Animal-to-Human Extrapolation of the Pharmacokinetic and Pharmacodynamic Properties of Buprenorphine

This investigation describes the interspecies scaling of the pharmacokinetics and pharmacodynamics of buprenorphine.

Data on the time course of the antinociceptive and respiratory depressant effects of buprenorphine in rats and in humans were simultaneously analysed on the basis of a mechanism-based pharmacokinetic-pharmacodynamic model.

An allometric three-compartment pharmacokinetic model described the time course of the concentration in plasma. The value of the allometric coefficient for clearance was 35.2mL/min (relative standard error [RSE] = 5.6%) and the value of the allometric exponent was 0.76 (RSE 5.61%). A combined biophase distribution-receptor association/dissociation model with a linear transduction function described hysteresis between plasma concentration and effect. The values of the drug-specific pharmacodynamic parameters were identical in rats and in humans. For the respiratory depressant effect, the values of the second-order rate constant of receptor association (k_on) and the first-order rate constant of receptor dissociation (k_off) were 0.23 mL/ng/min (RSE = 15.8%) and 0.014 min⁻¹ (RSE = 27.7%), respectively, and the value of the equilibrium dissociation constant (K_diss) was 0.13 nmol/L. The value of the intrinsic activity α was 0.52 (RSE = 3.4%). For the antinociceptive effect, the values of the k_on and k_off were 0.015 mL/ng/min (RSE = 18.3%) and 0.053 min⁻¹ (RSE = 23.1%), respectively. The value of the K_diss was 7.5 nmol/L. An allometric equation described the scaling of the system-specific parameter, the first-order distribution rate constant (keo). The value of the allometric coefficient for the k_e0 was 0.0303 min⁻¹ (RSE = 11.3%) and the value of the exponent was −0.28 (RSE = 9.6%).

The different values of the drug-specific pharmacodynamic parameters are consistent with the different opioid μ receptor subtypes involved in the antinociceptive and respiratory depressant effects.