Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and buccal administration of a highconcentration formulation of buprenorphine in conscious cats

Background The aim of this study was to describe the joint pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a high-concentration formulation of buprenorphine (Simbadol™) in cats. Methods Six healthy cats (4.9 ± 0.7 kg) were included in a prospective, randomized, blinded, crossover study. Simbadol™ (1.8 mg mL^-1 ) was administered by the subcutaneous (SC; 0.24 mg kg^-1 ), intravenous (IV; 0.12 mg kg^-1 ) or buccal (OTM; 0.12 mg kg^-1 ) route of administration and thermal thresholds (TT) were compared with a saline group (SAL). Thermal threshold testing and blood sampling were performed at predetermined time points up to 72 hours including a placebo group. Plasma buprenorphine and norbuprenorphine concentrations were measured using liquid chromatography mass spectrometry. A bespoke bicompartmental pharmacokinetic model simultaneously fitted data from two analytes/three routes of administration. Temporal changes in TT were analyzed using one-way ANOVA followed by Dunnett's test and treatment comparisons using two-way ANOVA with Bonferroni's correction (P < 0.05). Results Thermal thresholds were significantly increased after SC, IV and OTM from 1-24 hours (except 2 hours), 0.5-8 hours (except 6 hours), and 1-8 hours (except 6 hours), respectively, when compared with baseline. Thermal thresholds were significantly increased after SC (1-30 hours), IV (1-8 hours) and OTM (1-12 hours) when compared with SAL, but not different among buprenorphine-treated cats. The absolute buprenorphine clearance was 0.98 L kg^-1 hour^-1 , volume of distribution at steady state was 7.9 L kg^-1 and the elimination-half-life was 12.3 hours. Bioavailability for SC and OTM was 94% and 24%, respectively. Subcutaneous absorption was biphasic. An initial peak (0.08 hours) was followed by a slow (half-life 11.2 hours) and progressive (peak acceleration at 2.8 hours) uptake. Conclusion The SC administration of Simbadol™ was characterized by prolonged absorption half-life and sustained plasma concentrations yielding long-lasting antinociception (≥; 24 hours) when compared with the IV and OTM routes.