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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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Reticulocyte and platelet profiles in female (left) and male rats (right) after intravenous administration of vehicle (○), 0.1 (•), 1.0 (□) or 10 (▪) mg Hematide/kg every 3 weeks for 10 administrations followed by a 6-week recovery. Data are represented as mean values ± standard deviation. Arrows denote days of administration. For 0 through 1 mg/kg, 8 to 10 rats were sampled per dose per time-point through Days 188, Day 195 represented 18–20 animals while the remaining time-points represented 4–5 animals. Five to 10 rats were sampled per dose group for each time-point for the 10 mg/kg group. Results show a synchronicity with dosing; when sampling times occurred soon after dosing (Days 90 and 195/196, 5 days after administration) elevations in parameters are observed.
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fig04: Reticulocyte and platelet profiles in female (left) and male rats (right) after intravenous administration of vehicle (○), 0.1 (•), 1.0 (□) or 10 (▪) mg Hematide/kg every 3 weeks for 10 administrations followed by a 6-week recovery. Data are represented as mean values ± standard deviation. Arrows denote days of administration. For 0 through 1 mg/kg, 8 to 10 rats were sampled per dose per time-point through Days 188, Day 195 represented 18–20 animals while the remaining time-points represented 4–5 animals. Five to 10 rats were sampled per dose group for each time-point for the 10 mg/kg group. Results show a synchronicity with dosing; when sampling times occurred soon after dosing (Days 90 and 195/196, 5 days after administration) elevations in parameters are observed.

Mentions: Consistent with the stimulation of the red blood cell precursors and as expected for an erythropoiesis-stimulating agent, intravenous and subcutaneous Hematide induced reticulocytosis. The observed drug-induced changes on reticulocyte numbers were dependent upon sampling time in relationship to when the animals were dosed. Figure 4 depicts the changes in reticulocytes after intravenous administration. When blood samples were collected approximately 5–6 days after dose administration (terminal necropsies on Days 90 and 195/196), reticulocytes were significantly increased from controls at all Hematide dose levels. A compensatory decrease in reticulocytes, however, was observed when blood samples were collected approximately 3 weeks after dose administration. Reticulocyte numbers were typically less than control values 3 weeks after dosing, apparently in response to the increase in red blood cell numbers. Return of reticulocytes numbers towards vehicle-control values was observed following a 6-week recovery period in the groups administered 0.1 mg Hematide/kg, while rats at 1.0 mg Hematide/kg remained slightly decreased compared to concurrent controls in both sexes.


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)

Reticulocyte and platelet profiles in female (left) and male rats (right) after intravenous administration of vehicle (○), 0.1 (•), 1.0 (□) or 10 (▪) mg Hematide/kg every 3 weeks for 10 administrations followed by a 6-week recovery. Data are represented as mean values ± standard deviation. Arrows denote days of administration. For 0 through 1 mg/kg, 8 to 10 rats were sampled per dose per time-point through Days 188, Day 195 represented 18–20 animals while the remaining time-points represented 4–5 animals. Five to 10 rats were sampled per dose group for each time-point for the 10 mg/kg group. Results show a synchronicity with dosing; when sampling times occurred soon after dosing (Days 90 and 195/196, 5 days after administration) elevations in parameters are observed.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2667308&req=5

fig04: Reticulocyte and platelet profiles in female (left) and male rats (right) after intravenous administration of vehicle (○), 0.1 (•), 1.0 (□) or 10 (▪) mg Hematide/kg every 3 weeks for 10 administrations followed by a 6-week recovery. Data are represented as mean values ± standard deviation. Arrows denote days of administration. For 0 through 1 mg/kg, 8 to 10 rats were sampled per dose per time-point through Days 188, Day 195 represented 18–20 animals while the remaining time-points represented 4–5 animals. Five to 10 rats were sampled per dose group for each time-point for the 10 mg/kg group. Results show a synchronicity with dosing; when sampling times occurred soon after dosing (Days 90 and 195/196, 5 days after administration) elevations in parameters are observed.
Mentions: Consistent with the stimulation of the red blood cell precursors and as expected for an erythropoiesis-stimulating agent, intravenous and subcutaneous Hematide induced reticulocytosis. The observed drug-induced changes on reticulocyte numbers were dependent upon sampling time in relationship to when the animals were dosed. Figure 4 depicts the changes in reticulocytes after intravenous administration. When blood samples were collected approximately 5–6 days after dose administration (terminal necropsies on Days 90 and 195/196), reticulocytes were significantly increased from controls at all Hematide dose levels. A compensatory decrease in reticulocytes, however, was observed when blood samples were collected approximately 3 weeks after dose administration. Reticulocyte numbers were typically less than control values 3 weeks after dosing, apparently in response to the increase in red blood cell numbers. Return of reticulocytes numbers towards vehicle-control values was observed following a 6-week recovery period in the groups administered 0.1 mg Hematide/kg, while rats at 1.0 mg Hematide/kg remained slightly decreased compared to concurrent controls in both sexes.

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