Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

Jeanne C. Larson, Sara D. Allstadt, Timothy M. Fan, Chand Khanna, Paul J. Lunghofer, Ryan J. Hansen, Daniel L.PHD Gustafson, Alfred M. Legendre, Gina D. Galyon, Amy K. LeBlanc, Tomas Martin-Jimenez

Research output: Contribution to journalArticle

Abstract

OBJECTIVE To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. ANIMALS 5 healthy purpose-bred hounds. PROCEDURES The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received rapamycin (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography–tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and noncompartmental analyses. RESULTS Mean ± SD blood rapamycin terminal half-life, area under the concentrationtime curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/ mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in nanograms per milliliter. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, need to be determined.

Original languageEnglish (US)
Pages (from-to)65-71
Number of pages7
JournalAmerican journal of veterinary research
Volume77
Issue number1
DOIs
StatePublished - Jan 2016

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Sirolimus
pharmacokinetics
Pharmacokinetics
Dogs
dogs
blood
dosage
hounds
oral administration
half life
Therapeutic Uses
mass spectrometry
toxicity
breeds
Area Under Curve
sampling
Oral Administration
Half-Life
therapeutics
neoplasms

ASJC Scopus subject areas

  • veterinary(all)

Cite this

Larson, J. C., Allstadt, S. D., Fan, T. M., Khanna, C., Lunghofer, P. J., Hansen, R. J., ... Martin-Jimenez, T. (2016). Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs. American journal of veterinary research, 77(1), 65-71. https://doi.org/10.2460/ajvr.77.1.65

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs. / Larson, Jeanne C.; Allstadt, Sara D.; Fan, Timothy M.; Khanna, Chand; Lunghofer, Paul J.; Hansen, Ryan J.; Gustafson, Daniel L.PHD; Legendre, Alfred M.; Galyon, Gina D.; LeBlanc, Amy K.; Martin-Jimenez, Tomas.

In: American journal of veterinary research, Vol. 77, No. 1, 01.2016, p. 65-71.

Research output: Contribution to journalArticle

Larson, JC, Allstadt, SD, Fan, TM, Khanna, C, Lunghofer, PJ, Hansen, RJ, Gustafson, DLPHD, Legendre, AM, Galyon, GD, LeBlanc, AK & Martin-Jimenez, T 2016, 'Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs', American journal of veterinary research, vol. 77, no. 1, pp. 65-71. https://doi.org/10.2460/ajvr.77.1.65
Larson, Jeanne C. ; Allstadt, Sara D. ; Fan, Timothy M. ; Khanna, Chand ; Lunghofer, Paul J. ; Hansen, Ryan J. ; Gustafson, Daniel L.PHD ; Legendre, Alfred M. ; Galyon, Gina D. ; LeBlanc, Amy K. ; Martin-Jimenez, Tomas. / Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs. In: American journal of veterinary research. 2016 ; Vol. 77, No. 1. pp. 65-71.
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abstract = "OBJECTIVE To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. ANIMALS 5 healthy purpose-bred hounds. PROCEDURES The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received rapamycin (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography–tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and noncompartmental analyses. RESULTS Mean ± SD blood rapamycin terminal half-life, area under the concentrationtime curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/ mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in nanograms per milliliter. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, need to be determined.",
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AU - Hansen, Ryan J.

AU - Gustafson, Daniel L.PHD

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N2 - OBJECTIVE To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. ANIMALS 5 healthy purpose-bred hounds. PROCEDURES The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received rapamycin (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography–tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and noncompartmental analyses. RESULTS Mean ± SD blood rapamycin terminal half-life, area under the concentrationtime curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/ mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in nanograms per milliliter. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, need to be determined.

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