a The model estimates CL/F andktr for a dose of 150 mg (the reference). CL/F and ktr for other doses are calculated using the covariate effect (ktrCLDose): CL/F = 35.4 L/h × (Dose/150 mg)-0.430 andktr = 0.117 h-1 × (Dose/150 mg)-0.430
Figure legends
Fig. 1. Selected individual profiles of individually predicted (dashed lines) and observed values (dots) for plasma concentrations and effect (warmth detection threshold), respectively, over the first 50 hours after dose. Subjects #109 and #112 showed large variation in bupivacaine plasma levels even with the same dose, and subject #202 had lower plasma levels than #112 despite the higher dose. This phenomenon was present in all cohorts with more than one subject. Note the inter-individual variation in the presence and dominance of the fast and slow absorption peaks.
Fig. 2. Schematic representation of the population pharmacokinetic-pharmacodynamic model for bupivacaine. The fraction of total dose absorbed through the fast process (Fr) is limited to a value between 0 and 1. τ0 is the duration of the 0-order absorption process (the fast phase),k tr is the transit rate constant, Q/F is the intercompartmental clearance, CL/F is the apparent clearance, V/F is the apparent distribution volume of the central compartment, and V2/F is the apparent distribution volume of the peripheral compartment.
Fig. 3. Boxplots of inter-individual variability for apparent clearance (CL/F, blue) and transit rate constant (k tr, green) by dose for the base PK model (left) and the final PK model (right). As the final model accounts for the influence of dose on CL/F and k tr, the trend in the inter-individual variability disappears.
Fig. 4. Apparent clearance (CL/F) as a function of dose, as predicted by the model. Points (formulation A) and triangles (formulation B) are individually estimated values of CL/F for the subjects in this study. Diamonds are means of the individually estimated values of CL/F and error bars represent standard deviation. The solid line represents the function CL/F = 35.4 L/h × (Dose/150 mg)-0.430 (see Table 1).
Fig. 5. Population predicted profiles of plasma concentration (left) and effect as warmth detection threshold (right) over time after dose in hours. Solid lines represent population predicted values, dashed lines are individually predicted values, and points represent observed values.