Characterisation of the in vivo interactions between detomidine and methadone in horses: Pharmacokinetic and pharmacodynamic modelling

Author(s)

Gozalo-Marcilla, M. ^[1] ; Luna, S. P. L. ^[1] ; Moreira da Silva, R. ^[2] ; Crosignani, N. ^[1] ; Lopes, N. P. ^[2] ; Taylor, P. M. ^[3] ; Pelligand, L. ^[4]

Affiliation

^[1] Sao Paulo State Univ UNESP, Sch Vet Med & Anim Sci, Dept Vet Surg & Anaesthesiol, Botucatu, SP - Brazil

^[2] Univ Sao Paulo, Sch Pharmaceut Sci, NPPNS, Ribeirao Preto, SP - Brazil

^[3] Taylor Monroe, Ely, Cambs - England

^[4] Royal Vet Coll, Dept Clin Serv & Sci & Comparat Biomed Sci, Hatfield, Herts - England

• Document type: Journal article
• Source: EQUINE VETERINARY JOURNAL; v. 51, n. 4, p. 517-529, JUL 2019.
• Web of Science Citations: 3

Abstract

Background Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses. Objectives To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses. Study design Randomised, placebo-controlled, blinded, crossover. Methods Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 mu g/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 {[}MLD], 5 {[}MMD] or 10 {[}MHD] mu g/kg bwt). Venous blood samples were obtained at predetermined times between 0 and 360 min after drug administration. Plasma detomidine and methadone were measured using a single, liquid/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-MS/MS). Sequential PK/PD modelling compared rival models, with and without PK and PD interaction between drugs, to fit the PD data including height of the head above the ground (HHAG), a visual analogue scale for sedation (VAS), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility (GIM) {[}1]. Results Two and three compartment models best described the PK of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra-additive (partial antagonism) effect for HHAG (alpha = -1.33), VAS (alpha = -0.98) and GIM (alpha = -1.05), a positive potentiation for ET (pot = 0.0041) and TT (pot = 0.133) and a synergistic to additive effect for MT (alpha = 0.78). Main limitations This is a small experimental study. Conclusions Different PK/PD interactions were demonstrated for each PD parameter and could be modelled in vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations. (AU)

• FAPESP's process: 17/01425-6 - Clinical application of different constant rate infusions of detomidine and methadone in standing horses
• Grantee: Miguel Gozalo Marcilla
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 10/08967-0 - Evaluation of clinical and experimental pain in animals
• Grantee: Stelio Pacca Loureiro Luna
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/50265-3 - Distribution and metabolism of natural and synthetic xenobiotics: from the comprehension of reactional process to tissue imaging generation
• Grantee: Norberto Peporine Lopes
• Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 14/00474-5 - Antinociceptive effects and farmacokinetics in horses treated with different low doses of methadone and detomidine
• Grantee: Miguel Gozalo Marcilla
• Support Opportunities: Scholarships in Brazil - Post-Doctoral