Suarez-Kurtz Guilherme, Estrela Rita de Cássia E, Salvadori Myriam C
Division of Pharmacology, Diretoria de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
Ther Drug Monit. 2004 Feb;26(1):16-22. doi: 10.1097/00007691-200402000-00005.
To develop limited-sampling strategy (LSS) models for estimating prednisolone's area under plasma concentration versus time curve (AUC(0-infinity)), its maximum concentration in plasma (C(max)), and total clearance (CL/F). Healthy subjects (n = 24), enrolled in a bioequivalence study, received 20 mg PO of the prodrug prednisone as reference and test tablets, and plasma prednisolone concentrations (n = 576) were measured by a validated HPLC assay. A linear regression analysis of AUC(0-infinity), C(max), CL/F, and log(CL/F) against the plasma prednisolone concentrations for the reference formulation was carried out to develop LSS models to estimate these parameters. The LSS models were validated on the test formulation data sets and on simulated sets generated by the software ADAPT II. LSS models based on a single [1.5 hours for C(max) and 7 hours for AUC(0-infinity), CL/F, and log(CL/F)] plasma sample, accurately estimated (R2 = 0.84-0.97, mean bias < 1%; mean precision < 10%) these pharmacokinetic parameters. Validation tests indicated that the most informative single-point LSS models developed for the reference formulation provide precise estimates (R(2) > 0.83; mean bias < 3%; mean precision < 10%) of the corresponding pharmacokinetic parameters for the test formulation. LSS models based on the two most informative sampling points (1.5 and 7 hours) were required for accurate estimates (R(2) > 0.87; mean bias < 6%; mean precision < 8%) of prednisolone's C(max), AUC(0-infinity), CL/F, and log(CL/F) for the simulated data sets. Finally, bioequivalence assessment of the prednisone formulations, based on LSS-derived AUC(0-infinity) and C(max) values provided results identical to those obtained using the original values for these parameters. One- and 2-point LSS models provided accurate estimates of prednisolone's C(max), AUC(0-infinity), and CL/F, following single oral doses of prednisone, and allowed correct assessment of bioequivalence between two prednisone formulations.
为建立有限采样策略（LSS）模型以估算泼尼松龙的血浆浓度-时间曲线下面积（AUC(0-∞)）、其血浆最大浓度（C(max)）和总清除率（CL/F）。参加生物等效性研究的健康受试者（n = 24）口服20 mg的前药泼尼松作为参比制剂和受试制剂，通过经过验证的高效液相色谱法测定血浆中泼尼松龙的浓度（n = 576）。针对参比制剂，对AUC(0-∞)、C(max)、CL/F和log(CL/F)与血浆泼尼松龙浓度进行线性回归分析，以建立LSS模型来估算这些参数。LSS模型在受试制剂数据集和由ADAPT II软件生成的模拟数据集上进行了验证。基于单个血浆样本[C(max)为1.5小时，AUC(0-∞)、CL/F和log(CL/F)为7小时]的LSS模型能够准确估算（R2 = 0.84 - 0.97，平均偏差 < 1%；平均精密度 < 10%）这些药代动力学参数。验证试验表明，为参比制剂建立的最具信息量的单点LSS模型能够精确估算（R(2) > 0.83；平均偏差 < 3%；平均精密度 < 10%）受试制剂的相应药代动力学参数。对于模拟数据集而言，需要基于两个最具信息量采样点（1.5小时和7小时）的LSS模型才能准确估算（R(2) > 0.87；平均偏差 < 6%；平均精密度 < 8%）泼尼松龙的C(max)、AUC(0-∞)、CL/F和log(CL/F)。最后，基于LSS推导的AUC(0-∞)和C(max)值对泼尼松制剂进行生物等效性评估，所得结果与使用这些参数的原始值获得的结果相同。单剂量口服泼尼松后，单点和两点LSS模型能够准确估算泼尼松龙的C(max)、AUC(0-∞)和CL/F，并能正确评估两种泼尼松制剂之间的生物等效性。
