Pharmacokinetics and pharmacodynamics of ranitidine in critically ill children.
OBJECTIVE
To determine the pharmacokinetics and pharmacodynamics of ranitidine in critically ill children and to design a dosage regimen that achieves a gastric pH > or =4.


METHODS
Prospective, open-label, pharmacokinetic-pharmacodynamic study.


METHODS
Pediatric intensive care unit in a tertiary care children's hospital.


METHODS
Mechanically ventilated, critically ill children > or =10 kg who required intravenous ranitidine for stress ulcer prophylaxis.


METHODS
Ranitidine 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 x kg(-1) x hr(-1)). The infusion was increased incrementally (0.05 mg x kg(-1) x hr(-1)) until reaching gastric pH > or =4 for > or =75% of a 24-hr period, after which steady-state plasma concentrations were measured. Plasma concentrations were analyzed by high-pressure liquid chromatography.


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 x kg(-1) x hr(-1), 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 > or =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 x kg(-1) x hr(-1).


CONCLUSIONS
The 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 > or =4. Thereafter, gastric pH should be monitored and the dose of ranitidine adjusted accordingly.
Lugo
R A
RA
Department of Pharmacy Practice, the University of Utah College of Pharmacy, Salt Lake City, UT, USA.
Harrison
A M
AM
Cash
J
J
Sweeley
J
J
Vernon
D D
DD
D000293:Adolescent; D000897:Anti-Ulcer Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D003422:Critical Care; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007223:Infant; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D015278:Intensive Care Units, Pediatric; D008297:Male; D008657:Metabolic Clearance Rate; D011446:Prospective Studies; D011899:Ranitidine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D012121:Respiration, Artificial; D014018:Tissue Distribution
D000897:Anti-Ulcer Agents; D011899:Ranitidine