Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Clin Transl Sci. 2022 Jul;15(7):1776-1786. doi: 10.1111/cts.13295. Epub 2022 May 15.
Relapsed or resistant lupus nephritis (LN) is considered a difficult-to-treat type of LN, and enteric-coated mycophenolate sodium (EC-MPS) has been used in this condition. Therapeutic drug monitoring using the area under the plasma mycophenolic acid concentration from 0 to 12 h postdose (MPA-AUC ) ≥45 μg.h/ml is a useful approach to achieve the highest efficiency. This study assessed EC-MPS's pharmacokinetic (PK) and pharmacodynamic (PD) profiles and investigated an optimal level of the single time point of plasma MPA concentration. Nineteen biopsy-proven patients with class III/IV LN received 1440 mg/day of EC-MPS for 24 weeks. PK (maximum plasma MPA concentration [C ], time to C , and MPA-AUC ) and PD (activity of inosine-5'-monophosphate dehydrogenase [IMPDH]) parameters were measured at weeks 2, 8, 16, and 24. We found that IMPDH activity decreased from baseline by 31-42% within 2-4 h after dosing, coinciding with the increased plasma MPA concentration. MPA-AUC ≥45 μg.h/ml was best predicted by a single time point MPA concentration at C0.5, C2, C3, C4, and C8 (r = 0.516, 0.514, 0.540, 0.611, and 0.719, respectively), independent of dose, albumin, urine protein/creatinine ratio, and urinalysis. The MPA-C0.5 cutoff of 2.03 g/ml yielded the highest overall sensitivity of 85% and specificity of 88.2% in predicting MPA-AUC ≥45 μg.h/ml. A single timepoint of plasma MPA-C0.5 ≥2.03 μg/ml may help guide EC-MPS adjustment to achieve adequate drug exposure. Further study of EC-MPS used to validate this cutoff is warranted.
复发或难治性狼疮肾炎（LN）被认为是一种难以治疗的 LN 类型，肠溶性吗替麦考酚酯钠（EC-MPS）已被用于这种情况。通过测量给药后 0 至 12 小时内血浆麦考酚酸浓度下的面积（MPA-AUC）≥45μg.h/ml，来实现最高效率，是一种有用的方法。本研究评估了 EC-MPS 的药代动力学（PK）和药效动力学（PD）特征，并研究了血浆 MPA 浓度单点的最佳水平。19 名经活检证实的 III/IV 级 LN 患者接受 1440mg/天的 EC-MPS 治疗 24 周。在第 2、8、16 和 24 周测量 PK（最大血浆 MPA 浓度[C]、达峰时间[T]和 MPA-AUC）和 PD（肌苷-5'-单磷酸脱氢酶[IMPDH]活性）参数。我们发现，在给药后 2-4 小时内，IMPDH 活性从基线下降了 31-42%，同时血浆 MPA 浓度升高。MPA-AUC≥45μg.h/ml 最好由 C0.5、C2、C3、C4 和 C8 时的单点 MPA 浓度（r=0.516、0.514、0.540、0.611 和 0.719）预测，与剂量、白蛋白、尿蛋白/肌酐比和尿液分析无关。MPA-C0.5 的截断值为 2.03μg/ml 时，预测 MPA-AUC≥45μg.h/ml 的总敏感性为 85%，特异性为 88.2%。血浆 MPA-C0.5≥2.03μg/ml 的单点值可能有助于指导 EC-MPS 的调整，以实现足够的药物暴露。需要进一步研究 EC-MPS 来验证这一截止值。
