Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2-6 months

Objective: We determined the postoperative pharmacokinetics (PK), safety, and analgesic effects of ketorolac in 14 infants (aged < 6 months) receiving a single intravenous (IV) administration of racemic ketorolac or placebo. Background: Information on the PK of ketorolac in infants is limited. Unblinded studies suggest ketorolac may be useful in infants. Methods: This double-blinded, placebo-controlled study enrolled 14 infants (aged < 6 months) postoperatively. At 6-18 h after surgery, infants were randomized to receive placebo, 0.5 mg.kg(-1), or 1 mg.kg(-1) ketorolac IV. All infants received morphine sulfate as needed for pain control. Blood was collected up to 12-h postdosing. Analysis used noncompartmental and compartmental population modeling methods. Results: In addition to noncompartmental and empirical Bayes PK modeling, data were integrated with a previously studied data set comprising 25 infants and toddlers (aged 6-18 months). A two-compartmental model described the comprehensive data set. The population estimates of the R (+) isomer were (%CV): central volume of distribution 1130 (10%) ml, peripheral volume of distribution 626 (25%) ml, and clearance from the central compartment 7.40 (8%) ml.min(-1). Those of the S ()) isomer were 1930 (15%) ml, 319 (58%) ml, and 39.5 (13%) ml.min(-1). Typical elimination half-lives were 191 and 33 min, respectively. There was a trend for increased clearance and central volume with increasing age and weight. The base model suggested that clearance of the S ()) isomer was weakly related to age; however, when body size adjustment was added to the model, no covariates were significant. Safety assessment showed no changes in renal or hepatic function tests, surgical drain output, or continuous oximetry between groups. Cumulative morphine administration showed large inter-patient variability and was not different between groups. Conclusion: Stereo-isomer-specific clearance of ketorolac in infants (aged 2-6 months) shows rapid elimination of the analgesic S ()) isomer as reported in infants aged 6-18 months. No adverse effects were seen after a single IV ketorolac dose.