Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Eur J Clin Pharmacol. 2010 Nov;66(11):1137-41. doi: 10.1007/s00228-010-0878-2. Epub 2010 Aug 3.
Midazolam metabolic clearance to 1'-hydroxymidazolam is an accurate measure of CYP3A activity which requires extensive plasma and urine sampling. The objective of this study was to find a new limited sampling strategy (LSS) to predict midazolam metabolic clearance to 1'-hydroxymidazolam and subsequently CYP3A activity in an easy and reliable way, reducing costs and labour.
The development of this LSS is based on data from an in vivo drug-drug interaction study carried out in our clinical research unit. Various partial AUCs of midazolam were calculated and correlated with metabolic clearance of midazolam to 1'-hydroxymidazolam by non-linear regression. The correlation with highest r (2) values was chosen to predict the midazolam metabolic clearance. Statistical significance of this method was verified by calculating the 95% confidence interval of the differences (%) between predicted and measured metabolic clearance of midazolam to 1'-hydroxymidazolam.
The midazolam partial AUC from 2 to 4 h after oral administration correlated best with metabolic clearance of midazolam to 1'-hydroxymidazolam with r (2) = 0.9816. This partial AUC comprised four midazolam concentrations at 2, 2.5, 3 and 4 h after oral administration of a midazolam solution. The 95% confidence interval of the differences between predicted metabolic clearance and measured metabolic clearance of midazolam to 1'-hydroxymidazolam was -0.97 to +13.2.
The determination of the partial AUC using four plasma samples from 2 to 4 h after oral administration of a midazolam solution is proposed to be an easy and reliable CYP3A phenotyping measure which of course needs to be validated in prospective clinical trials.
咪达唑仑向 1'-羟基咪达唑仑的代谢清除率是一种准确测量 CYP3A 活性的方法，需要进行广泛的血浆和尿液采样。本研究的目的是找到一种新的有限采样策略（LSS），以便以简单可靠的方式预测咪达唑仑向 1'-羟基咪达唑仑的代谢清除率和随后的 CYP3A 活性，从而降低成本和劳动力。
该 LSS 的开发基于在我们的临床研究单位进行的一项药物相互作用的体内研究数据。计算了咪达唑仑的各种部分 AUC，并通过非线性回归与咪达唑仑向 1'-羟基咪达唑仑的代谢清除率相关联。选择与最高 r（2）值相关的相关性来预测咪达唑仑的代谢清除率。通过计算预测和测量的咪达唑仑向 1'-羟基咪达唑仑的代谢清除率之间的差异（%）的 95%置信区间来验证该方法的统计学意义。
口服后 2 至 4 小时的咪达唑仑部分 AUC 与咪达唑仑向 1'-羟基咪达唑仑的代谢清除率相关性最好，r（2）= 0.9816。该部分 AUC 由口服咪达唑仑溶液后 2、2.5、3 和 4 小时的四个咪达唑仑浓度组成。预测的咪达唑仑向 1'-羟基咪达唑仑的代谢清除率与测量的代谢清除率之间差异的 95%置信区间为-0.97 至+13.2。
建议使用口服咪达唑仑溶液后 2 至 4 小时的四个血浆样本测定部分 AUC，作为一种简单可靠的 CYP3A 表型测定方法，当然需要在前瞻性临床试验中进行验证。
