Kovarik J M, Mueller E A, Kallay Z, Smith H T, Lison A E, Arns W, Renner E
Department of Clinical Pharmacology, Sandoz Pharma Ltd, Basle, Switzerland.
J Clin Pharmacol. 1995 Dec;35(12):1136-43. doi: 10.1002/j.1552-4604.1995.tb04038.x.
A concentration-guided study was designed to maintain adequate immunosuppression and avoid excessive drug exposure while determining steady-state relative bioavailability of two cyclosporine G (CyG) oral formulations in stable renal transplant patients. In period I (week 1), 26 patients taking cyclosporine A (CyA)-based immunosuppressive regimens entered the study. Doses were titrated to maintain trough concentrations within a predefined range, as measured by fluorescence polarization immunoassay (FPIA). Patients were given an oral solution of CyG in period II (weeks 2-3), and a microemulsion capsule formulation of CyG in period III (weeks 4-5), with dose titration as necessary to achieve trough concentrations in a predefined range, as measured by FPIA. Full pharmacokinetic profiles were obtained on the last day of each study period. Treatment with CyA was reinitiated in period IV (week 6) at the same doses as at study entry. All blood samples were analyzed at the conclusion of the study using CyG- and CyA-specific high-performance liquid chromatography (HPLC). When changing from oral solution to capsule for CyG, an average 19% dose reduction was necessary to compensate for the elevated trough concentrations resulting from the increased bioavailability of the capsule formulation. The concentration-guided strategy was successful in avoiding over-exposure, and resulted in comparable values for area under the concentration-time curve (AUC) for both formulations of CyG. Dose normalization of the pharmacokinetic parameters subsequently allowed calculation of the relative bioavailability. Specifically, a faster rate and greater extent of CyG absorption from the capsule than the oral solution were manifested as a slightly earlier time to peak concentration (tmax), an average 44% increase in the maximum concentration (Cmax), and an average 29% increase in AUC. This experience demonstrated that a concentration-guided trial design allowed a drug development question for a compound with a narrow therapeutic index to be addressed safely and directly in the target patient population.
一项浓度引导研究旨在维持足够的免疫抑制并避免药物过度暴露，同时确定两种环孢素G（CyG）口服制剂在稳定的肾移植患者中的稳态相对生物利用度。在第I阶段（第1周），26名采用基于环孢素A（CyA）的免疫抑制方案的患者进入研究。通过荧光偏振免疫测定法（FPIA）测量，调整剂量以使谷浓度维持在预定范围内。在第II阶段（第2 - 3周），患者服用CyG口服溶液，在第III阶段（第4 - 5周），服用CyG微乳胶囊制剂，必要时调整剂量以通过FPIA测量使谷浓度达到预定范围。在每个研究阶段的最后一天获取完整的药代动力学曲线。在第IV阶段（第6周），以与研究开始时相同的剂量重新开始使用CyA治疗。在研究结束时，使用CyG和CyA特异性高效液相色谱法（HPLC）分析所有血样。当从CyG口服溶液更换为胶囊时，平均需要减少19%的剂量以补偿由于胶囊制剂生物利用度增加导致的谷浓度升高。浓度引导策略成功避免了药物过度暴露，并且两种CyG制剂的浓度 - 时间曲线下面积（AUC）值相当。随后对药代动力学参数进行剂量归一化，从而能够计算相对生物利用度。具体而言，与口服溶液相比，CyG从胶囊中的吸收速率更快且程度更大，表现为达峰浓度时间（tmax）略早，最大浓度（Cmax）平均增加44%，AUC平均增加29%。该经验表明，浓度引导的试验设计能够安全、直接地在目标患者群体中解决具有窄治疗指数化合物的药物开发问题。
