Mandema J W, Stanski D R
Department of Anesthesia, Stanford University School of Medicine.
Clin Pharmacol Ther. 1996 Dec;60(6):619-35. doi: 10.1016/S0009-9236(96)90210-6.
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.
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.
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.
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 (Emax model), time (waxing and waning of placebo effect), and an individual random effect. The drug concentration at half-maximal effect (EC50) and the first-order rate constant (keo) 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.
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.
建立一个群体药代动力学-药效学模型，以描述接受肌内注射酮咯酸治疗中度至重度术后疼痛的患者的疼痛缓解评分分布及补救用药时间。
数据分析方法涉及分析镇痛试验数据的复杂性：（1）重复测量；（2）有序分类反应变量；（3）非随机删失，因为如果患者疼痛缓解不足，他们可以服用急救药物。
患者（n = 522）接受单次口服或肌内注射安慰剂，或单次肌内注射10、30、60或90 mg酮咯酸以缓解术后疼痛。给药后长达6小时内，定期使用五类序数量表测量疼痛缓解情况。在此期间，288名患者因疼痛缓解不足而接受了额外用药。85名受试者有药代动力学数据。使用NONMEM程序对数据进行模型拟合。
药代动力学数据用具有一级吸收的二室模型能得到最佳描述。发现疼痛缓解是药物浓度（Emax模型）、时间（安慰剂效应的起伏）和个体随机效应的函数。疼痛缓解的半数最大效应时的药物浓度（EC50）和一级速率常数（keo）半衰期分别为0.37 mg/L和24分钟。发现补救用药的概率是观察到的疼痛缓解水平的函数，且随时间增加。蒙特卡洛模拟显示，在肌内注射10、30、60或90 mg酮咯酸后41、27、23和21分钟时，50%的患者实现了充分的疼痛缓解。在这四种剂量后，分别有50%、70%、78%和81%的患者在长达6小时内维持了充分的疼痛缓解。仅25%的患者使用安慰剂实现了充分的疼痛缓解。
建立了肌内注射酮咯酸镇痛效果的群体药代动力学-药效学模型。剂量、时间和疼痛充分缓解患者百分比之间的模拟关系表明，30 mg肌内注射酮咯酸是术后疼痛缓解的最佳初始剂量。
