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Pharmacokinetic analysis of continuous erythropoietin receptor activator disposition in adult sheep using a target-mediated, physiologic recirculation model and a tracer interaction methodology.

ABSTRACT: 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.

SUBMITTER: El-Komy MH

PROVIDER: S-EPMC3364499 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Pharmacokinetic analysis of continuous erythropoietin receptor activator disposition in adult sheep using a target-mediated, physiologic recirculation model and a tracer interaction methodology.

El-Komy Mohammed H MH Widness John A JA Veng-Pedersen Peter P

Drug metabolism and disposition: the biological fate of chemicals 20110105 4

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 treatmen ...[more]

PMID: 21209249

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Project description:Most pharmacodynamic (PD) models of cellular response assume a time-invariant (i.e., constant) cellular disposition despite known changes in the disposition with time, such as the reticulocyte residence time in the systemic circulation during stress erythropoiesis. To account for changes in cellular disposition, a comprehensive PD model that involves endogenous erythropoietin (Epo), reticulocytes, and hemoglobin responses was developed in phlebotomized sheep that considers a time-variant reticulocyte residence time and allows for the simultaneous determination of changes in the cellular disposition and cellular production. Five sheep were phlebotomized to hemoglobin concentrations of approximately 4 g/dl. Epo concentrations, reticulocytes, and hemoglobin concentrations were frequently sampled for 5-7 days prior to and 25-30 days following the phlebotomy. Initial steady-state conditions were assumed and the time-variant reticulocyte residence time in the systemic circulation was semiparametrically represented using a constrained spline function. Hemoglobin production was modeled using a Hill function via an effect site compartment. The initial steady state reticulocyte residence time in the systemic circulation was estimated as 0.477 (0.100) (mean (SD)) days, which maximally increased 2.01- to 2.64-fold higher than the initial steady-state residence time 5.95 (0.899) days post-phlebotomy (P < 0.01). On average, the residence time returned to steady-state values 15.4 (2.36) days post-phlebotomy, which was not significantly different from the initial steady-state value (P > 0.05). The baseline hemoglobin production rate was estimated at 0.0929 (0.0472) g/kg/day and the maximum production rate under stress phlebotomy was estimated at 0.504 (0.0422) g/kg/day. These data indicate that endogenously released Epo under acute anemic conditions can increase hemoglobin production approximately 5-fold. The determined increase in reticulocyte residence time produced under stress erythropoiesis is similar to the commonly reported 2- to 3-fold increase observed in human patients.

Project description:IntroductionErythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups.MethodsData from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0-12.0 g/dL)/upper (10.5-13.0 g/dL)], gender (female/male), age (<65/≥65), baseline N-terminal pro-B-type natriuretic peptide levels (<5000/≥5000), cardiovascular risk factors (diabetes/cardiac/vascular/none).ResultsAcross all subgroups analyzed, switching from shorter-acting erythropoiesis-stimulating agents to continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin concentrations in a high proportion of patients (78%), with only moderate hemoglobin fluctuations and a low number of dose changes. The safety profile across subgroups was as expected based on pre-existing risk factors; observed increases in adverse events were attributable to underlying risk factors rather than study drug.ConclusionsThis retrospective analysis of 13 trials showed that continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin levels across a number of clinically relevant patient subgroups, including those with higher inherent cardiovascular risk. The safety profile was consistent with that previously established in the chronic kidney disease population. CLINICALTRIALS.Gov identifiersNCT00413894/NCT00545571/NCT00517413/NCT00560404/NCT00882713/NCT00550680/NCT00576303/NCT00660023/NCT00717821/NCT00642850/NCT00605293/NCT00661505/NCT00699348.FundingF. Hoffmann-La Roche Ltd, Basel, Switzerland.

Project description:BackgroundThe monthly continuous erythropoietin receptor activator (CERA) utilization maintains stable hemoglobin (Hb) after conversion from weekly epoetin-β (EB); however, how the different pharmacologic properties affect the red blood cell (RBC) size determined by RBC distribution width (RDW) has not been evaluated yet. We assess the potential differences in iron metabolism, plasma erythropoietin (EPO), hepcidin, and soluble α-Klotho (α-Klotho) levels as an emergent hematopoiesis factor.MethodsThirty-seven chronic hemodialysis patients were included from January 2010 to November 2011 and randomized (1:1) to continue with EB or to convert to monthly CERA. Primary outcome was the mean change in Hb between groups at months 0, 3 and 6, and the percentage of patients who maintained stable Hb (Hb ± 1 g/dL from baseline level to month 6). Secondary outcomes were the influence on the erythropoietic process and iron metabolism markers. Thirty-one patients completed the study (CERA: n = 15, EB: n = 16).ResultsThe mean (95% confidence interval (CI)) Hb difference between groups was 0.28 g/dL (-0.36 to 0.93). There was no difference between the percentages of patients with stable Hb levels. In the CERA group RDW values increased progressively (interaction erythropoietin-stimulating agent (ESA) type and time on RDW values, F (1.57, 45.60) = 17.17, P < 0.01, partial η2 = 0.37) and the mean corpuscular volume changed at the different time points, (F (2, 28) = 29.12, P = 0.03, partial η2 = 0.23). During the evaluation period, in the CERA group, EPO was higher, and hepcidin and ferritin decreased significantly. α-Klotho decreased in both groups and correlated negatively with the changes on the RDW and positively with transferrin and serum iron. The number of serious adverse events was higher at the CERA group.ConclusionsMonthly CERA maintained Hb concentrations; however, it showed a significant effect on RDW, probably due to its impact on the EPO and hepcidin levels. α-Klotho decreased significantly in both groups, and its changes correlated with the changes in iron metabolism. Whether the RDW evolution was associated with the serious adverse events (SAEs) is a feasible hypothesis that needs to be confirmed in large studies.

Project description:BackgroundKnowledge of the physiologic requirement for iron, the core index for the formulation of a dietary reference intake (DRI), is of great importance for the health of a pregnant woman and her fetus, and can help a mother accurately plan her iron supplementation. However, direct measurements of the physiologic requirement for iron during pregnancy are still lacking.MethodEleven women of reproductive age from Hebei Province, China, who planned to become pregnant in the near future, were enrolled between January and March 2015 and included in the final analysis. Subjects participated in a 2-week metabolic trial in which they consumed 50 mg of the stable isotope 58Fe, and were then followed for ~ 2 years. The abundance of 58Fe and the total iron concentration in the circulation were measured using Multi-collector Inductively-Coupled Plasma Mass Spectrometry and Atomic Absorption Spectroscopy, respectively. The physiologic requirement for iron during pregnancy was then calculated by the formula derived from our previously published work.ResultsThe mean physiologic requirement for iron in the 11 subjects, across their entire pregnancies, was 3.05 mg.d- 1 in total and 44.0 μg.kg- 1.d- 1 after adjustment for body mass. The physiologic requirements for iron in the first, second, and third trimesters were 2.04 mg.d- 1, 3.26 mg.d- 1, and 4.13 mg.d- 1, respectively. When adjusted for body mass, the physiologic requirements for iron in different trimesters were 32.3 μg.kg- 1.d- 1, 46.9 μg.kg- 1.d- 1, and 55.7 μg.kg- 1.d- 1, respectively.ConclusionWe preliminarily explored the physiologic requirement for iron in pregnant women. The data demonstrated that pregnant women needed about twice iron than non-pregnant women. This research may be helpful for the design of future studies and the modification of iron DRIs.Trial registrationChiCTR, ChiCTR-OCH-14004302. Registered 14 February 2014, http://www.chictr.org.cn/showproj.aspx?proj=5267.

Dataset Information

Pharmacokinetic analysis of continuous erythropoietin receptor activator disposition in adult sheep using a target-mediated, physiologic recirculation model and a tracer interaction methodology.

Publications

Pharmacokinetic analysis of continuous erythropoietin receptor activator disposition in adult sheep using a target-mediated, physiologic recirculation model and a tracer interaction methodology.

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