肾移植术后环孢素A血药浓度监测及其体内吸收评价

Cyclosporine Absorption Profiling and Therapeutic Drug Monitoring in Stable Renal Allograft Recipients

关键词:  吸收  血药浓度监测  微乳化环孢素  肾移植

Key words:  absorption  therapeutic drug monitoring  cyclosporine microemulsion  renal transplantation

摘要:

目的 探讨肾移植术后稳定患者口服微乳化环孢素A(CsA-ME)的剂量与其血药浓度谷值(C₀)和给药后2 h的血药浓度(C₂)的关系及其随时间的变化趋势，从而评价CsA-ME的体内吸收过程。方法 采用荧光免疫偏振法(FPIA)对92例肾移植患者术后不同时间内测定全血中环孢素A的C₀和C₂浓度，并分别与每位患者每日每千克体重的用药剂量(ND)相比，得出其相应的浓度(即C₀/ND，C₂/ND)。计算C₂/C₀比值并对所得数据进行统计分析。结果 肾移植患者术后1~3个月内，C₀/ND和C₂/ND均增加。C₀/ND从(43±15)增加到(56±20) (ng·mL^-1)/(mg·kg^-1)，C₂/ND从(129±62)增加到(212±80) (ng·mL^-1)/(mg·kg^-1)，表明药物的吸收逐渐增加。但术后3~12个月内，C₂/ND维持原有水平，C₀/ND则逐渐降低为48±15 (ng·mL^-1)/(mg·kg^-1)，C₂/C₀比值则从4.5±1.9逐渐增加至5.2±2.3，表明药物在体内的消除代谢逐渐增加。术后3~12个月内，C₂/ND的个体间变异系数明显小于C₀/ND的个体间变异系数。结论 肾移植患者服用CsA-ME在术后3~12月内，其环孢素A在体内的累积清除率逐渐增加，表明术后一年内单纯用C₀作为监测指标已不能准确预测CsA-ME在体内的药物暴露总量，应结合C₂监测对于提高个体化的治疗将更有临床意义。

Abstract:

OBJECTIVE Therapetic drug monitoring for cyclosporine microemulsion (CsA-ME) is often performed using trough levels (C₀) or levels at 2 h post-dose (C₂). This analysis assessed changes in C₀ and C₂ and their relationship to CsA-ME dose over one year post-transplant in renal transplant patients. METHODS All 92 post-transplant patients in whom C₀ and C₂ were available at month 1, 3, 6, 12 were measured by FPIA. Normalized dose (ND) of CsA-ME, defined as dose per kilogram body weight, was caculated, together with C₀/ND, C₂/ND and C₂/C₀. RESULTS Both C₀/ND and C₂/ND increased between month 1 and 3: C₀/ND increased from 43±15 to 56±20 (ng·mL^-1)/(mg·kg^-1) and C₂/ND increased from 129±62 to 212±80 (ng·mL^-1)/(mg·kg^-1). Between month 3 and 12, C₂/ND remained stable but C₀/ND decreased to 48±15 (ng·mL^-1)/(mg·kg^-1) while the C₂/C₀ ratio increased from 4.5±1.9 to 5.2±2.3, indicating an acceleration of drug elimination. The inter-individual coefficient of variation was higher for C₂/ND than for C₀/ND at month 3 and 12. CONCLUSION CsA-ME clearance accelerates between month 3 and 12 post-transplant, resulting in lower C₀ levels for a given exposure. As a consequence, C₀ monitoring may not progressively underestimate CsA-ME exposure during the first year post-transplant. C₂ monitoring contributes to improve individualized CsA-ME treatment beyond month 3.