Circadian changes in mitoxantrone toxicity in mice: Relationship with plasma pharmacokinetics

Abstract

Circadian time-dependent differences in clinical toxicity of several anti-cancer agents were predicted from murine studies. Mitoxantrone is an anthracenedion (an anthracycline-related class of compounds) of increased clinical use, which may benefit from selective circadian timing. In 3 consecutive studies, a total of 428 male B6D2F1 mice aged from 8 to 10 weeks were synchronized by an alternation of 12 hr of light and 12 hr of darkness (LD 12:12). They received a single i.v. injection of mitoxantrone at one of 6 or 4 circadian stages differing by 4 or 6 hr. A dose-response relationship characterized body-weight loss and survival rate. Dose-toxicity relationship further closely depended upon circadian dosing time. Thus, a dose of 16 mg/kg killed 100% of the mice injected at 3 hr after light onset (HALO), and none of them at 11 or at 15 HALO (p from chi 2 < 0.001). Body-weight loss varied from 41% at 3 HALO to 32% at 15 HALO (p from ANOVA < 0.0001). Least hematologic toxicity and fastest recovery of a normal circulating leukocyte count corresponded to mitoxantrone injection near the middle of the dark-activity span, at 16 HALO. Similar findings characterized colonic and splenic lesions. Moreover, mitoxantrone was both distributed and eliminated faster after injection at 16 HALO. If such data apply to cancer patients, as was the case for other drugs investigated with this methodology, an afternoon infusion should enable high-dose mitoxantrone to be well tolerated.