Pharmacodynamic modeling of the acid inhibitory effect of ranitidine in patients in an intensive care unit during prolonged dosing: Characterization of tolerance

Objective: To characterize the relationship between the pharmacokinetics an d the acid inhibitory effect of ranitidine during prolonged dosing on the b asis of a physiologic indirect-response model, Methods: Multiple doses of ranitidine were administered to 18 patients in a n intensive care unit in an open randomized trial. All patients received an initial intravenous dose of 50 mg ranitidine; after 12 hours repeated inje ctions (50 mg every 6 hours) or a primed continuous infusion (50 mg plus 0. 125 mg/kg/h) was administered. Intragastric pH was monitored continuously f or at least 42 hours. Results: After the initial injection a time lag was observed between the in crease of plasma concentration and the increase of pH, With the indirect-re sponse model the rate of onset of effect (k(out)) could be estimated adequa tely by relating the inhibitory effect on acid secretion to the concentrati on according to a sigmoid E-max model. For administration of a single dose, estimated pharmacodynamic parameters were 4.5 +/- 0.9 h(-1) for k(out), 1. 4 +/- 0.1 for baseline pH, 0.051 +/- 0.012 mg/L for 50% inhibition constant , and 7.0 +/- 1.5 for Hill factor (mean +/- SEM; n = 18). Tolerance develop ed during subsequent dosing that could be described as a linear increase (b eta) of 50% inhibition constant with time (P = 0.0030 and 0.0045 mg/L/h for repeated and continuous administration, respectively). Conclusions: The developed physiologic indirect-response model may be used to quantify the pharmacokinetic-pharmacodynamic relationship of ranitidine during single and multiple dosing. During prolonged intravenous dosing, tol erance developed within 42 hours and could be characterized on the basis of the developed indirect-response model.