Zha J, Endrenyi L
Department of Pharmacology, University of Toronto, Ontario, Canada.
J Biopharm Stat. 1997 Mar;7(1):191-204. doi: 10.1080/10543409708835179.
Contrasts were evaluated for the maximum blood or plasma concentration (C(max)) of drugs measured after repeated and single oral administrations. Variances of C(max) were calculated and also simulated for a single drug as well as the comparison of two formulations, i.e., for the analysis of investigations of both bioavailability and bioequivalence. The coefficient of variation (CV) of C(max) was higher in the steady state than after a single drug administration when the variability of the disposition rate constant (k) was substantially larger than that of the absorption rate constant (k(a)). In turn, the CV of C(max) was substantially lower following repeated than after single drug administration when the variability of k(a) dominated that of k. The latter condition often prevails in practice since the relative variation of absorption rates generally substantially exceeds that of clearance (the latter being proportional to k). The statistical insensitivity is superimposed on the low kinetic sensitivity exhibited by C(max) following repeated drug administrations. Consequently, bioequivalence trials conducted in the steady state generally permit a declaration of equivalence even between drug products that have very different absorption rates.
对重复口服给药和单次口服给药后测得的药物最大血药浓度或血浆浓度（C(max)）进行了对比评估。计算了C(max)的方差，并针对单一药物以及两种制剂的比较进行了模拟，即用于生物利用度和生物等效性研究的分析。当处置速率常数（k）的变异性显著大于吸收速率常数（k(a)）的变异性时，稳态下C(max)的变异系数（CV）高于单次给药后。反之，当k(a)的变异性主导k的变异性时，重复给药后C(max)的CV显著低于单次给药后。后一种情况在实际中经常出现，因为吸收速率的相对变异性通常大大超过清除率的变异性（后者与k成正比）。统计不敏感性叠加在重复给药后C(max)表现出的低动力学敏感性上。因此，在稳态下进行的生物等效性试验通常允许宣布即使是吸收速率非常不同的药品之间也具有等效性。
