Chueh S C, Kahan B D
Department of Surgery, The University of Texas-Houston Medical School, 77030, USA.
J Am Soc Nephrol. 1998 Feb;9(2):297-304. doi: 10.1681/ASN.V92297.
The purpose of this study was to compare the accuracy of pretransplant test-dose pharmacokinetic (PK) profiling after administration of the microemulsion (CsA-ME; Neoral) versus the corn oil-based (CsA-GC; Sandimmune) gel capsule formulations of cyclosporin A (CsA) to estimate posttransplant CsA bioavailability and to individualize starting drug doses. The absolute oral bioavailability (F), clearance rate (CL), average blood concentration (C[av]), peak concentration (Cmax), and time to Cmax (tmax) values were calculated from paired intravenous and oral pretransplant PK profiles of renal transplant candidates, using CsA-GC (n = 70) or CsA-ME (n = 70) administration. The initial posttransplant oral CsA dose was estimated by linear extrapolation of the observed pretransplant value to the target concentration. Because higher mean F (P < 0.0001), but not CL, values were observed in end-stage renal disease patients after CsA-ME compared with CsA-GC treatment, the predicted starting doses for each therapy were markedly different (P < 0.01). From posttransplant days 5 to 7, 54% of patients treated with CsA-ME had a mean dose-normalized C(av) (C(av)/dose, D) value within 20% of the target concentration, compared with 42% of patients treated with CsA-GC (P = 0.03). Administration of the predicted oral dose of CsA-ME produced a Cmax > 700 ng/ml in 90% of patients from days 2 to 4, and in 97% from days 5 to 7, whereas administration of the predicted oral dose of CsA-GC produced a Cmax > 700 ng/ml in only 64 and 82% of patients during these same time periods, respectively (both P < 0.05). The mean estimated posttransplant F value of CsA-ME was significantly higher than that of CsA-GC; even at postoperative day 5 the value for CsA-GC was significantly lower than the pretransplant estimate (P < 0.01). Therefore, CsA-ME pretransplant PK profiles yield more accurate predictions for appropriate starting drug doses than those of CsA-GC.
本研究的目的是比较环孢素A（CsA）微乳剂（CsA-ME；新山地明）与玉米油基（CsA-GC；山地明）软胶囊制剂给药后移植前试验剂量药代动力学（PK）分析的准确性，以估计移植后CsA的生物利用度并个体化起始药物剂量。根据肾移植候选者移植前静脉和口服PK谱配对数据，分别采用CsA-GC（n = 70）或CsA-ME（n = 70）给药，计算绝对口服生物利用度（F）、清除率（CL）、平均血药浓度（C[av]）、峰浓度（Cmax）和达峰时间（tmax）值。通过将观察到的移植前值线性外推至目标浓度来估计移植后初始口服CsA剂量。由于与CsA-GC治疗相比，CsA-ME治疗的终末期肾病患者观察到更高的平均F值（P < 0.0001），但CL值无差异，因此每种治疗的预测起始剂量明显不同（P < 0.01）。移植后第5至7天，接受CsA-ME治疗的患者中有54%的平均剂量标准化C(av)（C(av)/剂量，D）值在目标浓度的20%以内，而接受CsA-GC治疗的患者为42%（P = 0.03）。在第2至4天，90%接受CsA-ME预测口服剂量的患者Cmax > 700 ng/ml，第5至7天为97%；而在相同时间段内，接受CsA-GC预测口服剂量的患者Cmax > 700 ng/ml的比例分别仅为64%和82%（均P < 0.05）。CsA-ME移植后平均估计F值显著高于CsA-GC；即使在术后第5天，CsA-GC的值也显著低于移植前估计值（P < 0.01）。因此，与CsA-GC相比，移植前CsA-ME的PK谱对合适的起始药物剂量能做出更准确的预测。
