Schädeli Franziska, Marti Hans-Peter, Frey Felix J, Uehlinger Dominik E
Division of Nephrology and Hypertension, University of Berne, Berne, Switzerland.
Clin Pharmacokinet. 2002;41(1):59-69. doi: 10.2165/00003088-200241010-00005.
The microemulsion formulation of cyclosporin (CsA-ME) has a less variable absorption profile than the standard formulation (CsA-S), but only limited information is available about once-daily administration of CsA-ME.
To develop a population pharmacokinetic model for once-daily CsA-ME that enables the prediction of individual steady-state area under the concentration-time curve (AUC) on the basis of blood concentration measurements and patient covariates.
The steady-state pharmacokinetics of once-daily cyclosporin were studied in 60 stable renal transplant recipients before and after conversion from CsA-S to CsA-ME. For each formulation, 7 blood samples were collected from 50 patients (group A) at sparse timepoints over 2 weeks, and 10 blood samples were collected from 10 patients (group B) at fixed timepoints over 24 hours. A 2-compartment population model assuming time-lagged first-order oral absorption was fitted to the data from group A, using nonlinear mixed effects modelling (NONMEM). The data from group B were used to evaluate the predictive performance of the model.
Mean [+/- SD; coefficient of variation (%CV)] CsA-S doses of 245mg (+/- 92) resulted in cyclosporin blood concentrations of 214 microg/L (+/- 70) after 12 hours and 108 microg/L (+/- 23) after 24 hours; the mean estimated AUC to 24 hours was 7658 microg x h/L (30%). With mean CsA-ME doses of 206mg (+/- 59), cyclosporin blood concentrations were 212 microg/L (+/- 33) and 132 microg/L (25%) after 12 and 24 hours, respectively, and the mean estimated AUC(24) was 9357 microg x h/L (23%). A strong correlation between 12-hour concentrations and AUC(24) was observed for CsA-ME (r = 0.95, p < 0.001), but not for CsA-S (r = 0.59, nonsignificant); the correlation between 24-hour trough concentrations and AUC(24) was weaker for both formulations (r = 0.64, p < 0.05 and r = 0.37, nonsignificant, respectively). On the basis of the population model derived from group A, the single best timepoint to predict AUC(24) from blood cyclosporin concentration was at 8 hours [AUC(24) (microg x h/L) = 19.6 x cyclosporin concentration at 8 hours (microg/L) + 3035], resulting in a prediction error of 8.3 +/- 6.6% when applied to the measured AUC(24) of group B. Adverse events were observed after conversion in 18 patients; these events generally resolved spontaneously or after dosage reduction, but twice-daily administration was required in some patients.
Switching from once-daily CsA-S to CsA-ME results in more consistent and predictable cyclosporin pharmacokinetics. Adjustment of dosage or regimen may be required in some patients.
环孢素微乳剂（CsA-ME）的吸收情况比标准制剂（CsA-S）更稳定，但关于CsA-ME每日一次给药的信息有限。
建立一个CsA-ME每日一次给药的群体药代动力学模型，以便根据血药浓度测量值和患者协变量预测个体稳态血药浓度-时间曲线下面积（AUC）。
在60例稳定的肾移植受者中研究了从CsA-S转换为CsA-ME前后每日一次环孢素的稳态药代动力学。对于每种制剂，从50例患者（A组）中在2周内的稀疏时间点采集7份血样，从10例患者（B组）中在24小时内的固定时间点采集10份血样。使用非线性混合效应模型（NONMEM），对A组数据拟合一个假设存在时间延迟的一级口服吸收的二室群体模型。B组数据用于评估模型的预测性能。
CsA-S平均剂量为245mg（±92）时，12小时后环孢素血药浓度为214μg/L（±70），24小时后为108μg/L（±23）；24小时的平均估计AUC为7658μg·h/L（30%）。CsA-ME平均剂量为206mg（±59）时，12小时和24小时后环孢素血药浓度分别为212μg/L（±33）和132μg/L（25%），平均估计AUC(24)为9357μg·h/L（23%）。CsA-ME的12小时浓度与AUC(24)之间存在强相关性（r = 0.95，p < 0.001），而CsA-S则无（r = 0.59，无显著性）；两种制剂的24小时谷浓度与AUC(24)之间的相关性均较弱（分别为r = 0.64，p < 0.05和r = 0.37，无显著性）。根据A组得出的群体模型，从环孢素血药浓度预测AUC(24)的最佳单一时间点为8小时[AUC(24)（μg·h/L）= 19.6×8小时时的环孢素浓度（μg/L）+ 3035]，应用于B组测量的AUC(24)时预测误差为8.3±6.6%。转换后18例患者出现不良事件；这些事件通常自行缓解或在减量后缓解，但部分患者需要每日两次给药。
从每日一次CsA-S转换为CsA-ME可使环孢素药代动力学更一致且可预测。部分患者可能需要调整剂量或给药方案。
