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 (k out ) could be estimated adequately by relating the inhibitory effect on acid secretion to the concentration 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 developed during subsequent dosing that could be described as a linear increase (β) of 50% inhibition constant with time (β = 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. Clinical Pharmacology & Therapeutics (1999) 66 , 140–151; doi: 10.1053/cp.1999.v66.99988