Oral versus intravenous vinorelbine: clinical safety profile

Abstract

The availability of chemotherapeutic drugs administrable by oral route represents a step forward in the management of cancer patients. Among oral agents, vinorelbine is particularly interesting for its pharmacological characteristics and clinical efficacy. Oral vinorelbine is rapidly absorbed (1.5-3 hours) with an elimination half-life of approximately 40 hours. It shows a low level of binding to plasma proteins (13%), is highly bound to platelets (78%) and has a hepatic metabolism and an absolute bioavailability of 40% with a moderate and similar interpatient variability for the two forms. Food has no influence on the pharmacokinetic profile of oral vinorelbine even if nausea/vomiting is less frequent and less severe in the fed patients than in the fasting patients. Therefore, to ensure patient comfort, it is recommended that oral vinorelbine is administered with a snack. All the metabolites of oral vinorelbine have been identified and, among these, only deacetyl-vinorelbine presented activity demonstrating that for both oral and intravenous (i.v.) routes of administration the drug has the same metabolism pattern. Oral vinorelbine is eliminated mainly in a unconjugated form via the bile. In this process, the CYP 3A4 isoform of cytochrome P450 is mostly involved. Absorption of oral vinorelbine is not delayed in elderly patients. After oral administration, blood concentrations of vinorelbine in elderly patients are within the range of values observed in younger patients. The absolute bioavailability is close to 38% in elderly whereas it is close to 40% in younger patients. This difference is not significant. As compared to the intravenous drug, oral vinorelbine demonstrated linear pharmacokinetics as well an absolute bioavailability of approximately 40%, and a reliable dose-correspondence of 80 mg/m2 oral form --> 30 mg/m2 i.v. and 60 mg/m2 oral --> 25 mg/m2 i.v. Therefore, i.v. and oral forms show similar interindividual variability, same metabolism pattern, reproducible intra-patient blood exposure, and same pharmacokinetic-pharmacodynamic relationship. Oral vinorelbine has shown significant activity in advanced non-small cell lung cancer. Given at 60 mg/m2/week for the first 3 administrations and then increased to 80 mg/m2/week achieved the same efficacy as i.v. vinorelbine in terms of progression-free survival, overall survival, objective response. Mild-to-moderate gastrointestinal toxicity, easily manageable with standard treatment was recorded. Reproducible efficacy compared to previously reported results with vinorelbine i.v. Also, in advanced breast cancer, oral vinorelbine has shown significant activity with a good therapeutic index. Albeit no formal comparison between the oral and the intravenous formulations of vinorelbine has been made, however, the oral route seems to offer major advantages to patients who are faced with a clear decrease in the frequency of hospital admissions as compared to that needed to give intravenous chemotherapy.

BubR1 is frequently repressed in acute myeloid leukemia and its re-expression sensitizes cells to antimitotic therapy

“…The serum levels of commonly administered spindle poisons, such as vincristine, vindesine, vinblastine, vinorelbine and taxol, are higher only within a short period of time after administration. 20,[31][32][33] Prolonged exposure to rather low serum levels may lead to induction of apoptosis only in those tumors that are highly sensitive to spindle poisons. However, we noted that AML cells are not able to undergo a sustained mitotic block even in the presence of high doses of spindle poison as evidenced in its extreme form by the finding of sister-chromatid separation in the presence of spindle disruption.…”

Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer

“…Oral vinorelbine (VRL) has shown bioavailability of 40%, which is practically not influenced by food or age, moderate interpatient variability, and linear pharmacokinetics (17)(18)(19)(20). Its metabolism has been elucidated and only 4-O-deacetylvinorelbine (DVRL) has been found active (21)(22)(23)(24).…”

“…Its metabolism has been elucidated and only 4-O-deacetylvinorelbine (DVRL) has been found active (21)(22)(23)(24). Both VRL and DVRL are mostly eliminated via the bile, and only limited amounts are excreted in urine (20,25). The elimination half-life of VRL is ∼40 hours and 168 hours for DVRL (20,25,26).…”

“…Both VRL and DVRL are mostly eliminated via the bile, and only limited amounts are excreted in urine (20,25). The elimination half-life of VRL is ∼40 hours and 168 hours for DVRL (20,25,26).…”

A Dose Escalation Study of Biweekly Oral Vinorelbine and Gemcitabine in Patients with Solid Tumors

“…The oral formulation of vinorelbine is particularly interesting because it is rapidly absorbed, has an elimination half-life of 40 h, is highly bound to platelets, has a hepatic metabolism and an absolute bioavailability of 40%, being similar to that of the parental drug [7]. Pharmacologic exposure of 80 and 60 mg/m 2 of oral vinorelbine per week is equivalent to that of the standard doses of 30 and 25 mg/m 2 , respectively, administered intravenously [8], whereas food has no effect on its pharmacokinetics [9]. …”