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Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations

BACKGROUND: For medication control in several jurisdictions, withdrawal time is the period of refrain from racing after drug administration. It is set by adding a safety period to an experimental detection time. However, there are no reports of statistical analyses of detection time for the determin...

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Autores principales: Kuroda, Taisuke, Minamijima, Yohei, Nomura, Motoi, Yamashita, Shozo, Yamada, Masayuki, Nagata, Shunichi, Mita, Hiroshi, Tamura, Norihisa, Fukuda, Kentaro, Kuwano, Atsutoshi, Kusano, Kanichi, Toutain, Pierre‐Louis, Sato, Fumio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546317/
https://www.ncbi.nlm.nih.gov/pubmed/34719043
http://dx.doi.org/10.1111/evj.13532
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author Kuroda, Taisuke
Minamijima, Yohei
Nomura, Motoi
Yamashita, Shozo
Yamada, Masayuki
Nagata, Shunichi
Mita, Hiroshi
Tamura, Norihisa
Fukuda, Kentaro
Kuwano, Atsutoshi
Kusano, Kanichi
Toutain, Pierre‐Louis
Sato, Fumio
author_facet Kuroda, Taisuke
Minamijima, Yohei
Nomura, Motoi
Yamashita, Shozo
Yamada, Masayuki
Nagata, Shunichi
Mita, Hiroshi
Tamura, Norihisa
Fukuda, Kentaro
Kuwano, Atsutoshi
Kusano, Kanichi
Toutain, Pierre‐Louis
Sato, Fumio
author_sort Kuroda, Taisuke
collection PubMed
description BACKGROUND: For medication control in several jurisdictions, withdrawal time is the period of refrain from racing after drug administration. It is set by adding a safety period to an experimental detection time. However, there are no reports of statistical analyses of detection time for the determination of withdrawal time in flunixin meglumine‐treated horses. OBJECTIVE: To analyse the population pharmacokinetics of flunixin in horses through the generation of a dataset for detection time statistical analysis and predictions via Monte Carlo simulation. STUDY DESIGN: Experimental study. METHODS: Drug plasma and urine concentrations following single intravenous administration of flunixin 1.1 mg/kg bodyweight (BW) in 10 horses and multiple administration of q 24 hours for 5 days in 10 horses were measured using liquid chromatography with tandem mass spectrometry (LC‐MS/MS). Data were modelled using a nonlinear mixed effect model followed by Monte Carlo simulation. Irrelevant plasma concentration (IPC) and irrelevant urine concentration (IUC) were calculated using the Toutain approach. Detection times were obtained considering the time after the last administration for selected quantiles of 5000 hypothetical horses under the international screening limit (ISL) proposed by the International Federation of Horseracing Authorities (plasma: 1 ng/mL, urine; 100 ng/mL). RESULTS: For a regimen of 1.1 mg/kg BW q 24 hours, the IPC and IUC values were 2.0 and 73.0 ng/mL respectively. Detection times in plasma above the ISL for 90% of simulated horses were estimated as 74 hours after a single 1.1 mg/kg dose administration, 149 and 199 hours after multiple doses over 5 days at either 24‐ or 12‐hour intervals respectively. Corresponding detection times in urine were 46, 68 and 104 hours respectively. MAIN LIMITATION: Only female horses were investigated. CONCLUSIONS: Statistical detection times for different flunixin meglumine regimens indicated a delay of detection time in plasma after multiple administrations under ISL.
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spelling pubmed-95463172022-10-14 Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations Kuroda, Taisuke Minamijima, Yohei Nomura, Motoi Yamashita, Shozo Yamada, Masayuki Nagata, Shunichi Mita, Hiroshi Tamura, Norihisa Fukuda, Kentaro Kuwano, Atsutoshi Kusano, Kanichi Toutain, Pierre‐Louis Sato, Fumio Equine Vet J Experimental and Basic Research Studies BACKGROUND: For medication control in several jurisdictions, withdrawal time is the period of refrain from racing after drug administration. It is set by adding a safety period to an experimental detection time. However, there are no reports of statistical analyses of detection time for the determination of withdrawal time in flunixin meglumine‐treated horses. OBJECTIVE: To analyse the population pharmacokinetics of flunixin in horses through the generation of a dataset for detection time statistical analysis and predictions via Monte Carlo simulation. STUDY DESIGN: Experimental study. METHODS: Drug plasma and urine concentrations following single intravenous administration of flunixin 1.1 mg/kg bodyweight (BW) in 10 horses and multiple administration of q 24 hours for 5 days in 10 horses were measured using liquid chromatography with tandem mass spectrometry (LC‐MS/MS). Data were modelled using a nonlinear mixed effect model followed by Monte Carlo simulation. Irrelevant plasma concentration (IPC) and irrelevant urine concentration (IUC) were calculated using the Toutain approach. Detection times were obtained considering the time after the last administration for selected quantiles of 5000 hypothetical horses under the international screening limit (ISL) proposed by the International Federation of Horseracing Authorities (plasma: 1 ng/mL, urine; 100 ng/mL). RESULTS: For a regimen of 1.1 mg/kg BW q 24 hours, the IPC and IUC values were 2.0 and 73.0 ng/mL respectively. Detection times in plasma above the ISL for 90% of simulated horses were estimated as 74 hours after a single 1.1 mg/kg dose administration, 149 and 199 hours after multiple doses over 5 days at either 24‐ or 12‐hour intervals respectively. Corresponding detection times in urine were 46, 68 and 104 hours respectively. MAIN LIMITATION: Only female horses were investigated. CONCLUSIONS: Statistical detection times for different flunixin meglumine regimens indicated a delay of detection time in plasma after multiple administrations under ISL. John Wiley and Sons Inc. 2021-11-25 2022-09 /pmc/articles/PMC9546317/ /pubmed/34719043 http://dx.doi.org/10.1111/evj.13532 Text en © 2021 The Authors. Equine Veterinary Journal published by John Wiley & Sons Ltd on behalf of EVJ Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Experimental and Basic Research Studies
Kuroda, Taisuke
Minamijima, Yohei
Nomura, Motoi
Yamashita, Shozo
Yamada, Masayuki
Nagata, Shunichi
Mita, Hiroshi
Tamura, Norihisa
Fukuda, Kentaro
Kuwano, Atsutoshi
Kusano, Kanichi
Toutain, Pierre‐Louis
Sato, Fumio
Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations
title Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations
title_full Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations
title_fullStr Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations
title_full_unstemmed Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations
title_short Medication control of flunixin in racing horses: Possible detection times using Monte Carlo simulations
title_sort medication control of flunixin in racing horses: possible detection times using monte carlo simulations
topic Experimental and Basic Research Studies
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546317/
https://www.ncbi.nlm.nih.gov/pubmed/34719043
http://dx.doi.org/10.1111/evj.13532
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