Pharmacokinetic‐pharmacodynamic (PK‐PD) modelling in non‐steady‐state studies and arterio‐venous drug concentration differences.

In conducting a non‐steady‐state pharmacokinetic (PK)‐pharmacodynamic (PD) study there is potential for the observed effect (E) vs time, and venous plasma drug concentration (C) vs time, profiles to display temporal displacement with respect to each other. This is most frequently observed when there exists a distributional nonequilibrium across the effect organ giving rise to hysteresis, i.e. observed C preceding E in the time domain, with the resulting potential for a counterclockwise loop to be generated in the observed E vs C plot (when data are connected in time‐order). Such temporal displacement does not afford direct prediction of the steady‐state E vs C PD relationship. When an arterio‐venous (A‐V) difference exists across the tissues of the blood sampling compartment (i.e. the arm), and this arises solely from an elimination process then drug concentration in the respective peripheral arterial plasma and venous plasma compartments will be in equilibrium at all times during a non‐steady‐state PK experiment. If there are no other sources of temporal displacement in the relationship between E and C then the observed E vs C plot will be a direct predictor of the steady‐state E vs C PD relationship. In contrast when the A‐V difference is of a distributional nature then proteresis, i.e. observed E preceding C in the time domain, will arise with the potential for the generation of a clockwise loop in the observed E vs C relationship. Simulated error‐incorporated E vs time, and C vs time, data was analysed by semi‐parametric implementation of an effect‐ compartment link‐model that affords accurate steady‐state E vs C PD predictions (without the requirement of sampling arterial blood) from data that incorporates the concurrent presence of: (i) distributional nonequilibrium across the effect organ, and (ii) distributional A‐V non‐ equilibrium. Accurate steady‐state E vs C PD predictions were achieved irrespective of the comparative magnitudes of the two nonequilibria, i.e. whether the rate of equilibration across the effect organ was faster than, or slower than, the rate of equilibration across the arm (resulting in a clockwise or counterclockwise loop in the observed E vs C plot, respectively), or indeed if one or other of the nonequilibria is essentially absent. When the rate of equilibration across the effect organ is slower than the rate of A‐V equilibration (i.e. counterclockwise loop generated in the observed E vs C plot) then the need to model for the underlying A‐V nonequilibrium is redundant, i.e. accurate steady‐state E vs C PD predictions can be achieved with implementation (strictly incorrectly) of a more simple link parameterised solely to model for distributional nonequilibrium across the effect organ.(ABSTRACT TRUNCATED AT 400 WORDS)