Rougier Florent, Ducher Michel, Maurin Michel, Corvaisier Stéphane, Claude Daniel, Jelliffe Roger, Maire Pascal
UMR CNRS 5558-ADCAPT Service Pharmaceutique, Hôpital Antoine Charial, Francheville, France.
Clin Pharmacokinet. 2003;42(5):493-500. doi: 10.2165/00003088-200342050-00007.
To develop a model that relates the probability of occurrence of nephrotoxicity to the cumulative area under the curve (AUC) of amikacin serum concentration.
This was a retrospective study of two groups of patients in whom nephrotoxicity was observed after administration of amikacin. The first group consisted of patients treated with once-daily administration (ODA) [n = 13]. The second group consisted of patients treated with twice-daily administration (TDA) [n = 22].
The probability of nephrotoxicity occurrence.
The model is a powerful tool to represent and describe the influence of the dosage regimen on aminoglycoside nephrotoxicity. The onset of nephrotoxicity is delayed in the ODA group (p = 0.01) for the same total daily dose among the two groups. The cumulative serum AUC values at onset of nephrotoxicity were greater for the ODA group (p = 0.029). In addition, for the same probability of nephrotoxicity occurrence (50%), the cumulative AUC for the ODA dosage regimen is 2 613 mg. h/L versus only 1 521 mg. h/L for the TDA dosage regimen. The difference in nephrotoxicity between ODA and TDA is greatest for a cumulative AUC of 2 495 mg. h/L, which corresponds to standard therapy with amikacin 900 mg/day during a 7-day period, i.e. 15 mg/kg/day for a 60kg patient with normal renal function (initial creatinine clearance >80 mL/min). For an AUC above 2 495 mg. h/L, the difference in nephrotoxicity decreases slowly to zero. This result means that ODA is especially justified when the treatment is administered over a short duration, i.e. less than 7 days.
The utility of selecting ODA in order to obtain less nephrotoxicity in comparison with TDA is therefore not established when the treatment is prolonged. In clinical use, the choice of the dosage regimen is not clear-cut, and both expected efficacy and expected toxicity must be taken into account in order to obtain an overall optimisation of each patient's therapy.
建立一个将肾毒性发生概率与阿米卡星血清浓度曲线下面积（AUC）累计值相关联的模型。
这是一项对两组使用阿米卡星后出现肾毒性的患者进行的回顾性研究。第一组由接受每日一次给药（ODA）治疗的患者组成（n = 13）。第二组由接受每日两次给药（TDA）治疗的患者组成（n = 22）。
肾毒性发生的概率。
该模型是一种强大的工具，可用于表示和描述给药方案对氨基糖苷类药物肾毒性的影响。在两组总日剂量相同的情况下，ODA组肾毒性的发生延迟（p = 0.01）。肾毒性发生时ODA组的血清AUC累计值更高（p = 0.029）。此外，对于相同的肾毒性发生概率（50%），ODA给药方案的累计AUC为2613mg·h/L，而TDA给药方案仅为1521mg·h/L。当累计AUC为2495mg·h/L时，ODA和TDA之间的肾毒性差异最大，这相当于在7天内使用900mg/天的阿米卡星进行标准治疗，即对于肾功能正常（初始肌酐清除率>80mL/min）的60kg患者，剂量为15mg/kg/天。对于AUC高于2495mg·h/L的情况，肾毒性差异缓慢降至零。这一结果意味着，当治疗持续时间较短（即少于7天）时，ODA尤其合理。
因此，当治疗时间延长时，与TDA相比，选择ODA以降低肾毒性的效用尚未确立。在临床应用中，给药方案的选择并不明确，为了全面优化每位患者的治疗，必须同时考虑预期疗效和预期毒性。
