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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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Dose-and time-dependent increases in haemoglobin (Hgb) after intravenous administration. Male rats received vehicle (○), 0.1 (∂), 1.0 (□) or 10 (▪) mg Hematide/kg/dose every 3 weeks for 6 months. Data are expressed as mean ± standard deviation with arrowheads denoting days of injection. For 0 through 1 mg/kg, 10 rats were sampled per dose per time-point through Day 188, Day 195 represented 18–20 animals while the remaining time-points represented 5 animals. Six to 10 rats were sampled per dose group for each time-point for the 10 mg/kg group.
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fig01: Dose-and time-dependent increases in haemoglobin (Hgb) after intravenous administration. Male rats received vehicle (○), 0.1 (∂), 1.0 (□) or 10 (▪) mg Hematide/kg/dose every 3 weeks for 6 months. Data are expressed as mean ± standard deviation with arrowheads denoting days of injection. For 0 through 1 mg/kg, 10 rats were sampled per dose per time-point through Day 188, Day 195 represented 18–20 animals while the remaining time-points represented 5 animals. Six to 10 rats were sampled per dose group for each time-point for the 10 mg/kg group.

Mentions: Regardless of the route of administration (i.e. intravenous versus subcutaneous), Hematide administration resulted in erythropoiesis, which led to pronounced and sustained polycythemia at the 1 and 10 mg/kg doses. The effect of intravenous Hematide administration every 3 weeks for 6 months on haemoglobin levels in normocythemic male rats is depicted in fig. 1. In addition, the figure delineates the time-course for the reversibility of the Hematide-induced haemoglobin increases following the 6-week recovery period. By Day 125, the haemoglobin levels in the 0.1, 1, and 10 mg/kg groups were 18.9 ± 0.73, 22.9 ± 0.75, and 25.4 ± 1.40 g/dl, which reflect a increase of 1.6, 5.6, and 8.1 g Hgb/dl, respectively, over the concurrent vehicle control group (17.3 g/dl). The changes in haematology had reversed following cessation of treatment (Day 190).


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)

Dose-and time-dependent increases in haemoglobin (Hgb) after intravenous administration. Male rats received vehicle (○), 0.1 (∂), 1.0 (□) or 10 (▪) mg Hematide/kg/dose every 3 weeks for 6 months. Data are expressed as mean ± standard deviation with arrowheads denoting days of injection. For 0 through 1 mg/kg, 10 rats were sampled per dose per time-point through Day 188, Day 195 represented 18–20 animals while the remaining time-points represented 5 animals. Six to 10 rats were sampled per dose group for each time-point for the 10 mg/kg group.
© Copyright Policy
Related In: Results  -  Collection

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

fig01: Dose-and time-dependent increases in haemoglobin (Hgb) after intravenous administration. Male rats received vehicle (○), 0.1 (∂), 1.0 (□) or 10 (▪) mg Hematide/kg/dose every 3 weeks for 6 months. Data are expressed as mean ± standard deviation with arrowheads denoting days of injection. For 0 through 1 mg/kg, 10 rats were sampled per dose per time-point through Day 188, Day 195 represented 18–20 animals while the remaining time-points represented 5 animals. Six to 10 rats were sampled per dose group for each time-point for the 10 mg/kg group.
Mentions: Regardless of the route of administration (i.e. intravenous versus subcutaneous), Hematide administration resulted in erythropoiesis, which led to pronounced and sustained polycythemia at the 1 and 10 mg/kg doses. The effect of intravenous Hematide administration every 3 weeks for 6 months on haemoglobin levels in normocythemic male rats is depicted in fig. 1. In addition, the figure delineates the time-course for the reversibility of the Hematide-induced haemoglobin increases following the 6-week recovery period. By Day 125, the haemoglobin levels in the 0.1, 1, and 10 mg/kg groups were 18.9 ± 0.73, 22.9 ± 0.75, and 25.4 ± 1.40 g/dl, which reflect a increase of 1.6, 5.6, and 8.1 g Hgb/dl, respectively, over the concurrent vehicle control group (17.3 g/dl). The changes in haematology had reversed following cessation of treatment (Day 190).

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