Terziivanov Dimiter, Bozhinova Kristina, Dimitrova Velislava, Atanasova Ivanka
Clinic for Therapeutics and Clinical Pharmacology, University Hospital St. I. Rilsky, Sofia, Bulgaria.
Clin Pharmacokinet. 2003;42(15):1393-409. doi: 10.2165/00003088-200342150-00006.
To explore the ability of the nonparametric expectation maximisation (NPEM) method of population pharmacokinetic modelling to deal with sparse data in estimating systemic caffeine clearance for monitoring and evaluation of cytochrome P450 (CYP) 1A2 activity.
Nonblind, single-dose clinical investigation in 34 non-related adult Bulgarian Caucasians (18 women and 16 men, aged between 18 and 62 years) with normal and reduced renal function.
Each participant received oral caffeine 3 mg/kg. Two blood samples per individual were taken according to the protocol for measuring caffeine plasma concentrations. A total of 67 measured concentrations were used to obtain NPEM estimates of caffeine clearance. Paraxanthine/caffeine plasma ratios were calculated and correlated with clearance estimates. Graphical methods and tests for normality were applied and parametric and nonparametric statistical tests were used for comparison.
NPEM median estimates of caffeine absorption and elimination rate constants, k(a) = 4.54 h(-1) and k(el) = 0.139 h(-1), as well as of fractional volume of distribution and plasma clearance, V(S1) = 0.58 L/kg and CL(S1) = 0.057 L/h/kg, agreed well with reported values from more 'data rich' studies. Significant correlations were observed between paraxanthine/caffeine ratios at 3, 8 and 10 hours and clearance (Spearman rank correlation coefficients, r(s), >0.74, p </= 0.04). Sex or renal function caused no significant differences in clearance. Heavy smokers and drinkers showed 2-fold higher CYP1A2 activity. Normality tests and graphical methods of analysing caffeine clearance supported a non-Gaussian and multicomponent distribution of CYP1A2 activity.
Collectively, the results show that the NPEM method is suitable and relevant for large-scale epidemiological studies of population phenotyping for cancer susceptibility and for abnormal liver function by monitoring CYP1A2 activity based on sparse caffeine data.
探讨群体药代动力学建模的非参数期望最大化（NPEM）方法在处理稀疏数据以估计全身咖啡因清除率方面的能力，用于监测和评估细胞色素P450（CYP）1A2活性。
对34名无亲缘关系的保加利亚成年白种人（18名女性和16名男性，年龄在18至62岁之间）进行非盲、单剂量临床研究，这些参与者肾功能正常或减退。
每位参与者口服3mg/kg咖啡因。根据测量咖啡因血浆浓度的方案，每人采集两份血样。共67个测量浓度用于获得咖啡因清除率的NPEM估计值。计算了副黄嘌呤/咖啡因血浆比值，并将其与清除率估计值进行关联。应用了图形方法和正态性检验，并使用参数和非参数统计检验进行比较。
NPEM对咖啡因吸收和消除速率常数的中位数估计值，k(a)=4.54 h(-1)和k(el)=0.139 h(-1)，以及分布分数体积和血浆清除率，V(S1)=0.58 L/kg和CL(S1)=0.057 L/h/kg，与来自更多“数据丰富”研究的报告值吻合良好。在3、8和10小时时，副黄嘌呤/咖啡因比值与清除率之间观察到显著相关性（斯皮尔曼等级相关系数，r(s)>0.74，p≤0.04）。性别或肾功能对清除率无显著差异。重度吸烟者和饮酒者的CYP1A2活性高2倍。咖啡因清除率的正态性检验和图形分析方法支持CYP1A2活性的非高斯和多组分分布。
总体而言，结果表明NPEM方法适用于通过基于稀疏咖啡因数据监测CYP1A2活性进行癌症易感性和肝功能异常的群体表型大规模流行病学研究。
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