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Chronic pharmacological and safety evaluation of Hematide, a PEGylated peptidic erythropoiesis-stimulating agent, in rodents.

Woodburn KW, Wilson SD, Fong KL, Schatz PJ, Spainhour CB, Norton D - Basic Clin. Pharmacol. Toxicol. (2008)

Bottom Line: The primary pharmacology of Hematide resulted in erythroid polycythemia as measured by elevated haemoglobin levels that were time- and dose-dependent.Systemic exposures, based on both area under the curve (AUC) and maximum concentration (C(max)), were substantially greater for intravenous than subcutaneous administration.In conclusion, Hematide is a potent erythropoiesis-stimulating agent, and the studies provide support for the safety of clinical development, including chronic dosing, for the treatment of anaemia associated with chronic renal failure.

View Article: PubMed Central - PubMed

Affiliation: Affymax Inc, Palo Alto, CA, USA. kathryn_woodburn@affymax.com

ABSTRACT
Hematide is a synthetic peptide-based, PEGylated erythropoiesis-stimulating agent, which is being developed for the chronic treatment of anaemia associated with chronic renal failure. To support the safety of long-term dosing of chronic renal failure patients, a comprehensive toxicology programme was implemented including rat subchronic and chronic studies. Rats were administered 0, 0.1, 1 and 10 mg/kg of Hematide every 3 weeks for 3 months via subcutaneous injection or for 6 months via intravenous injection. The dosing period was followed by a 6-week follow-up period. The primary pharmacology of Hematide resulted in erythroid polycythemia as measured by elevated haemoglobin levels that were time- and dose-dependent. The pharmacology profiles were similar regardless of administration route. For example, for male rats at Day 90, subcutaneous dosing resulted in haemoglobin increases of 2.7, 4.5 and 6.9 g/dl for 0.1, 1 and 10 mg Hematide/kg respectively, compared to 2.8, 5.7 and 7.4 g/dl increases for intravenous dosing. Histopathological changes were related to the prolonged severe polycythemia induced in normocythemic animals administered an erythropoiesis-stimulating agent. The findings included extramedullary haematopoiesis in the spleen and liver, bone marrow hypercellularity and organ congestion. Microscopic findings were reversible, demonstrating a return towards control findings within 6 weeks following cessation of dosing. Systemic exposures, based on both area under the curve (AUC) and maximum concentration (C(max)), were substantially greater for intravenous than subcutaneous administration. No Hematide-specific antibodies were detected. In conclusion, Hematide is a potent erythropoiesis-stimulating agent, and the studies provide support for the safety of clinical development, including chronic dosing, for the treatment of anaemia associated with chronic renal failure.

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Iron and bilirubin profiles are consistent with accelerated erythropoiesis, polycythemia, increased red blood cell (RBC) turnover and subsequent recovery. Mean values ± standard deviation after intravenous administration of vehicle every 3 weeks (○), 0.1 (•), 1.0 (□) or 10 (▪) mg Hematide/kg to male rats for 6 months followed by a 6-week recovery. Arrows denote day of administration. Data for RBCs and haemotocrit (Hct) were obtained from the same animals represented in fig. 1. For Fe and bilirubin (TBili) determination, 0 through 1 mg/kg, 10 rats were sampled on Day 1, 9 to 10 on Day 90, 18 to 20 on Day 195 and 5 on Day 232. For the 10 mg/kg groups, 10 animals were sampled on Day 1, 1 on Day 90 and 7 on Day 195.
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fig05: Iron and bilirubin profiles are consistent with accelerated erythropoiesis, polycythemia, increased red blood cell (RBC) turnover and subsequent recovery. Mean values ± standard deviation after intravenous administration of vehicle every 3 weeks (○), 0.1 (•), 1.0 (□) or 10 (▪) mg Hematide/kg to male rats for 6 months followed by a 6-week recovery. Arrows denote day of administration. Data for RBCs and haemotocrit (Hct) were obtained from the same animals represented in fig. 1. For Fe and bilirubin (TBili) determination, 0 through 1 mg/kg, 10 rats were sampled on Day 1, 9 to 10 on Day 90, 18 to 20 on Day 195 and 5 on Day 232. For the 10 mg/kg groups, 10 animals were sampled on Day 1, 1 on Day 90 and 7 on Day 195.

Mentions: Alterations in serum chemistry were generally considered to be secondary to the exaggerated pharmacology of Hematide with findings being reversed after the 6-week recovery periods. Hematide-associated changes were generally similar after intravenous or subcutaneous dose administration. The alterations in serum chemistry included increases in bilirubin and aspartate aminotransferase and an initial decrease and subsequent increase in serum iron. Small increases, deemed toxicologically insignificant, in creatinine levels were observed at Day 195 in the mid-and high-dose groups (0.5 ± 0.09 mg/dl for 10 mg/kg males compared to 0.4 ± 0.02 mg/dl for concurrent controls; 0.6 ± 0.16 mg/dl for 10 mg/kg females compared to 0.5 ± 0.05 mg/dl for concurrent controls, P < 0.05). The changes in bilirubin and serum iron are depicted in fig. 5, and are considered to be secondary sequelae to the marked increases in red blood cells and haemotocrit. The increases in bilirubin and aspartate aminotransferase are likely due to increased erythrocyte turnover secondary to accelerated erythropoiesis and/or red blood cell haemolysis. The initial serum iron depletion on Days 90 and 195 is likely the result of incorporation into haemoglobin during rapid erythrocyte production (e.g. a functional iron deficiency). By Day 232, total serum iron was increased, which likely reflects the release of iron during erythrocyte breakdown secondary to significant polycythemia.


Chronic pharmacological and safety evaluation of Hematide, a PEGylated peptidic erythropoiesis-stimulating agent, in rodents.

Woodburn KW, Wilson SD, Fong KL, Schatz PJ, Spainhour CB, Norton D - Basic Clin. Pharmacol. Toxicol. (2008)

Iron and bilirubin profiles are consistent with accelerated erythropoiesis, polycythemia, increased red blood cell (RBC) turnover and subsequent recovery. Mean values ± standard deviation after intravenous administration of vehicle every 3 weeks (○), 0.1 (•), 1.0 (□) or 10 (▪) mg Hematide/kg to male rats for 6 months followed by a 6-week recovery. Arrows denote day of administration. Data for RBCs and haemotocrit (Hct) were obtained from the same animals represented in fig. 1. For Fe and bilirubin (TBili) determination, 0 through 1 mg/kg, 10 rats were sampled on Day 1, 9 to 10 on Day 90, 18 to 20 on Day 195 and 5 on Day 232. For the 10 mg/kg groups, 10 animals were sampled on Day 1, 1 on Day 90 and 7 on Day 195.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2667308&req=5

fig05: Iron and bilirubin profiles are consistent with accelerated erythropoiesis, polycythemia, increased red blood cell (RBC) turnover and subsequent recovery. Mean values ± standard deviation after intravenous administration of vehicle every 3 weeks (○), 0.1 (•), 1.0 (□) or 10 (▪) mg Hematide/kg to male rats for 6 months followed by a 6-week recovery. Arrows denote day of administration. Data for RBCs and haemotocrit (Hct) were obtained from the same animals represented in fig. 1. For Fe and bilirubin (TBili) determination, 0 through 1 mg/kg, 10 rats were sampled on Day 1, 9 to 10 on Day 90, 18 to 20 on Day 195 and 5 on Day 232. For the 10 mg/kg groups, 10 animals were sampled on Day 1, 1 on Day 90 and 7 on Day 195.
Mentions: Alterations in serum chemistry were generally considered to be secondary to the exaggerated pharmacology of Hematide with findings being reversed after the 6-week recovery periods. Hematide-associated changes were generally similar after intravenous or subcutaneous dose administration. The alterations in serum chemistry included increases in bilirubin and aspartate aminotransferase and an initial decrease and subsequent increase in serum iron. Small increases, deemed toxicologically insignificant, in creatinine levels were observed at Day 195 in the mid-and high-dose groups (0.5 ± 0.09 mg/dl for 10 mg/kg males compared to 0.4 ± 0.02 mg/dl for concurrent controls; 0.6 ± 0.16 mg/dl for 10 mg/kg females compared to 0.5 ± 0.05 mg/dl for concurrent controls, P < 0.05). The changes in bilirubin and serum iron are depicted in fig. 5, and are considered to be secondary sequelae to the marked increases in red blood cells and haemotocrit. The increases in bilirubin and aspartate aminotransferase are likely due to increased erythrocyte turnover secondary to accelerated erythropoiesis and/or red blood cell haemolysis. The initial serum iron depletion on Days 90 and 195 is likely the result of incorporation into haemoglobin during rapid erythrocyte production (e.g. a functional iron deficiency). By Day 232, total serum iron was increased, which likely reflects the release of iron during erythrocyte breakdown secondary to significant polycythemia.

Bottom Line: The primary pharmacology of Hematide resulted in erythroid polycythemia as measured by elevated haemoglobin levels that were time- and dose-dependent.Systemic exposures, based on both area under the curve (AUC) and maximum concentration (C(max)), were substantially greater for intravenous than subcutaneous administration.In conclusion, Hematide is a potent erythropoiesis-stimulating agent, and the studies provide support for the safety of clinical development, including chronic dosing, for the treatment of anaemia associated with chronic renal failure.

View Article: PubMed Central - PubMed

Affiliation: Affymax Inc, Palo Alto, CA, USA. kathryn_woodburn@affymax.com

ABSTRACT
Hematide is a synthetic peptide-based, PEGylated erythropoiesis-stimulating agent, which is being developed for the chronic treatment of anaemia associated with chronic renal failure. To support the safety of long-term dosing of chronic renal failure patients, a comprehensive toxicology programme was implemented including rat subchronic and chronic studies. Rats were administered 0, 0.1, 1 and 10 mg/kg of Hematide every 3 weeks for 3 months via subcutaneous injection or for 6 months via intravenous injection. The dosing period was followed by a 6-week follow-up period. The primary pharmacology of Hematide resulted in erythroid polycythemia as measured by elevated haemoglobin levels that were time- and dose-dependent. The pharmacology profiles were similar regardless of administration route. For example, for male rats at Day 90, subcutaneous dosing resulted in haemoglobin increases of 2.7, 4.5 and 6.9 g/dl for 0.1, 1 and 10 mg Hematide/kg respectively, compared to 2.8, 5.7 and 7.4 g/dl increases for intravenous dosing. Histopathological changes were related to the prolonged severe polycythemia induced in normocythemic animals administered an erythropoiesis-stimulating agent. The findings included extramedullary haematopoiesis in the spleen and liver, bone marrow hypercellularity and organ congestion. Microscopic findings were reversible, demonstrating a return towards control findings within 6 weeks following cessation of dosing. Systemic exposures, based on both area under the curve (AUC) and maximum concentration (C(max)), were substantially greater for intravenous than subcutaneous administration. No Hematide-specific antibodies were detected. In conclusion, Hematide is a potent erythropoiesis-stimulating agent, and the studies provide support for the safety of clinical development, including chronic dosing, for the treatment of anaemia associated with chronic renal failure.

Show MeSH
Related in: MedlinePlus