Office of Pharmaceutical Science Center for Drug Evaluation and Research Food and Drug Administration, 10903 New Hampshire Avenue, Building 51, Rm. 4108, Silver Spring, Maryland 20993-0002, USA.
Pharm Res. 2011 Aug;28(8):1939-47. doi: 10.1007/s11095-011-0421-x. Epub 2011 Apr 13.
Assessment of bioavailability/bioequivalence generally relies on the comparison of rate and extent of drug absorption between products. Rate of absorption is commonly expressed by peak concentration (C(max)) and time to peak concentration (T(max)), although these parameters are indirect measures of absorption rate. Recognizing the importance of systemic exposure to drug efficacy and safety, FDA recommended that systemic exposure be better used for bioavailability/bioequivalence assessment. Apart from peak exposure and total exposure, FDA also recommended a new metric for early exposure that is considered necessary when a control of input rate is critical to ascertain drug efficacy and/or safety profile. The early exposure can be measured by truncating the area under the curve at T(max) of the reference product (PAUC(r,tmax)) or some designated early time after dosing. The choice of truncation is most appropriately based on PK/PD relationship or efficacy/safety data for the drug under examination. Compared with C(max), PAUC(r,tmax) has higher sensitivity in detecting formulation differences and may be more variable. If the metric is highly variable, the reference-scaling approach can be employed for bioequivalence evaluation. The partial area metric is useful in PK/PD characterization as well as in the evaluation of bioavailability, bioequivalence and/or comparability.
生物利用度/生物等效性评估通常依赖于产品间药物吸收速率和程度的比较。吸收速率通常用峰浓度 (C(max)) 和达峰时间 (T(max)) 表示，尽管这些参数是吸收速率的间接衡量指标。鉴于系统暴露对药物疗效和安全性的重要性，FDA 建议更好地使用系统暴露来评估生物利用度/生物等效性。除了峰暴露和总暴露外，FDA 还推荐了一种新的早期暴露指标，当控制输入速率对于确定药物疗效和/或安全性特征至关重要时，该指标被认为是必要的。早期暴露可以通过在参比产品的 T(max) 处截断曲线下面积（PAUC(r,tmax)) 或给药后某个指定的早期时间来测量。截断的选择最适合基于待检查药物的 PK/PD 关系或疗效/安全性数据。与 C(max) 相比，PAUC(r,tmax) 在检测配方差异方面具有更高的灵敏度，并且可能更具变异性。如果该指标高度可变，则可以采用参比缩放方法进行生物等效性评估。部分面积指标在 PK/PD 特征描述以及生物利用度、生物等效性和/或可比性评估中都很有用。
