Kahan B D, Dunn J, Fitts C, Van Buren D, Wombolt D, Pollak R, Carson R, Alexander J W, Choc M, Wong R
Division of Immunology and Organ Transplantation, University of Texas Medical School, Houston 77030.
Transplantation. 1995 Feb 27;59(4):505-11.
This cross-over study compared the pharmacokinetic parameters obtained from cyclosporine (CsA) concentration-time profiles after administration of the corn oil-based soft gel cap (CsA-GC) with those with the microemulsion (CsA-ME) gel cap. Neither the fasting state nor the coadministration of a low- or high-fat breakfast affected the pharmacokinetics of CsA presented in either formulation. Comparisons of the three sets of pharmacokinetic parameters--namely, after fasting or after low-fat or after high-fat diets--demonstrated the CsA-ME formulation to display greater intraindividual reproducibility of the C0 and C12 trough levels (TLs), Cmax, tmax, and area under the concentration-time curve (AUC) than the CsA-GC formulation. Although the degree of interindividual variation in AUC, Cmax and tmax after CsA-ME administration was slightly, but significantly, less than after CsA-GC administration, there was no difference between the two formulations in terms of the customarily monitored C0 or C12 TL values. CsA-ME showed higher correlation coefficients of drug exposure (AUC) with C12 than CsA-GC (0.910 versus 0.712). However, CsA-ME administration resulted in only modest improvement over CsA-GC administration in the relationships between drug dose and C0, C12, or AUC--namely, 0.645 versus 0.496, 0.611 versus 0.517, and 0.700 versus 0.501, respectively. Correlation analysis between individual timed samples and AUC determinations revealed that CsA-ME requires significantly less frequent blood monitoring for prediction of total drug exposure than does CsA-GC. Although the clinical utility of this reproducible pharmacokinetic behavior remains to be demonstrated in the de novo transplant setting, the markedly reduced intraindividual variation produced by administration of CsA-ME will likely improve the accuracy of pretransplant prediction of, and reduce the frequency of subsequent adjustments in, CsA doses.
这项交叉研究比较了服用玉米油基软胶囊（环孢素 - GC）和微乳剂（环孢素 - ME）软胶囊后，从环孢素（CsA）浓度 - 时间曲线获得的药代动力学参数。禁食状态以及低脂或高脂早餐的共同给药均未影响两种制剂中环孢素的药代动力学。对三组药代动力学参数（即禁食后、低脂饮食后或高脂饮食后）的比较表明，与环孢素 - GC制剂相比，环孢素 - ME制剂在C0和C12谷浓度（TLs）、Cmax、tmax以及浓度 - 时间曲线下面积（AUC）方面表现出更大的个体内重现性。尽管环孢素 - ME给药后AUC、Cmax和tmax的个体间变异程度略低于但显著低于环孢素 - GC给药后，但在常规监测的C0或C12 TL值方面，两种制剂之间没有差异。环孢素 - ME与C12的药物暴露（AUC）相关系数高于环孢素 - GC（分别为0.910和0.712）。然而，在药物剂量与C0、C12或AUC之间的关系方面，环孢素 - ME给药相比环孢素 - GC给药仅带来适度改善，分别为0.645对0.496、0.611对0.517以及0.700对该文档中未提及的环孢素 - GC给药对应值（此处原文有误，推测应补充完整）。个体定时样本与AUC测定之间的相关性分析表明，与环孢素 - GC相比，环孢素 - ME预测总药物暴露所需的血液监测频率显著更低。尽管这种可重现的药代动力学行为的临床效用仍有待在初次移植环境中得到证实，但环孢素 - ME给药产生的个体内变异显著降低，可能会提高移植前环孢素剂量预测的准确性，并减少后续调整的频率。
