rate constant
- KD
- dissociation constant
- ksyn
- EPOR synthesis rate constant
- R0
- initial total EPOR concentration.
- Received September 2, 2010.
- Accepted December 28, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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