Preliminary pharmacokinetics of intravenous and subcutaneous dolasetron and pharmacodynamics of subcutaneous dolasetron in healthy cats

Andrea K. Herndon, Jessica M. Quimby, Liberty G. Sieberg, Leigh Davis, Amber L. Caress, Sabina Ligas, Ryan J. Hansen, Luke A. Wittenburg, Danial L. Gustafson

Research output: Contribution to journalArticle

Abstract

Objectives: The objectives were to evaluate the pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) dolasetron and the pharmacodynamics (PDs) of SC dolasetron in healthy cats. Methods: Five cats with unremarkable complete blood count, serum biochemistry and urinalyses were utilized. In the PK study, cats received 0.8 mg/kg SC and IV dolasetron in a crossover format. Serum samples were obtained via a jugular catheter at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the administration of dolasetron. Dolasetron and the active metabolite hydrodolasetron were measured using liquid chromatography/tandem mass spectrometry. Non-compartmental PK analysis was performed. In the PD study, SC dolasetron (0.8 mg/kg and 1.0 mg/kg) and saline were administered 30 mins prior to administration of 0.44 mg/kg intramuscular xylazine in a randomized three-way crossover. Number of emetic events, lip licks, time to onset of emesis and visual nausea score were scored by a blinded observer. Results: In the PK study, dolasetron was quickly metabolized to the active metabolite hydrodolasetron, limiting assessment of dolasetron PK parameters. Median (range) PK parameters for IV hydrodolasetron were as follows: maximum serum concentration (Cmax) 116 ng/ml (69–316 ng/ml), time to maximum concentration (Tmax) 0.5 h (0.3–0.5 h), half-life 3.3 h (2.9–7.2 h) and area under the curve until the last measurable concentration (AUClast) 323 h/ng/ml (138–454 h/ng/ml). Median (range) PK parameters for SC hydrodolasetron were as follows: Cmax 67.9 ng/ml (60.4–117 ng/ml), Tmax 0.5 h (0.5–1.0 h), half-life 3.8 h (2.9–5.3 h) and AUClast 437 h/ng/ml (221.5–621.8 h/ng/ml). There was no significant difference in exposure to hydrodolasetron between the routes of administration. With regard to PD, when dolasetron was administered prior to xylazine, there was no significant difference in the mean number of emetic events, lip licks, time to onset of emesis or visual nausea score when compared with saline. Conclusions and relevance: Administration of 0.8 mg/kg dolasetron does not maintain serum concentrations of active metabolite for 24 h. Administration of dolasetron at 0.8 mg/kg and 1 mg/kg did not prevent xylazine-induced vomiting. Additional feline dose studies are needed to determine if a higher dose is efficacious.

Original languageEnglish (US)
JournalJournal of Feline Medicine and Surgery
DOIs
StateAccepted/In press - Sep 1 2017

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pharmacology
pharmacokinetics
Cats
Pharmacokinetics
cats
xylazine
blood serum
emetics
Xylazine
nausea
lips
metabolites
half life
Emetics
Vomiting
Lip
Serum
urinalysis
Nausea
Half-Life

ASJC Scopus subject areas

  • Small Animals

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Preliminary pharmacokinetics of intravenous and subcutaneous dolasetron and pharmacodynamics of subcutaneous dolasetron in healthy cats. / Herndon, Andrea K.; Quimby, Jessica M.; Sieberg, Liberty G.; Davis, Leigh; Caress, Amber L.; Ligas, Sabina; Hansen, Ryan J.; Wittenburg, Luke A.; Gustafson, Danial L.

In: Journal of Feline Medicine and Surgery, 01.09.2017.

Research output: Contribution to journalArticle

Herndon, Andrea K. ; Quimby, Jessica M. ; Sieberg, Liberty G. ; Davis, Leigh ; Caress, Amber L. ; Ligas, Sabina ; Hansen, Ryan J. ; Wittenburg, Luke A. ; Gustafson, Danial L. / Preliminary pharmacokinetics of intravenous and subcutaneous dolasetron and pharmacodynamics of subcutaneous dolasetron in healthy cats. In: Journal of Feline Medicine and Surgery. 2017.
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title = "Preliminary pharmacokinetics of intravenous and subcutaneous dolasetron and pharmacodynamics of subcutaneous dolasetron in healthy cats",
abstract = "Objectives: The objectives were to evaluate the pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) dolasetron and the pharmacodynamics (PDs) of SC dolasetron in healthy cats. Methods: Five cats with unremarkable complete blood count, serum biochemistry and urinalyses were utilized. In the PK study, cats received 0.8 mg/kg SC and IV dolasetron in a crossover format. Serum samples were obtained via a jugular catheter at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the administration of dolasetron. Dolasetron and the active metabolite hydrodolasetron were measured using liquid chromatography/tandem mass spectrometry. Non-compartmental PK analysis was performed. In the PD study, SC dolasetron (0.8 mg/kg and 1.0 mg/kg) and saline were administered 30 mins prior to administration of 0.44 mg/kg intramuscular xylazine in a randomized three-way crossover. Number of emetic events, lip licks, time to onset of emesis and visual nausea score were scored by a blinded observer. Results: In the PK study, dolasetron was quickly metabolized to the active metabolite hydrodolasetron, limiting assessment of dolasetron PK parameters. Median (range) PK parameters for IV hydrodolasetron were as follows: maximum serum concentration (Cmax) 116 ng/ml (69–316 ng/ml), time to maximum concentration (Tmax) 0.5 h (0.3–0.5 h), half-life 3.3 h (2.9–7.2 h) and area under the curve until the last measurable concentration (AUClast) 323 h/ng/ml (138–454 h/ng/ml). Median (range) PK parameters for SC hydrodolasetron were as follows: Cmax 67.9 ng/ml (60.4–117 ng/ml), Tmax 0.5 h (0.5–1.0 h), half-life 3.8 h (2.9–5.3 h) and AUClast 437 h/ng/ml (221.5–621.8 h/ng/ml). There was no significant difference in exposure to hydrodolasetron between the routes of administration. With regard to PD, when dolasetron was administered prior to xylazine, there was no significant difference in the mean number of emetic events, lip licks, time to onset of emesis or visual nausea score when compared with saline. Conclusions and relevance: Administration of 0.8 mg/kg dolasetron does not maintain serum concentrations of active metabolite for 24 h. Administration of dolasetron at 0.8 mg/kg and 1 mg/kg did not prevent xylazine-induced vomiting. Additional feline dose studies are needed to determine if a higher dose is efficacious.",
author = "Herndon, {Andrea K.} and Quimby, {Jessica M.} and Sieberg, {Liberty G.} and Leigh Davis and Caress, {Amber L.} and Sabina Ligas and Hansen, {Ryan J.} and Wittenburg, {Luke A.} and Gustafson, {Danial L.}",
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T1 - Preliminary pharmacokinetics of intravenous and subcutaneous dolasetron and pharmacodynamics of subcutaneous dolasetron in healthy cats

AU - Herndon, Andrea K.

AU - Quimby, Jessica M.

AU - Sieberg, Liberty G.

AU - Davis, Leigh

AU - Caress, Amber L.

AU - Ligas, Sabina

AU - Hansen, Ryan J.

AU - Wittenburg, Luke A.

AU - Gustafson, Danial L.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Objectives: The objectives were to evaluate the pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) dolasetron and the pharmacodynamics (PDs) of SC dolasetron in healthy cats. Methods: Five cats with unremarkable complete blood count, serum biochemistry and urinalyses were utilized. In the PK study, cats received 0.8 mg/kg SC and IV dolasetron in a crossover format. Serum samples were obtained via a jugular catheter at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the administration of dolasetron. Dolasetron and the active metabolite hydrodolasetron were measured using liquid chromatography/tandem mass spectrometry. Non-compartmental PK analysis was performed. In the PD study, SC dolasetron (0.8 mg/kg and 1.0 mg/kg) and saline were administered 30 mins prior to administration of 0.44 mg/kg intramuscular xylazine in a randomized three-way crossover. Number of emetic events, lip licks, time to onset of emesis and visual nausea score were scored by a blinded observer. Results: In the PK study, dolasetron was quickly metabolized to the active metabolite hydrodolasetron, limiting assessment of dolasetron PK parameters. Median (range) PK parameters for IV hydrodolasetron were as follows: maximum serum concentration (Cmax) 116 ng/ml (69–316 ng/ml), time to maximum concentration (Tmax) 0.5 h (0.3–0.5 h), half-life 3.3 h (2.9–7.2 h) and area under the curve until the last measurable concentration (AUClast) 323 h/ng/ml (138–454 h/ng/ml). Median (range) PK parameters for SC hydrodolasetron were as follows: Cmax 67.9 ng/ml (60.4–117 ng/ml), Tmax 0.5 h (0.5–1.0 h), half-life 3.8 h (2.9–5.3 h) and AUClast 437 h/ng/ml (221.5–621.8 h/ng/ml). There was no significant difference in exposure to hydrodolasetron between the routes of administration. With regard to PD, when dolasetron was administered prior to xylazine, there was no significant difference in the mean number of emetic events, lip licks, time to onset of emesis or visual nausea score when compared with saline. Conclusions and relevance: Administration of 0.8 mg/kg dolasetron does not maintain serum concentrations of active metabolite for 24 h. Administration of dolasetron at 0.8 mg/kg and 1 mg/kg did not prevent xylazine-induced vomiting. Additional feline dose studies are needed to determine if a higher dose is efficacious.

AB - Objectives: The objectives were to evaluate the pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) dolasetron and the pharmacodynamics (PDs) of SC dolasetron in healthy cats. Methods: Five cats with unremarkable complete blood count, serum biochemistry and urinalyses were utilized. In the PK study, cats received 0.8 mg/kg SC and IV dolasetron in a crossover format. Serum samples were obtained via a jugular catheter at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 h after the administration of dolasetron. Dolasetron and the active metabolite hydrodolasetron were measured using liquid chromatography/tandem mass spectrometry. Non-compartmental PK analysis was performed. In the PD study, SC dolasetron (0.8 mg/kg and 1.0 mg/kg) and saline were administered 30 mins prior to administration of 0.44 mg/kg intramuscular xylazine in a randomized three-way crossover. Number of emetic events, lip licks, time to onset of emesis and visual nausea score were scored by a blinded observer. Results: In the PK study, dolasetron was quickly metabolized to the active metabolite hydrodolasetron, limiting assessment of dolasetron PK parameters. Median (range) PK parameters for IV hydrodolasetron were as follows: maximum serum concentration (Cmax) 116 ng/ml (69–316 ng/ml), time to maximum concentration (Tmax) 0.5 h (0.3–0.5 h), half-life 3.3 h (2.9–7.2 h) and area under the curve until the last measurable concentration (AUClast) 323 h/ng/ml (138–454 h/ng/ml). Median (range) PK parameters for SC hydrodolasetron were as follows: Cmax 67.9 ng/ml (60.4–117 ng/ml), Tmax 0.5 h (0.5–1.0 h), half-life 3.8 h (2.9–5.3 h) and AUClast 437 h/ng/ml (221.5–621.8 h/ng/ml). There was no significant difference in exposure to hydrodolasetron between the routes of administration. With regard to PD, when dolasetron was administered prior to xylazine, there was no significant difference in the mean number of emetic events, lip licks, time to onset of emesis or visual nausea score when compared with saline. Conclusions and relevance: Administration of 0.8 mg/kg dolasetron does not maintain serum concentrations of active metabolite for 24 h. Administration of dolasetron at 0.8 mg/kg and 1 mg/kg did not prevent xylazine-induced vomiting. Additional feline dose studies are needed to determine if a higher dose is efficacious.

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