Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats.

OBJECTIVE: To describe simultaneous pharmacokinetics (PK) and thermal antinociception after intravenous (i.v.), intramuscular (i.m.) and subcutaneous (SC) buprenorphine in cats. STUDY
DESIGN: Randomized, prospective, blinded, three period crossover experiment. ANIMALS: Six healthy adult cats weighing 4.1±0.5 kg.
METHODS: Buprenorphine (0.02 mg kg(-1)) was administered i.v., i.m. or s.c.. Thermal threshold (TT) testing and blood collection were conducted simultaneously at baseline and at predetermined time points up to 24 hours after administration. Buprenorphine plasma concentrations were determined by liquid chromatography tandem mass spectrometry. TT was analyzed using anova (p<0.05). A pharmacokinetic-pharmacodynamic (PK-PD) model of the i.v. data was described using a model combining biophase equilibration and receptor association-dissociation kinetics.
RESULTS: TT increased above baseline from 15 to 480 minutes and at 30 and 60 minutes after i.v. and i.m. administration, respectively (p<0.05). Maximum increase in TT (mean±SD) was 9.3±4.9°C at 60 minutes (i.v.), 4.6±2.8°C at 45 minutes (i.m.) and 1.9±1.9°C at 60 minutes (s.c.). TT was significantly higher at 15, 60, 120 and 180 minutes, and at 15, 30, 45, 60 and 120 minutes after i.v. administration compared to i.m. and s.c., respectively. I.v. and i.m. buprenorphine concentration-time data decreased curvilinearly. S.c. PK could not be modeled due to erratic absorption and disposition. I.v. buprenorphine disposition was similar to published data. The PK-PD model showed an onset delay mainly attributable to slow biophase equilibration (t(1/2) k(e0)=47.4 minutes) and receptor binding (k(on)=0.011 mL ng(-1) minute(-1)). Persistence of thermal antinociception was due to slow receptor dissociation (t(1/2) k(off)=18.2 minutes). CONCLUSIONS AND CLINICAL RELEVANCE: I.v. and i.m. data followed classical disposition and elimination in most cats. Plasma concentrations after i.v. administration were associated with antinociceptive effect in a PK-PD model including negative hysteresis. At the doses administered, the i.v. route should be preferred over the i.m. and s.c. routes when buprenorphine is administered to cats.