(Left) Observed (symbols) and model-predicted (lines) response (tail flick) vs. time of drug X after different doses given by the intravenous (red) and.

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(Left) Observed (symbols) and model-predicted (lines) response (tail flick) vs. time of drug X after different doses given by the intravenous (red) and subcutaneous (blue) routes. (Left) Observed (symbols) and model-predicted (lines) response (tail flick) vs. time of drug X after different doses given by the intravenous (red) and subcutaneous (blue) routes. The subcutaneous doses were 10, 50, and 100 µg, and the intravenous doses were 3 and 10 µg. Note the slow terminal decline of the 10 µg subcutaneous dose compared with the 10 µg intravenous dose, suggesting absorption rate–limited elimination. (Right) Schematic illustration of the biophase (top) and the turnover response (bottom) models. The drug in the biophase stimulates the production of the antinociceptive response. Also note that we have added a transit compartment to mimic the concave buildup of response. Ka denotes the first-order input rate constant, Ab is the biophase amount, k is the first-order elimination rate constant, S(Ab) is the stimulatory “drug mechanism” function, kin is the turnover rate, R is the measured (biomarker) response, and kout is the fractional turnover rate. IV, intraveonous; SC, subcutaneous. Johan Gabrielsson et al. Pharmacol Rev 2019;71:89-122 Copyright © 2018 by The Author(s)‏