Suri A, Grundy B L, Derendorf H
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville 32610, USA.
Int J Clin Pharmacol Ther. 1997 Jan;35(1):1-8.
The main objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK/PD) model for the analgesic effect of ibuprofen and flurbiprofen using subjective as well as objective parameters. Serum concentrations of the individual enantiomers after oral administration of racemic ibuprofen (400 mg) and flurbiprofen (100 mg) were monitored using reversed phase HPLC. The pharmacokinetic data of the S-enantiomer was linked to the effect data using a hypothetical effect compartment. The effect data were fitted to Emax model. PK/PD analysis were performed using both objective (evoked potentials) and subjective (pain intensity scale) parameters. Concentrations of S-ibuprofen were found to be consistently larger than of R-ibuprofen and differed in various pharmacokinetic parameters after oral administration of racemic ibuprofen. Pharmacokinetic parameters of the enantiomers of flurbiprofen, such as volume of administration and clearance, also differed. Comparison of cumulative effects calculated as the area under the effect-time curve (AUCE) showed a statistically significant difference from placebo for both ibuprofen and flurbiprofen using evoked potential values. However, using pain rating values ibuprofen AUCE did not differ statistically significant from placebo whereas flurbiprofen AUCE did. PK/PD modeling of both evoked potentials and pain rating data than in evoked potential data. Hence, EP monitoring may allow to evaluate analgesic activity with a smaller number of subjects than pain rating.
本研究的主要目的是使用主观和客观参数建立布洛芬和氟比洛芬镇痛作用的药代动力学-药效学（PK/PD）模型。采用反相高效液相色谱法监测口服消旋布洛芬（400mg）和氟比洛芬（100mg）后各对映体的血清浓度。使用假设的效应室将S-对映体的药代动力学数据与效应数据相关联。效应数据拟合至Emax模型。使用客观（诱发电位）和主观（疼痛强度量表）参数进行PK/PD分析。发现口服消旋布洛芬后，S-布洛芬的浓度始终高于R-布洛芬，且在各种药代动力学参数上存在差异。氟比洛芬对映体的药代动力学参数，如给药量和清除率，也有所不同。以效应-时间曲线下面积（AUCE）计算的累积效应比较显示，使用诱发电位值时，布洛芬和氟比洛芬与安慰剂相比均有统计学显著差异。然而，使用疼痛评分值时，布洛芬的AUCE与安慰剂相比无统计学显著差异，而氟比洛芬的AUCE有差异。与诱发电位数据相比，诱发电位和疼痛评分数据的PK/PD模型均显示出更快的起效时间和更高的最大效应。因此，与疼痛评分相比，通过监测诱发电位可能只需较少数量的受试者就能评估镇痛活性。
