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A novel nasal powder formulation of glucagon: toxicology studies in animal models.

Reno FE, Normand P, McInally K, Silo S, Stotland P, Triest M, Carballo D, Piché C - BMC Pharmacol Toxicol (2015)

Bottom Line: In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects.The studies reported here revealed no safety concerns associated with GNP in animal models.This novel drug product is well tolerated in animal models.

View Article: PubMed Central - PubMed

Affiliation: , 130 Macaw Lane, Merritt Island, FL, 32952, USA. freno1@cfl.rr.com.

ABSTRACT

Background: Glucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic glucagon (10% w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety of this formulation was evaluated in four studies in animal models.

Methods: The first study evaluated 28-day sub-chronic toxicology in rats treated intranasally with 1 and 2 mg of GNP/day (0.1 and 0.2 mg glucagon/rat/day). The second study evaluated 28-day sub-chronic toxicology in dogs administered 20 and 40 mg of formulation/dog/day (2 and 4 mg glucagon/dog/day) intranasally. A pulmonary insufflation study assessed acute toxicology following intra-tracheal administration of 0.5 mg of GNP (0.05 mg glucagon) to rats. Local tolerance to 30 mg of GNP (equivalent to 3 mg glucagon, the final dose for humans) was tested through direct administration into the eyes of rabbits.

Results: There were no test article-related adverse effects on body weight and/or food consumption, ophthalmology, electrocardiography, hematology, coagulation parameters, clinical chemistry, urinalysis, or organ weights, and no macroscopic findings at necropsy in any study. In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects. In dogs, the only adverse findings following sub-chronic use were transient (<30 s) salivation and sneezing immediately post-treatment and mild to moderate reversible histological changes to the nasal mucosa. Daily dosing over 28 days in rats resulted in mild to moderate, unilateral or bilateral erosion/ulceration of the olfactory epithelium, frequently with minimal to mild, acute to sub-acute inflammation of the lamina propria at the dorsal turbinates of the nasal cavity in 2/10 males and 3/10 females in the high-dose group (0.2 mg glucagon/day). These lesions resolved completely over 14 days. Histological examination of tissues from both sub-chronic studies in dogs and rats revealed no microscopic findings. In rabbits, clinical observations noted in the GNP-treated eye and/or surrounding areas included ≥1 of the following: clear discharge, red conjunctiva, partial closure, and swelling of the peri-orbital area, which correlated with erythema and edema noted during ocular observations and grading.

Discussion: The studies reported here revealed no safety concerns associated with GNP in animal models. Studies published earlier have highlighted the local safety profile of intranasally administered cyclodextrins (a component of GNP). The choline group, the phosphate group, and the saturated 12-carbon aliphatic chain that are present in the dodecylphosphocholine excipient used in GNP are all present in the phospholipids and lecithins seen ubiquitously in mammalian cell membranes and are unlikely to pose safety concerns; this notion is supported by several studies conducted by the authors that revealed no safety concerns. Taken together, these results suggest that intranasal delivery of GNP holds promise as a future rescue medication for use by caregivers to treat insulin-induced hypoglycemic episodes in patients with type 1 or type 2 diabetes.

Conclusion: This novel drug product is well tolerated in animal models.

No MeSH data available.


Related in: MedlinePlus

Mean (+ SE) glucagon serum concentration profiles in rats following a single intra-nasal administration—Day 1. Glucagon concentrations on Day 1 (linear scale, gender combined). Levels were below the lower limit of quantification (LLOQ, 200 pg/mL) in all samples collected from rats in the control groups and low- and high-dose groups prior to dosing on Day 1. Following the first intra-nasal drug administration on Day 1, only four of 12 animals in the low-dose GNP group displayed levels of glucagon above the LLOQ. Following a single high-dose GNP intra-nasal administration, all animals (12 of 12) displayed levels above LLOQ on at least one occasion, and mean glucagon concentration levels increased quickly in rat serum to reach peak levels within 10 min and declined over the sampling interval
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Fig2: Mean (+ SE) glucagon serum concentration profiles in rats following a single intra-nasal administration—Day 1. Glucagon concentrations on Day 1 (linear scale, gender combined). Levels were below the lower limit of quantification (LLOQ, 200 pg/mL) in all samples collected from rats in the control groups and low- and high-dose groups prior to dosing on Day 1. Following the first intra-nasal drug administration on Day 1, only four of 12 animals in the low-dose GNP group displayed levels of glucagon above the LLOQ. Following a single high-dose GNP intra-nasal administration, all animals (12 of 12) displayed levels above LLOQ on at least one occasion, and mean glucagon concentration levels increased quickly in rat serum to reach peak levels within 10 min and declined over the sampling interval

Mentions: Levels of glucagon were below the lower limit of quantification (LLOQ, 200 pg/mL) in all serum samples collected from rats in the control groups, and low- and high-dose groups prior to dosing on Day 1. Following the first intra-nasal (IN) administration on Day 1, only 4 of 12 animals in the low-dose group displayed levels of glucagon above LLOQ while 12 of 12 animals in the high-dose group displayed levels above LLOQ on at least one occasion. The mean glucagon concentration levels increased quickly in rat serum to reach peak levels within 10 min and declined over the sampling interval in both treated groups, but peak levels were higher in the high-dose group. Following Day 1 administration, mean systemic exposure (AUC0-t) to glucagon increased with dose (8095 vs. 172,893 pg.min/mL, for the low- and high-dose groups, respectively) and mean peak glucagon was observed 10 min after dosing and increased with dose (390 vs. 9961 pg/mL, for the low- and high-dose groups, respectively) (Fig. 2, Table 2).Fig. 2


A novel nasal powder formulation of glucagon: toxicology studies in animal models.

Reno FE, Normand P, McInally K, Silo S, Stotland P, Triest M, Carballo D, Piché C - BMC Pharmacol Toxicol (2015)

Mean (+ SE) glucagon serum concentration profiles in rats following a single intra-nasal administration—Day 1. Glucagon concentrations on Day 1 (linear scale, gender combined). Levels were below the lower limit of quantification (LLOQ, 200 pg/mL) in all samples collected from rats in the control groups and low- and high-dose groups prior to dosing on Day 1. Following the first intra-nasal drug administration on Day 1, only four of 12 animals in the low-dose GNP group displayed levels of glucagon above the LLOQ. Following a single high-dose GNP intra-nasal administration, all animals (12 of 12) displayed levels above LLOQ on at least one occasion, and mean glucagon concentration levels increased quickly in rat serum to reach peak levels within 10 min and declined over the sampling interval
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4621930&req=5

Fig2: Mean (+ SE) glucagon serum concentration profiles in rats following a single intra-nasal administration—Day 1. Glucagon concentrations on Day 1 (linear scale, gender combined). Levels were below the lower limit of quantification (LLOQ, 200 pg/mL) in all samples collected from rats in the control groups and low- and high-dose groups prior to dosing on Day 1. Following the first intra-nasal drug administration on Day 1, only four of 12 animals in the low-dose GNP group displayed levels of glucagon above the LLOQ. Following a single high-dose GNP intra-nasal administration, all animals (12 of 12) displayed levels above LLOQ on at least one occasion, and mean glucagon concentration levels increased quickly in rat serum to reach peak levels within 10 min and declined over the sampling interval
Mentions: Levels of glucagon were below the lower limit of quantification (LLOQ, 200 pg/mL) in all serum samples collected from rats in the control groups, and low- and high-dose groups prior to dosing on Day 1. Following the first intra-nasal (IN) administration on Day 1, only 4 of 12 animals in the low-dose group displayed levels of glucagon above LLOQ while 12 of 12 animals in the high-dose group displayed levels above LLOQ on at least one occasion. The mean glucagon concentration levels increased quickly in rat serum to reach peak levels within 10 min and declined over the sampling interval in both treated groups, but peak levels were higher in the high-dose group. Following Day 1 administration, mean systemic exposure (AUC0-t) to glucagon increased with dose (8095 vs. 172,893 pg.min/mL, for the low- and high-dose groups, respectively) and mean peak glucagon was observed 10 min after dosing and increased with dose (390 vs. 9961 pg/mL, for the low- and high-dose groups, respectively) (Fig. 2, Table 2).Fig. 2

Bottom Line: In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects.The studies reported here revealed no safety concerns associated with GNP in animal models.This novel drug product is well tolerated in animal models.

View Article: PubMed Central - PubMed

Affiliation: , 130 Macaw Lane, Merritt Island, FL, 32952, USA. freno1@cfl.rr.com.

ABSTRACT

Background: Glucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic glucagon (10% w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety of this formulation was evaluated in four studies in animal models.

Methods: The first study evaluated 28-day sub-chronic toxicology in rats treated intranasally with 1 and 2 mg of GNP/day (0.1 and 0.2 mg glucagon/rat/day). The second study evaluated 28-day sub-chronic toxicology in dogs administered 20 and 40 mg of formulation/dog/day (2 and 4 mg glucagon/dog/day) intranasally. A pulmonary insufflation study assessed acute toxicology following intra-tracheal administration of 0.5 mg of GNP (0.05 mg glucagon) to rats. Local tolerance to 30 mg of GNP (equivalent to 3 mg glucagon, the final dose for humans) was tested through direct administration into the eyes of rabbits.

Results: There were no test article-related adverse effects on body weight and/or food consumption, ophthalmology, electrocardiography, hematology, coagulation parameters, clinical chemistry, urinalysis, or organ weights, and no macroscopic findings at necropsy in any study. In rats, direct intra-tracheal insufflation at a dose of 0.5 mg of GNP/rat (0.05 mg glucagon/rat) did not result in adverse clinical, macroscopic, or microscopic effects. In dogs, the only adverse findings following sub-chronic use were transient (<30 s) salivation and sneezing immediately post-treatment and mild to moderate reversible histological changes to the nasal mucosa. Daily dosing over 28 days in rats resulted in mild to moderate, unilateral or bilateral erosion/ulceration of the olfactory epithelium, frequently with minimal to mild, acute to sub-acute inflammation of the lamina propria at the dorsal turbinates of the nasal cavity in 2/10 males and 3/10 females in the high-dose group (0.2 mg glucagon/day). These lesions resolved completely over 14 days. Histological examination of tissues from both sub-chronic studies in dogs and rats revealed no microscopic findings. In rabbits, clinical observations noted in the GNP-treated eye and/or surrounding areas included ≥1 of the following: clear discharge, red conjunctiva, partial closure, and swelling of the peri-orbital area, which correlated with erythema and edema noted during ocular observations and grading.

Discussion: The studies reported here revealed no safety concerns associated with GNP in animal models. Studies published earlier have highlighted the local safety profile of intranasally administered cyclodextrins (a component of GNP). The choline group, the phosphate group, and the saturated 12-carbon aliphatic chain that are present in the dodecylphosphocholine excipient used in GNP are all present in the phospholipids and lecithins seen ubiquitously in mammalian cell membranes and are unlikely to pose safety concerns; this notion is supported by several studies conducted by the authors that revealed no safety concerns. Taken together, these results suggest that intranasal delivery of GNP holds promise as a future rescue medication for use by caregivers to treat insulin-induced hypoglycemic episodes in patients with type 1 or type 2 diabetes.

Conclusion: This novel drug product is well tolerated in animal models.

No MeSH data available.


Related in: MedlinePlus