PMID- 30710067 OWN - NLM STAT- MEDLINE DCOM- 20200724 LR - 20200724 IS - 1549-490X (Electronic) IS - 1083-7159 (Print) IS - 1083-7159 (Linking) VI - 24 IP - 8 DP - 2019 Aug TI - A Pilot Study of Vinorelbine Safety and Pharmacokinetics in Patients with Varying Degrees of Liver Dysfunction. PG - 1137-1145 LID - 10.1634/theoncologist.2018-0336 [doi] AB - BACKGROUND: Vinorelbine has demonstrated anticancer activity and is primarily metabolized in the liver. This single-institution, phase I pilot study describes the safety and pharmacokinetics of vinorelbine in patients with varying degrees of hepatic impairment. MATERIALS AND METHODS: Patients with treatment-refractory solid tumors were enrolled into treatment arms based on vinorelbine dose (weekly infusions of 7.5-30 mg/m(2)) and liver function (normal liver function, mild, moderate, or severe liver dysfunction). Vinorelbine pharmacokinetics were evaluated to describe its relationship with liver function. Indocyanine green (ICG) clearance was assessed for correlation with pharmacokinetics. RESULTS: Forty-seven patients were enrolled, and a total of 108 grade 3-4 treatment-related adverse events (AEs) occurred. Of these, grade 3-4 myelosuppression was the most common (34.3%). Thirty-three (30.6%), 22 (20.4%), and 9 (8.3%) grade 3-4 AEs were observed in the vinorelbine 20 mg/m(2)/severe, 15 mg/m(2)/moderate, and 7.5 mg/m(2)/severe liver dysfunction groups, respectively, with the majority being nonhematologic toxicities. ICG clearance decreased as liver function worsened. Vinorelbine pharmacokinetics were not correlated with ICG elimination or the degree of liver dysfunction. CONCLUSION: For patients with severe liver dysfunction (bilirubin >3.0 mg/dL), vinorelbine doses >/=7.5 mg/m(2) are poorly tolerated. The high incidence of grade 3-4 AEs with 15 mg/m(2) vinorelbine in moderate liver dysfunction (bilirubin 1.5-3.0 mg/dL) raises concerns for its safety in this population. Vinorelbine pharmacokinetics are not affected by liver dysfunction; however, levels of the active metabolite 4-O-deacetylvinorelbine were not measured and may be higher in patients with liver dysfunction if its elimination is impacted by liver impairment to a greater degree than the parent drug. IMPLICATIONS FOR PRACTICE: Vinorelbine remains widely prescribed in advanced malignancies and is under development in immunotherapy combinations. Given vinorelbine is primarily hepatically metabolized, understanding its safety and pharmacokinetics in liver dysfunction remains paramount. In this phase I pilot study, weekly vinorelbine at doses >/=7.5 mg/m(2) is poorly tolerated in those with severe liver dysfunction. Furthermore, a high incidence of grade 3-4 toxicities was observed with vinorelbine at 15 mg/m(2) in those with moderate liver dysfunction. Vinorelbine pharmacokinetics do not appear affected by degree of liver dysfunction. Further evaluation of levels of the free drug and active metabolites in relationship to liver function are warranted. CI - (c) AlphaMed Press 2019. FAU - Gong, Jun AU - Gong J AD - Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA. AD - Department of Internal Medicine, Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, California, USA. FAU - Cho, May AU - Cho M AD - Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA. AD - Department of Internal Medicine, Division of Hematology and Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California, USA. FAU - Gupta, Rohan AU - Gupta R AD - Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA. FAU - Synold, Timothy W AU - Synold TW AD - Department of Cancer Biology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California, USA. FAU - Frankel, Paul AU - Frankel P AD - Division of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, California, USA. FAU - Ruel, Christopher AU - Ruel C AD - Division of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, California, USA. FAU - Fakih, Marwan AU - Fakih M AD - Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA. FAU - Chung, Vincent AU - Chung V AD - Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA. FAU - Lim, Dean AU - Lim D AD - Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA. FAU - Chao, Joseph AU - Chao J AD - Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA jchao@coh.org. LA - eng GR - K12 CA001727/CA/NCI NIH HHS/United States GR - P30 CA033572/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190201 PL - England TA - Oncologist JT - The oncologist JID - 9607837 RN - 0 (Antineoplastic Agents, Phytogenic) RN - Q6C979R91Y (Vinorelbine) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents, Phytogenic/administration & dosage/*adverse effects/pharmacokinetics MH - Area Under Curve MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Drug Resistance, Neoplasm MH - Drug-Related Side Effects and Adverse Reactions/diagnosis/*epidemiology MH - Female MH - Hepatobiliary Elimination/physiology MH - Humans MH - Incidence MH - Liver/physiopathology MH - Liver Diseases/diagnosis/etiology/*physiopathology MH - Liver Function Tests MH - Male MH - Middle Aged MH - Neoplasms/complications/*drug therapy MH - Severity of Illness Index MH - Vinorelbine/administration & dosage/*adverse effects/pharmacokinetics PMC - PMC6693729 OTO - NOTNLM OT - Indocyanine green OT - Liver dysfunction OT - Pharmacokinetics OT - Safety OT - Vinorelbine COIS- Disclosures of potential conflicts of interest may be found at the end of this article. EDAT- 2019/02/03 06:00 MHDA- 2020/07/25 06:00 PMCR- 2020/02/01 CRDT- 2019/02/03 06:00 PHST- 2018/06/11 00:00 [received] PHST- 2019/01/03 00:00 [accepted] PHST- 2019/02/03 06:00 [pubmed] PHST- 2020/07/25 06:00 [medline] PHST- 2019/02/03 06:00 [entrez] PHST- 2020/02/01 00:00 [pmc-release] AID - theoncologist.2018-0336 [pii] AID - ONCO12835 [pii] AID - 10.1634/theoncologist.2018-0336 [doi] PST - ppublish SO - Oncologist. 2019 Aug;24(8):1137-1145. doi: 10.1634/theoncologist.2018-0336. Epub 2019 Feb 1.