Gaspari F, Perico N, Pisoni R, Anedda M F, Signorini O, Caruso R, Gotti E, Remuzzi G
Department of Transplant Immunology and Innovative Antirejection Therapies, Ospedali Riuniti Bergamo, Mario Negri Institute for Pharmacological Research, Italy.
Clin Transplant. 1998 Oct;12(5):379-90.
How to convert from traditional cyclosporine (CsA) to the microemulsion formulation in stable renal transplant patients is still a matter of debate. The present study was designed to evaluate the effects of changeover from traditional Sandimmune to Neoral formulation at two dose-ratio conversions on CsA pharmacokinetics, safety and tolerability particularly in terms of renal function. Thirty outpatients regularly followed at our Clinical Research Center were randomized to 1:1 or 1:0.75 dose-ratio conversion and assigned to the two groups according to a comparable renal function and time post-transplant. Patients underwent CsA pharmacokinetic evaluation and renal function measurements (GFR and RPF) before, at day 15, and at month 6 after conversion to Neoral formulation. More consistent CsA concentration-time profiles with Neoral than traditional formulation were obtained at the two time points of evaluation after conversion. At 1:1 dose-ratio conversion an increased absorption rate, reflected by a shorter time to maximum blood CsA concentration (Tmax), and a greater bioavailability, as shown by an increase in the peak CsA concentration (Cmax) and the 12-h exposure to drug defined by the area under the time-concentration curve (AUC0-->12 h) was found 15 d and 6 months after conversion to Neoral formulation. A similar AUC as compared with traditional Sandimmune was observed in those patients randomized to receive a 25% lower dose of Neoral formulation. All of patients defined as 'low' absorbers became 'high' absorbers as early as 15 d after conversion to Neoral formulation at 1:1 or 0.75 dose-ratio regimen. Overall mean GFR was unchanged in both conversion regimens during the 6 months of follow-up. However, there was a tendency to lower GFR even in some patients randomized to 1:0.75 conversion but mostly in those with 1:1 conversion. A limited sampling strategy utilizing three blood samples (0, 1, 3 h post-dosing of Neoral formulation) provided an excellent correlation with actual drug exposure (r = 0.977). Enhanced CsA absorption with the microemulsion formulation results in increased drug exposure that may reduce GFR in some patients who undergo 1:1 dose-ratio conversion. The Neoral formulation that permits a more effective, consistent, and predictable absorption of CsA may represent a great advantage in order to prevent acute and possibly chronic rejections. Efforts have to be made to find optimal therapeutic range and dosing schedule for this new formulation, which may be facilitated by using the limited sampling approach to predict AUC after only three-point sampling.
在稳定的肾移植患者中，如何从传统环孢素（CsA）转换为微乳剂剂型仍存在争议。本研究旨在评估在两种剂量比转换情况下，从传统的山地明转换为新山地明剂型对CsA药代动力学、安全性和耐受性的影响，尤其是对肾功能的影响。在我们临床研究中心定期随访的30名门诊患者被随机分为1:1或1:0.75剂量比转换组，并根据相当的肾功能和移植后时间分为两组。患者在转换为新山地明剂型前、转换后第15天和第6个月接受CsA药代动力学评估和肾功能测量（肾小球滤过率和肾血浆流量）。转换后两个评估时间点，新山地明的CsA浓度-时间曲线比传统剂型更一致。在转换为新山地明剂型后15天和6个月时，1:1剂量比转换时吸收速率增加，表现为达到最大血CsA浓度（Tmax）的时间缩短，生物利用度更高，表现为CsA峰值浓度（Cmax）增加以及由时间-浓度曲线下面积定义的12小时药物暴露量（AUC0→12 h）增加。在随机接受低25%剂量新山地明剂型的患者中，观察到与传统山地明相似的AUC。所有被定义为“低”吸收者在转换为新山地明剂型后15天，在1:1或0.75剂量比方案下都变成了“高”吸收者。在6个月的随访期间，两种转换方案中总体平均肾小球滤过率均未改变。然而，即使在一些随机分配到1:0.75转换组的患者中也有肾小球滤过率降低的趋势，但主要是在1:1转换组的患者中。利用三个血样（新山地明剂型给药后0、1、3小时）的有限采样策略与实际药物暴露具有良好的相关性（r = 0.977）。微乳剂剂型增强的CsA吸收导致药物暴露增加，这可能会使一些接受1:1剂量比转换的患者肾小球滤过率降低。新山地明剂型能够更有效、一致且可预测地吸收CsA，这可能是预防急性和可能的慢性排斥反应的一大优势。必须努力为这种新剂型找到最佳治疗范围和给药方案，使用有限采样方法仅通过三点采样预测AUC可能有助于实现这一点。
