Mahmood Iftekhar
From the Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food & Drug Administration, Bethesda, Maryland, USA.
Ther Drug Monit. 2007 Jun;29(3):271-8. doi: 10.1097/FTD.0b013e318042d3c4.
In recent years, with the advent of pediatric exclusivity and requirements for conducting clinical studies involving children, emphasis has been placed on finding safe and efficacious doses of drugs for children. It has been suggested that one can predict the clearance (CL) of a drug in children according to this equation: CL in the child = Adult CL * (Weight of the child/70)0.75. In light of the controversy surrounding the exponent of 0.75 for the prediction of clearance, the objectives of the study were as follows: (1) to develop allometric equations based on body weight or age to predict clearance of a drug in children; (2) to determine if the fixed exponent of 0.75 is a suitable exponent for the prediction of clearance in children from adult data, as compared with the allometric exponent generated for individual drugs; (3) to determine if the allometric equation generated on the basis of age predicts clearance in children better or worse than the allometric equation generated on the basis of body weight; and (4) to propose a new approach based on the findings of the current evaluation. Five methods were used to predict drug clearance in children. Six drugs were used in the evaluation, and drug clearance in each child was predicted for a given drug. Besides evaluating the exponent of 0.75, allometric equations were developed using double log plots of clearance versus body weight or age. The exponents of the allometric equations were then used to predict drug clearance by replacement of 0.75 in the aforementioned equation. The results of the study indicate that 0.75 is not the best exponent for prediction of drug clearance in children, and a more suitable approach is to develop an allometric relationship for a given drug in children. For all 6 drugs, there were 77 children in whom the clearance was predicted. There were 48 observations for which error in the predicted clearance was 50% or more with use of the exponent 0.75, whereas there were only 13 observations with prediction error > or = 50% when 0.75 was replaced by an allometric exponent developed for a given drug. In order to predict drug clearance in children with reasonable accuracy, an allometric equation should be developed for every drug and the exponent 0.75 should be replaced by the exponent of the allometric equation developed for that drug.
近年来，随着儿科药物独占期的出现以及开展涉及儿童的临床研究的要求，人们开始着重寻找儿童用药的安全有效剂量。有人提出，可以根据以下公式预测儿童药物清除率（CL）：儿童CL = 成人CL×(儿童体重/70)^0.75。鉴于围绕预测清除率时指数0.75存在的争议，本研究的目的如下：（1）基于体重或年龄建立异速生长方程，以预测儿童药物清除率；（2）与针对个别药物生成的异速生长指数相比，确定固定指数0.75是否适合根据成人数据预测儿童清除率；（3）确定基于年龄生成的异速生长方程预测儿童清除率的效果优于还是差于基于体重生成的异速生长方程；（4）根据当前评估结果提出一种新方法。采用了五种方法预测儿童药物清除率。评估中使用了六种药物，并针对每种药物预测每个儿童的药物清除率。除了评估指数0.75外，还通过清除率与体重或年龄的双对数图建立了异速生长方程。然后，将异速生长方程的指数代入上述公式中替换0.75，以预测药物清除率。研究结果表明，0.75并非预测儿童药物清除率的最佳指数，更合适的方法是针对儿童特定药物建立异速生长关系。对于所有6种药物，共对77名儿童的清除率进行了预测。使用指数0.75时，有48次预测清除率的误差达到或超过50%，而当用针对特定药物生成的异速生长指数替换0.75时，只有13次预测误差≥50%。为了合理准确地预测儿童药物清除率，应为每种药物建立异速生长方程，并将指数0.75替换为针对该药物建立的异速生长方程的指数。
