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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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Related in: MedlinePlus

Comparable pharmacological response after intravenous and subcutaneous administration. Generation of mean haemoglobin (Hgb) ± standard deviation after intravenous (closed symbols) and (open symbols) subcutaneous administration every 3 weeks to male rats. Animals were dosed with vehicle (circles), 0.1 (squares), 1.0 (triangles), or 10 (diamonds) mg/kg. Arrows denote administration days. Each point represents the mean of 9–10 animals through Day 90 and 5–10 animals for Day 104.
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fig02: Comparable pharmacological response after intravenous and subcutaneous administration. Generation of mean haemoglobin (Hgb) ± standard deviation after intravenous (closed symbols) and (open symbols) subcutaneous administration every 3 weeks to male rats. Animals were dosed with vehicle (circles), 0.1 (squares), 1.0 (triangles), or 10 (diamonds) mg/kg. Arrows denote administration days. Each point represents the mean of 9–10 animals through Day 90 and 5–10 animals for Day 104.

Mentions: Comparable pharmacological responses, with respect to haematopoiesis, were observed when Hematide was administered to rats via the subcutaneous or intravenous routes every 3 weeks for a total of five injections. Following administration of Hematide, there was a dose-dependent increase in haemoglobin level, the magnitude of which was similar between intravenous and subcutaneous administration at each respective dose level and for each respective time-point evaluated. Day 90 haemoglobin values in male rats are representative of the comparability in the pharmacological response for intravenous and subcutaneous administration of Hematide. Subcutaneous dosing resulted in haemoglobin increases of 2.7, 4.5 and 6.9 g/dl over concurrent controls for 0.1, 1 and 10 mg Hematide/kg, respectively, compared to 2.8, 5.7 and 7.4 g/dl increases, respectively, for intravenous dosing. Figure 2 illustrates the temporal relationship between haemoglobin increases and duration of dosing and number of doses following intravenous and subcutaneous Hematide administration.


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)

Comparable pharmacological response after intravenous and subcutaneous administration. Generation of mean haemoglobin (Hgb) ± standard deviation after intravenous (closed symbols) and (open symbols) subcutaneous administration every 3 weeks to male rats. Animals were dosed with vehicle (circles), 0.1 (squares), 1.0 (triangles), or 10 (diamonds) mg/kg. Arrows denote administration days. Each point represents the mean of 9–10 animals through Day 90 and 5–10 animals for Day 104.
© Copyright Policy
Related In: Results  -  Collection

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

fig02: Comparable pharmacological response after intravenous and subcutaneous administration. Generation of mean haemoglobin (Hgb) ± standard deviation after intravenous (closed symbols) and (open symbols) subcutaneous administration every 3 weeks to male rats. Animals were dosed with vehicle (circles), 0.1 (squares), 1.0 (triangles), or 10 (diamonds) mg/kg. Arrows denote administration days. Each point represents the mean of 9–10 animals through Day 90 and 5–10 animals for Day 104.
Mentions: Comparable pharmacological responses, with respect to haematopoiesis, were observed when Hematide was administered to rats via the subcutaneous or intravenous routes every 3 weeks for a total of five injections. Following administration of Hematide, there was a dose-dependent increase in haemoglobin level, the magnitude of which was similar between intravenous and subcutaneous administration at each respective dose level and for each respective time-point evaluated. Day 90 haemoglobin values in male rats are representative of the comparability in the pharmacological response for intravenous and subcutaneous administration of Hematide. Subcutaneous dosing resulted in haemoglobin increases of 2.7, 4.5 and 6.9 g/dl over concurrent controls for 0.1, 1 and 10 mg Hematide/kg, respectively, compared to 2.8, 5.7 and 7.4 g/dl increases, respectively, for intravenous dosing. Figure 2 illustrates the temporal relationship between haemoglobin increases and duration of dosing and number of doses following intravenous and subcutaneous Hematide administration.

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