Relationship between circadian rhythm of vinorelbine toxicity and efficacyin P388-bearing mice

The relevance of chronopharmacology for improving tolerability and antitumo r efficacy of the antimitotic drug vinorelbine was investigated in female B 6D2F(1) mice standardized with 12 h of light and 12 h of darkness. A single i.v. vinorelbine dose (26 mg/kg) was given to 279 mice at 7, 11, 19, or 23 hours after light onset (HALO). Bone marrow necrosis and leukopenia were n early twice as large in the mice injected at 7 HALO as compared with those treated at 19 HALO (ANOVA: p < .001 and p = 0.004, respectively). The relev ance of vinorelbine dosing time for antitumor efficacy was assessed in 672 P388 leukemia-bearing mice. Vinorelbine was injected as a single dose (20, 24, 26, or 30 mg/kg) or weekly (20, 24, 26, or 28 mg/kg/injection x 3) at o ne of six circadian times, 4 h apart. A significant correlation between sin gle dose and median survival time was limited to vinorelbine administration at 19 or 23 HALO. An increase in the vinorelbine weekly dose shortened med ian survival time in the mice treated at 7 HALO (20 mg/kg: 29 days; 24 mg/k g: 17 days; and 26 mg/kg: 6 days) but significantly improved it in those tr eated at 19 HALO (20 mg/kg: 28.5 days; 24 mg/kg: 32 days; and 26 mg/kg: 36 days). The study demonstrates the circadian rhythm dependence of maximum to lerated dose and the need to deliver maximum tolerated dose at the least to xic time to achieve survival improvement through chronotherapy. This may be obtained with an evening administration of vinorelbine in cancer patients.