Li Hong, Mager Donald E, Sandmaier Brenda M, Storer Barry E, Boeckh Michael J, Bemer Meagan J, Phillips Brian R, Risler Linda J, McCune Jeannine S
Department of Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York.
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Schools of Medicine, University of Washington, Seattle, Washington.
Biol Blood Marrow Transplant. 2014 Aug;20(8):1121-9. doi: 10.1016/j.bbmt.2014.03.032. Epub 2014 Apr 13.
A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker.
一种在造血细胞移植（HCT）受者中实现移植后免疫抑制个性化的新方法，是评估肌苷单磷酸脱氢酶（IMPDH）活性，将其作为霉酚酸（MPA）诱导免疫抑制的药物特异性生物标志物。这项前瞻性研究评估了56例非清髓性HCT受者在第+21天早晨口服霉酚酸酯（MMF）后5个时间点外周血单个核细胞（PMNCs）中的总MPA、游离MPA和总MPA葡萄糖醛酸苷血浆浓度以及IMPDH活性。观察到患者间在药代动力学和药效学方面存在显著差异，并通过群体药代动力学-药效学模型进行了准确表征。IMPDH活性随MPA血浆浓度升高而降低，在大多数患者中，最大抑制作用与MPA浓度最大值同时出现。MPA浓度与IMPDH活性之间的总体关系由直接抑制最大效应模型描述，总MPA的IC50为3.23mg/L，游离MPA的IC50为57.3ng/mL。第+21天IMPDH效应曲线下面积（AUEC）与巨细胞病毒再激活、非复发死亡率和总死亡率相关。总之，建立了一个药代动力学-药效学模型，该模型将HCT受者服用MMF后血浆MPA浓度与PMNCs中的IMPDH活性联系起来。未来的研究应验证该模型，并确认第+21天IMPDH AUEC是一种预测性生物标志物。
