Relationship between circadian rhythm of vinorelbine toxicity and efficacy in P388-bearing mice.

The relevance of chronopharmacology for improving tolerability and antitumor efficacy of the antimitotic drug vinorelbine was investigated in female B6D2F1 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 nearly 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 relevance 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 one of six circadian times, 4 h apart. A significant correlation between single dose and median survival time was limited to vinorelbine administration at 19 or 23 HALO. An increase in the vinorelbine weekly dose shortened median survival time in the mice treated at 7 HALO (20 mg/kg: 29 days; 24 mg/kg: 17 days; and 26 mg/kg: 6 days) but significantly improved it in those treated 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 tolerated dose and the need to deliver maximum tolerated dose at the least toxic time to achieve survival improvement through chronotherapy. This may be obtained with an evening administration of vinorelbine in cancer patients.

Vinorelbine (Navelbine). A new semisynthetic vinca alkaloid.

Vinorelbine (Navelbine) is a new, semisynthetic 5'Nor-vinca-alkaloid, modified on the catharantine ring, developed by Pierre Fabre Médicament. Vinorelbine is a potent as the other vinca alkaloids to inhibit mitotic microtubule polymerization. On the other hand, its activity is lower on axonal microtubule. Preclinical studies have shown its broad spectrum of activity in vitro and its antitumoral efficacy comparable or higher to that of other vinca alkaloids against murine tumors and in xenograft models. The main experimental toxicity of vinorelbine is a reversible leucopenia. No neurotoxicity was evidenced in rats, dogs and monkeys. After i.v. injection in patients, the plasma kinetic is described by a tricompartimental model with a high clearance, a very large volume of distribution and a long terminal half life, intermediate between vincristine and vinblastine. Tissue uptake of vinorelbine is very intense, probably related to its high liposolubility, leading to high tissue concentration compared to plasma. Phase I trial using weekly i.v. administration demonstrated a maximal tolerated dose (MTD) of 27.5 to 35.4 mg/m2 and the recommended dose was established at 30 mg/m2 weekly. In Phase II studies, Vinorelbine was shown to be effective in at least 4 types of cancer: Non-small cell lung cancer (remission rate: 33%), breast cancer (45%), advanced ovarian cancer (15% in heavily pretreated patients), Hodgkin's disease (90%). In all the trials, side effects are generally limited to a reversible and non-cumulative leucopenia. Neurotoxicity appears to be mild, similar to that observed with vinblastine and much less severe than with vincristine. No evidence of cardiac, pulmonary, renal, hepatic or other organ system toxicity has emerged.(ABSTRACT TRUNCATED AT 250 WORDS)