Pharmacokinetics and pharmacodynamics of ranitidine in critically ill children

OBJECTIVETo determine the pharmacokinetics and pharmacodynamics of ranitidine in critically ill children and to design a dosage regimen that achieves a gastric pH ≥4. DESIGNProspective, open-label, pharmacokinetic-pharmacodynamic study. SETTINGPediatric intensive care unit in a tertiary care children’s hospital. PATIENTSMechanically ventilated, critically ill children ≥10 kg who required intravenous ranitidine for stress ulcer prophylaxis. INTERVENTIONSRanitidine pharmacokinetics were determined after a single intravenous dose. Gastric pH was monitored hourly via nasogastric pH probe. After the last blood sample, patients received an intravenous bolus of ranitidine (0.5 mg/kg) followed by a continuous infusion (0.1 mg·kg·hr). The infusion was increased incrementally (0.05 mg·kg·hr) until reaching gastric pH ≥4 for ≥75% of a 24-hr period, after which steady-state plasma concentrations were measured. Plasma concentrations were analyzed by high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS Twenty-three children (ranging in age from 1.4 to 17.1 yrs) were studied. Pharmacokinetic variables included a clearance of 511.7 ± 219.7 mL·kg·hr, volume of distribution of 1.53 ± 0.99 L/kg, and half-life of 3.01 ± 1.35 hrs. After the single intravenous dose (1.52 ± 0.47 mg/kg), gastric pH increased from 1.6 ± 1.0 to 5.1 ± 1.1 (p < .001), which was associated with a plasma concentration of 373 ± 257 ng/mL. Based on the pharmacokinetic variables, the dose of intravenous ranitidine required to target 373 ng/mL as the average steady-state concentration is 1.5 mg/kg administered every 8 hrs. During the continuous infusion, the mean steady-state ranitidine concentration associated with gastric pH ≥4 was 287 ± 133 ng/mL. This concentration may be achieved with an intravenous loading dose of 0.45 mg/kg followed by a continuous infusion of 0.15 mg·kg·hr. CONCLUSIONSThe pharmacokinetics of ranitidine in critically ill children are variable. The description of ranitidine’s pharmacokinetics and pharmacodynamics in this study may used to design an initial ranitidine dosage regimen that targets a gastric pH ≥4. Thereafter, gastric pH should be monitored and the dose of ranitidine adjusted accordingly.