Pharmacokinetic analysis. (A) TDZ trough concentrations were measured on days 1, 5, 8, 10, 17, 22, 29, and 36 for each study cohort. Plasma TDZ concentrations reached a steady state by day 5, and TDZ remained detectable up to day 29. In cohort III, TDZ was discontinued early for patients 12 and 13, and only patient 11 received doses to achieve steady-state plasma TDZ concentrations. This patient received TDZ at dose level III (100 mg every 6 hours) for the first 10 days (solid line), after which TDZ was deescalated to 50 mg every 6 hours (broken line) up to day 16 and discontinued thereafter. Data for cohorts I and II are displayed as mean ± standard error at each assessment point. (B) Plasma TDZ levels at steady state in relation to the target 10 μM concentration (conc.), previously shown to be effective against human AML in vitro.6 Data are expressed as cohort means and 95% CI. (C) Sum of plasma TDZ and its 2 active metabolites (2-sulfoxide and 2-sulfone) with DRD2 antagonistic effects in relation to the target concentration of 10 μM. Data are expressed as cohort means and 95% CI. (D) Sum of circulating DRD2 antagonist levels for individual patients normalized to daily dose of TDZ. Patient variation in plasma DRD2 antagonist level was associated with CYP2D6 genotype and its predicted drug metabolism phenotypes (difference between group means: 18.22, 95% CI: 4.1 to 32.3; P = .01).
