Beaubien A R, Desjardins S, Ormsby E, Bayne A, Carrier K, Cauchy M J, Henri R, Hodgen M, Salley J, St Pierre A
Drug Toxicology Division, Health Protection Branch, Ottawa, Ontario, Canada.
Am J Otolaryngol. 1989 Jul-Aug;10(4):234-43. doi: 10.1016/0196-0709(89)90002-1.
A sigmoid curve was found to closely describe the relationship between the incidence of amikacin ototoxicity (greater than or equal to 15 dB hearing loss at a given frequency) and either (1) total dose, or (2) the area under the curve (AUC) describing plasma drug concentration v time over the total period of amikacin administration (total AUC) in continuously infused guinea pigs. Total dose or total AUC estimates of the drug exposure required to produce ototoxicity in 50% of the animals (ED50s) were not significantly different over an eight-fold range of dosing rates or plasma concentrations. A theoretical explanation for this result is that ototoxicity occurs only when a critical amount of drug is accumulated at the ototoxic site by an essentially unidirectional process with a rate that is slow and linearly related to the extracellular drug concentration. The sigmoid relationships for pooled data were parallel in slope for all hearing frequencies from 2 to 32 kHz, and the ED50s showed a strong negative linear relationship to the log of the hearing frequency over this range. The magnitude of ototoxicity expressed as the number of octaves (frequency ratios of 2) for which hearing loss damage was continuous from 32 kHz downward, was correlated to both total dose (r = .605) and total AUC (r = 0.703). No relationship between ototoxicity and plasma level or dosing rate was found. The extreme steepness of the dose-effect curve for the incidence of ototoxicity greatly amplified the variability between individuals and offers an explanation for the unpredictability of aminoglycoside ototoxicity in human patients. The results indicate that either total dose or total AUC (in cases of highly unpredictable blood levels), and not peak or trough serum levels, should be used as an index of ototoxic risk and that the safety limits of drug exposure should be set conservatively.
在持续输注的豚鼠中，发现一条S形曲线能紧密描述阿米卡星耳毒性发生率（在给定频率下听力损失大于或等于15 dB）与以下两者之间的关系：(1) 总剂量，或 (2) 描述阿米卡星给药全过程血浆药物浓度随时间变化的曲线下面积（AUC）（总AUC）。在8倍剂量率或血浆浓度范围内，导致50%动物出现耳毒性所需的药物暴露的总剂量或总AUC估计值（ED50）并无显著差异。对此结果的一种理论解释是，只有当一定量的药物以基本上单向的过程在耳毒性部位积累，且积累速率缓慢且与细胞外药物浓度呈线性相关时，才会发生耳毒性。合并数据的S形关系在2至32 kHz的所有听力频率上斜率平行，并且在此频率范围内，ED50与听力频率的对数呈强负线性关系。以从32 kHz向下听力损失持续的倍频程数（频率比为2）表示的耳毒性程度，与总剂量（r = 0.605）和总AUC（r = 0.703）均相关。未发现耳毒性与血浆水平或给药速率之间存在关系。耳毒性发生率的剂量 - 效应曲线极其陡峭，极大地放大了个体间的变异性，并为人类患者中氨基糖苷类耳毒性的不可预测性提供了解释。结果表明，应将总剂量或总AUC（在血药水平高度不可预测的情况下）而非血清峰浓度或谷浓度用作耳毒性风险指标，并且应保守设定药物暴露的安全限度。
