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Circadian changes in mitoxantrone toxicity in mice: relationship with plasma pharmacokinetics
F Lévi1, M Tampellini, G Metzger
1Laboratoire Rythmes Biologiques et Chronothérapeutique, Brousse, Villejuif, France.
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.
Insights
Circadian timing significantly impacts mitoxantrone toxicity in mice. Administering this chemotherapy agent in the afternoon reduced side effects and improved survival, suggesting optimized dosing schedules for cancer patients.
Area of Science:
- Pharmacology
- Oncology
- Chronobiology
Background:
- Circadian rhythms influence drug toxicity and efficacy.
- Mitoxantrone, an anthracenedione, is used in cancer therapy.
- Previous murine studies predicted time-dependent toxicity for anti-cancer agents.
Purpose of the Study:
- To investigate the circadian time-dependent toxicity of mitoxantrone in mice.
- To determine if adjusting mitoxantrone administration time can reduce adverse effects.
- To establish optimal dosing schedules for mitoxantrone based on circadian rhythms.
Main Methods:
- 428 male B6D2F1 mice were synchronized to a 12-hour light/12-hour dark cycle.
- Mice received a single intravenous injection of mitoxantrone at various circadian stages.
- Dose-response relationships for body weight loss, survival rate, hematologic toxicity, and organ lesions were analyzed.
Main Results:
- Mitoxantrone toxicity was highly dependent on circadian dosing time.
- A dose of 16 mg/kg was lethal when administered at 3 hours after light onset (HALO) but not at 11 or 15 HALO.
- Body weight loss was significantly reduced when mitoxantrone was given later in the day (15 HALO vs. 3 HALO).
- Least toxicity and fastest recovery were observed with administration near the middle of the activity span (16 HALO).
- Faster drug distribution and elimination occurred at 16 HALO.
Conclusions:
- Circadian-timed administration of mitoxantrone can significantly reduce its toxicity in mice.
- Afternoon administration of mitoxantrone may allow for better tolerance of high doses in cancer patients.
- These findings support the clinical application of chronotherapy for mitoxantrone treatment.