Autor(es)

Gozalo-Marcilla, Miguel ; da Silva, Rodrigo Moreira ; Loureiro Luna, Stelio Pacca ; de Oliveira, Alice Rodrigues ; Fonseca, Mariana Werneck ; Lopes, Norberto Peporine ; Taylor, Polly M. ; Pelligand, Ludovic

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS; v. 42, n. 6, p. 7-pg., 2019-10-04.

Resumo

The alpha(alpha)(2)-agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output). (AU)

• Processo FAPESP: 14/00474-5 - Efeitos antinociceptivos e farmacocinética em equinos tratados com diferentes doses baixas de metadona e detomidina
• Beneficiário: Miguel Gozalo Marcilla
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 14/50265-3 - Metabolismo e distribuicao de xenobioticos naturais e sinteticos:da compreensao dos processos reacionais a geracao de imagens teciduais.
• Beneficiário: Norberto Peporine Lopes
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático
• Processo FAPESP: 17/01425-6 - Aplicação clínica de diferentes taxas de infusão de detomidina e metadona em cavalos em estação.
• Beneficiário: Miguel Gozalo Marcilla
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 10/08967-0 - Avaliação da dor clínica e experimental em animais
• Beneficiário: Stelio Pacca Loureiro Luna
• Modalidade de apoio: Auxílio à Pesquisa - Temático