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Population pharmacodynamic model for ketorolac analgesia
Author(s) -
Mandema Jaap W.,
Stanski Donald R.
Publication year - 1996
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(96)90210-6
Subject(s) - nonmem , medicine , anesthesia , placebo , ketorolac , pharmacodynamics , analgesic , population , pain relief , pharmacokinetics , dosing , pharmacology , alternative medicine , environmental health , pathology
Objective To derive a population pharmacokinetic‐pharmacodynamic model that characterizes the distribution of pain relief scores and remedication times observed in patients receiving intramuscular ketorolac for the treatment of moderate to severe postoperative pain. Background The data analysis approach deals with the complexities of analyzing analgesic 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. Methods Patients ( n = 522) received a single oral or intramuscular administration of placebo or a single intramuscular dose of 10, 30, 60, or 90 mg ketorolac for postoperative pain relief. Pain relief was measured periodically with use of a five‐category ordinal scale up to 6 hours after dosing. In this period, 288 patients received additional medication because of insufficient pain relief. Pharmacokinetic data was available for 85 subjects. Models were fitted to the data with the NONMEM program. Results The pharmacokinetic data was best described by a two‐compartment model with first‐order absorption. Pain relief was found to be a function of drug concentration (E max model), time (waxing and waning of placebo effect), and an individual random effect. The drug concentration at half‐maximal effect (EC 50 ) and the first‐order rate constant (k eo ) half‐life for pain relief were 0.37 mg/L and 24 minutes. The probability of remedication was found to be a function of the 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 maintained up to 6 hours in 50%, 70%, 78%, and 81% of patients after these four doses. Only 25% of the patients achieved adequate pain relief with placebo. Conclusions A population pharmacokinetic‐pharmacodynamic model for the analgesic efficacy of intramuscular ketorolac was derived. The simulated relationship between dose, time, and percentage of patients with adequate pain relief suggested that 30 mg intramuscular ketorolac was the optimal initial dose for postoperative pain relief. Clinical Pharmacology & Therapeutics (1996) 60 , 619–635; doi: