Population pharmacokinetic analysis of pegylated human erythropoietin in rats

Jolling, Koen; Pérez‐Ruixo, Juan José; Hemeryck, Alex; Piotrovskij, V K; Greway, Tony

doi:10.1002/jps.20200

Cited by 26 publications

(20 citation statements)

References 14 publications

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“…We explain our contradictory results by: first the difference in the age of the animals in (A) and (B), and second, the interanimal and/or occasion variabilities. Because the body weight is accounted for in our PK parameters, the correlation between body weight and EPO clearance that was previously established [25,26] may not be considered as an influence factor to explain our observed differences.…”

Section: Pharmacokineticscontrasting

confidence: 50%

Time‐dependent clearance and hematological pharmacodynamics upon erythropoietin multiple dosing in rats

Ait‐Oudhia

Scherrmann

Krzyzanski

2010

Biopharm & Drug Disp

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The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEPO) upon its repeated administrations were investigated. Two groups (A and B) of normal Wistar rats received rHuEPO intravenously at 450 or 1350 IU/kg thrice weekly for 2 and 6 weeks. PK studies were conducted following days 0 and 4 for group (A) and days 0, 17 and 28 for group (B), then, washout PK were assessed on days 11 and 36 for both groups. Reticulocytes (RET), red blood cells (RBC) and hemoglobin (Hb) were evaluated daily until day 14, then every 2 days until day 30 for group (A) and 59 for group (B). The total clearance CL(Total) increased with the dose but decreased over time. Its decay reached 20% and 55% between the first and last full PK in both treatment arms. RET peaked on day 5 and were 77.6% and 87.3% higher than baselines for the two dosing regimen. Their nadirs occurred on days 22 and 55 and were 37.9% and 47.3% below normal values. Hb peaked on days 10 and 34 and was 28.9% and 38.6% above the baseline level, its nadirs occurred on days 25 and 57 and were 13.1% and 16% below baselines. Control animals showed stable baselines over the study but with moderate variability. In conclusion, rHuEPO exhibits a nonlinear PK with a time-dependent decrease of its CL(Total). During exposure, RET, RBC and Hb showed a tolerance effect. After exposure, the rebound was characterized for RET, RBC, but not Hb.

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Section: Pharmacokineticscontrasting

confidence: 50%

Time‐dependent clearance and hematological pharmacodynamics upon erythropoietin multiple dosing in rats

Ait‐Oudhia

Scherrmann

Krzyzanski

2010

Biopharm & Drug Disp

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“…The rotating sampling strategy used in our study allowed simultaneous determination of PK/PD data without hematological disturbance by bleeding alone. This staggered sampling strategy has been also used successfully for intensive sampling in small animals (Hartley et al, 2003;Jolling et al, 2004) to determine hematological parameters.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Administration in Rats

Woo

Krzyzanski

Jusko

2006

J Pharmacol Exp Ther

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The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEPO) were studied in rats after single i.v. and s.c. administration at three dose levels (450, 1350, and 4050 IU/kg). The plasma concentrations of rHuEPO and its erythropoietic effects including reticulocyte (RET), red blood cell (RBC), and hemoglobin (Hb) levels were determined. A two-compartment model with dual input rate and nonlinear disposition was used to characterize the PK of rHuEPO. The catenary indirect response model with several compartments reflecting the bone marrow and circulating erythropoietic cells was applied. The s.c. doses exhibited slow absorption (T max ϭ 12 h) and incomplete bioavailability (F ϭ 0.59). In placebo groups, RBC and Hb values gradually increased over time with growth of the rats, and the changes in the baselines monitored from 8 to 32 weeks of age were described by a nonlinear growth function. All doses resulted in dose-dependent increases in RET counts followed by an immediate decline below the baseline at around 6 days and returned to the predose level in 21-24 days after dosing. A subsequent steady increase of RBC and Hb levels followed and reached peaks at 6 days. A tolerance phenomenon observed at all dose levels was modeled by a negative feedback inhibition with the relative change in Hb level. The PK/PD model well described the erythropoietic effects of rHuEPO as well as tolerance, thereby yielding important PD parameters (S max ϭ 1.87 and SC 50 ϭ 65.37 mIU/ml) and mean lifespans of major erythropoietic cell populations in rats.Erythropoietin (EPO) is a glycoprotein hormone (30.5 kDa) produced in adult kidneys, and it is the major regulator of red cell production. Tissue hypoxia is the primary stimulus of the production of endogenous EPO. EPO binds to its receptors on the surface of erythroid progenitors in bone marrow, leading to their survival, proliferation, and differentiation, which in turn produces an increase in RBC and hemoglobin (Hb) concentrations (Fisher, 2003). Conversely, an excessive increase in RBC mass suppresses erythropoiesis to prevent blood from becoming more viscous, leading to the possibility of thrombosis and stroke. One study showed that transfusion polycythemia depressed bone marrow activity and reduced production of RBC in normal subjects (Birkhill et al., 1951). The negative feedback control in erythropoiesis has also been observed in humans after the subsequent rises of RBC and Hb following rHuEPO administration (Ramakrishnan et al., 2004). The exact mechanism and the primary regulators responsible for the counter-regulation are, however, not clearly elucidated.Comprehensive PK/PD models have been developed to quantitatively account for the pharmacokinetics and erythropoietic effects of rHuEPO (Ramakrishnan et al., 2003(Ramakrishnan et al., , 2004. The models depict nonlinear disposition kinetics and absorption kinetics mainly characterized by prolonged absorption and variable, incomplete bioavailability upon s.c. administration. Because eryth...

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“…Whether a similar relative improvement in half-life can be obtained by site-specific PEGylation of a properly glycosylated mammalian cell-derived Epo analog remains to be determined. Other researchers reported that modification of mammalian cell-derived Epo with multiple 5 kDa-amine-reactive PEGs increased the protein's half-life approximately 9-fold following intravenous administration to rats [30]. The significant glycosylation and pharmacokinetic differences between Epo proteins expressed in insect and mammalian cells precluded meaningful in vivo efficacy comparisons between proteins expressed using these different host systems.…”

Section: Discussionmentioning

confidence: 99%

Design of homogeneous, monopegylated erythropoietin analogs with preserved in vitro bioactivity

Long

Doherty

Eisenberg

et al. 2006

Experimental Hematology

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Objective-Erythropoietin (Epo) bioactivity is significantly reduced by modification of lysine residues with amine-reactive reagents, which are the most commonly used reagents for attaching polyethylene glycols (PEGs) to proteins to improve protein half-life in vivo. The aims of this study were to determine whether Epo bioactivity can be preserved by targeting attachment of maleimidePEGs to engineered cysteine analogs of Epo, and to determine whether the PEGylated Epo cysteine analogs have improved pharmacokinetic properties in vivo. Materials and Methods-Thirty-fourEpo cysteine analogs were constructed by site-directed mutagenesis and expressed as secreted proteins in baculovirus-infected insect cells. Following purification, monoPEGylated derivatives of 12 cysteine analogs were prepared using 20 kDamaleimide-PEGs. In vitro biological activities of the proteins were measured in an Epo-dependent cell proliferation assay. Plasma levels of insect cell-expressed wild type Epo (BV Epo) and a PEGylated Epo cysteine analog were quantitated by ELISA following intravenous administration to rats.Results-Biological activities of 17 purified Epo cysteine analogs and 10 purified PEGylated Epo cysteine analogs were comparable to that of BV Epo in the in vitro bioassay. The only PEGylated cysteine analogs that displayed consistently reduced in vitro bioactivities were substitutions for lysine residues, PEG-K45C and PEG-K154C. The PEGylated Epo cysteine analog had a slower initial distribution phase and a longer terminal half-life than BV Epo in rats, but the majority of both proteins were cleared rapidly from the circulation.Conclusions-Targeted attachment of maleimide-PEGs to engineered Epo cysteine analogs permits rational design of monoPEGylated Epo analogs with minimal loss of in vitro biological activity. Insect cell-expressed EPO proteins are cleared rapidly from the circulation in rats, possibly due to improper glycosylation. Site-specific PEGylation appears to improve the pharmacokinetic properties of Epo.

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Population pharmacokinetic analysis of pegylated human erythropoietin in rats

Cited by 26 publications

References 14 publications

Time‐dependent clearance and hematological pharmacodynamics upon erythropoietin multiple dosing in rats

Time‐dependent clearance and hematological pharmacodynamics upon erythropoietin multiple dosing in rats

Pharmacokinetic and Pharmacodynamic Modeling of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Administration in Rats

Design of homogeneous, monopegylated erythropoietin analogs with preserved in vitro bioactivity

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