POPULATION PHARMACODYNAMIC MODEL FOR KETOROLAC ANALGESIA

Objective: To derive a population pharmacokinetic-pharmacodynamic mode l that characterizes the distribution of pain relief scores and remedi cation times observed in patients receiving intramuscular ketorolac fo r the treatment of moderate to severe postoperative pain. Background: The data analysis approach deals with the complexities of analyzing an algesic trial data: (1) repeated measurements, (2) ordered categorical response variables, and (3) nonrandom censoring because the patients can take a rescue medication if their pain relief is insufficient. Met hods: Patients (n = 522) received a single oral or intramuscular admin istration of placebo or a single intramuscular dose of 10, 30, 60, or 90 mg ketorolac for postoperative pain relief. Pain relief was measure d periodically with use of a five-category ordinal scale up to 6 hours after dosing. In this period, 288 patients received additional medica tion because of insufficient pain relief. Pharmacokinetic data was ava ilable for 85 subjects. Models were fitted to the data with the NONMEM program. Results: The pharmacokinetic data was best described by a tw o-compartment model with first-order absorption. Pain relief was found to be a function of drug concentration (E(m)ax model), time (waxing a nd waning of placebo effect), and an individual random effect. The dru g concentration at half-maximal effect (EC(50)) and the first-order ra te constant (k(eo)) half-life for pain relief were 0.37 mg/L and 24 mi nutes. The probability of remedication was found to be a function of t he observed level of pain relief and was found to increase with time. Monte Carlo simulations showed that adequate pain relief was achieved in 50% of the patients at 41, 27, 23, and 21 minutes after 10, 30, 60, or 90 mg of intramuscular ketorolac. Adequate pain relief was maintai ned up to 6 hours in 50%, 70%, 78%, and 81% of patients after these fo ur doses. Only 25% of the patients achieved adequate pain relief with placebo. Conclusions: A population pharmacokinetic-pharmacodynamic mod el for the analgesic efficacy of intramuscular ketorolac was derived. The simulated relationship between dose, time, and percentage of patie nts with adequate pain relief suggested that 30 mg intramuscular ketor olac was the optimal initial dose for postoperative pain relief.