Ratain M J, Mick R, Janisch L, Berezin F, Schilsky R L, Vogelzang N J, Kut M
Department of Medicine, University of Chicago IL 60637, USA.
Pharmacogenetics. 1996 Feb;6(1):93-101. doi: 10.1097/00008571-199602000-00008.
Amonafide is extensively metabolized, including conversion by N-acetylation to an active metabolite. Our previous studies have shown that fast acetylators of amonafide have increased toxicity, and we have recommended doses of 250 and 375 mg m-2 day-1 for 5 days, for fast and slow acetylators, respectively. Despite phenotype-specific dosing, significant variability in leukopenia persisted. The goal of this study was to construct and validate a pharmacodynamic model-based dosing strategy for amonafide, to try to further decrease inter-patient variability in leukopenia. The model was based on a training data set of 41 patients previously treated with amonafide. The first cycle nadir WBC was modelled as a function of dose, acetylator phenotype and baseline patient factors. This model was validated prospectively on patients similar to those in our previous studies. Based on the training data set, the optimal model was defined by three factors: acetylator phenotype, gender, and pretreatment WBC. Using this model and a target WBC nadir of 1700 microliters-1, six dosing strata were prospectively evaluated. A total of 24 fast acetylators received either 238 or 276 mg m-2 day-1 and 20 slow acetylators received between 345 and 485 mg m-2 day-1. The mean (+/- SE) error (deviation from target nadir) was 430 (+/- 240) cells microliters-1. Submaximal treatment (yielding grade 0-1 leukopenia) was limited to 20% of patients, while 55% experienced grade 2-3 toxicity. A complex dosing strategy for amonafide is feasible, employing prospective acetylator phenotyping, model-guided dosing, and adaptive control.
氨苯吖啶可被广泛代谢，包括通过N - 乙酰化转化为活性代谢物。我们之前的研究表明，氨苯吖啶的快速乙酰化者毒性增加，我们分别推荐快速和慢速乙酰化者的剂量为250和375 mg m-2 天-1，持续5天。尽管采用了根据表型特异性给药，但白细胞减少的显著变异性仍然存在。本研究的目的是构建并验证基于药效学模型的氨苯吖啶给药策略，试图进一步降低患者间白细胞减少的变异性。该模型基于41例先前接受氨苯吖啶治疗的患者的训练数据集。将首个周期的最低点白细胞计数建模为剂量、乙酰化者表型和患者基线因素的函数。该模型在与我们之前研究中的患者相似的患者中进行了前瞻性验证。基于训练数据集，最佳模型由三个因素定义：乙酰化者表型、性别和预处理白细胞计数。使用该模型和目标最低点白细胞计数为1700微升-1，前瞻性评估了六个给药层次。共有24名快速乙酰化者接受了238或276 mg m-2 天-1的剂量，20名慢速乙酰化者接受了345至485 mg m-2 天-1的剂量。平均（±标准误）误差（与目标最低点的偏差）为430（±240）个细胞微升-1。次最大治疗（产生0 - 1级白细胞减少）仅限于20%的患者，而55%的患者经历了2 - 3级毒性。采用前瞻性乙酰化者表型分析、模型指导给药和自适应控制的氨苯吖啶复杂给药策略是可行的。
