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 and the acid inhibitory effect of ranitidine during prolonged dosing on the basis of a physiologic indirect-response model.
METHODS: Multiple doses of ranitidine were administered to 18 patients in an intensive care unit in an open randomized trial. All patients received an initial intravenous dose of 50 mg ranitidine; after 12 hours repeated injections (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 for at least 42 hours.
RESULTS: After the initial injection a time lag was observed between the increase of plasma concentration and the increase of pH. With the indirect-response model the rate of onset of effect (kout) could be estimated adequately by relating the inhibitory effect on acid secretion to the concentration according to a sigmoid Emax model. For administration of a single dose, estimated pharmacodynamic parameters were 4.5 +/- 0.9 h(-1) for kout, 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 developed during subsequent dosing that could be described as a linear increase (beta) of 50% inhibition constant with time (beta = 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, tolerance developed within 42 hours and could be characterized on the basis of the developed indirect-response model.

RCT Entities:   Population Interventions Outcomes