A pilot study of vinorelbine safety and pharmacokinetics (PKs) in patients (pts) with varying degrees of liver dysfunction (LD).

Abstract

432 Background: Prospective data to support dosing guidelines for intravenous (IV) vinorelbine in pts with LD are limited. One study recommends standard 30 mg/m2 weekly for total bilirubin ≤2 mg/dL and a 50% dose reduction for bilirubin > 2 mg/dL. Another study recommends no dose modifications for bilirubin up to 3X the upper limit of normal (ULN). This phase I study describes the safety and PKs of vinorelbine in pts with varying degrees of hepatic impairment. Methods: Pts with treatment-refractory solid tumors received weekly IV 30 mg/m2 vinorelbine for normal liver function, 20 mg/m2 for mild LD defined as bilirubin < 1.5 mg/dL but aspartate aminotransferase (AST)/alanine aminotransferase (ALT) 1.5-2.5X ULN or alkaline phosphatase (ALK) 1.5-3X ULN, 15 mg/m2 or 30 mg/m2 for moderate LD defined as bilirubin 1.5-3.0 mg/dL and/or AST/ALT > 2.5 or ALK > 3X ULN, and 7.5 mg/m2 or 20 mg/m2 for severe LD defined as bilirubin > 3.0 mg/dL. Vinorelbine PKs were evaluated to describe its relationship with liver function. Results: 47 patients were enrolled (61.7% gastrointestinal and hepatobiliary cancers) and a total of 248 treatment-related adverse events (AEs) occurred. All-grade myelosuppression was the most common AE overall (41.1%). Out of 71 grade ≥3 AEs, 17 (23.9%) were grade 4 in severity with the majority (15/17) being myelosuppression. Rates of grade 4 hematologic AEs in the normal liver function and the 7.5 mg/m2 severe LD group were low ( < 10%). 4/17 grade 4 hematologic AEs were observed in the mild LD group while the remainder and majority occurred in the moderate-severe LD groups. Vinorelbine PKs were not correlated with the degree of LD, however free drug levels or levels of the active metabolite 4-O-deacetylvinorelbine were not measured. Conclusions: Weekly vinorelbine at 30 mg/m2 and 7.5 mg/m2 appears safe with normal liver function and severe LD, respectively. High rates of grade 4 myelosuppression with 15-30 mg/m2 vinorelbine in moderate-severe LD raise concerns for its safety in this population. Vinorelbine PKs are not affected by LD. However, it is possible that levels of the active metabolite could be higher in pts with LD if its elimination is impacted by LD to a greater extent than the parent drug. Clinical trial information: NCT00540982.