INDIVIDUALIZED DOSING OF AMONAFIDE BASED ON A PHARMACODYNAMIC MODEL INCORPORATING ACETYLATOR PHENOTYPE AND GENDER

Amonafide is extensively metabolized, including conversion by N-acetyl ation to an active metabolite. Our previous studies have shown that fa st acetylators of amonafide have increased toxicity, and we have recom mended doses of 250 and 375 mg m(-2) day(-1) for 5 days, for fast and slow acetylators, respectively. Despite phenotype-specific dosing, sig nificant variability in leukopenia persisted. The goal of this study w as to construct and validate a pharmacodynamic model-based dosing stra tegy for amonafide, to try to further decrease inter-patient variabili ty in leukopenia. The model was based on a training data set of 41 pat ients previously treated with amonafide. The first cycle nadir WBC was modelled as a function of dose, acetylator phenotype and baseline pat ient factors. This model was validated prospectively on patients simil ar to those in our previous studies. Based on the training data set, t he optimal model was defined by three factors: acetylator phenotype, g ender, and pretreatment WBC. Using this model and a target WBC nadir o f 1700 mu l(-1), six dosing strata were prospectively evaluated. A tot al 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 mu l(-1). Submaximal treatment (yielding grade 0-1 leukopenia) was limited to 20% of patients, while 55% experienced grade 2-3 toxici ty. A complex dosing strategy for amonafide is feasible, employing pro spective acetylator phenotyping, model-guided dosing, and adaptive con trol.