Pharmacokinetics of eribulin mesylate in patients with solid tumors and hepatic impairment

• Published in: Cancer chemotherapy and pharmacology Vol. 70; no. 6; pp. 823 - 832
• Main Authors: Devriese, L. A., Witteveen, P. O., Marchetti, S., Mergui-Roelvink, M., Reyderman, L., Wanders, J., Jenner, A., Edwards, G., Beijnen, J. H., Voest, E. E., Schellens, J. H. M.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01-12-2012; Springer; Springer Nature B.V
• Subjects: Aged; Analysis of Variance; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - blood; Antineoplastic Agents - pharmacokinetics; Area Under Curve; Biological and medical sciences; Cancer Research; Drug Administration Schedule; Female; Furans - administration & dosage; Furans - adverse effects; Furans - blood; Furans - pharmacokinetics; Gastroenterology. Liver. Pancreas. Abdomen; Hepatic Insufficiency - complications; Hepatic Insufficiency - metabolism; Humans; Ketones - administration & dosage; Ketones - adverse effects; Ketones - blood; Ketones - pharmacokinetics; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - complications; Neoplasms - drug therapy; Neoplasms - metabolism; Netherlands; Oncology; Original Article; Other diseases. Semiology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Treatment Outcome; Tumors; Child-Pugh; Microtubule dynamics inhibitor; Hepatic impairment; Pharmacokinetics; Eribulin mesylate; Antineoplastic agent; Human; Solid tumor; Eribulin; Hepatic disease; Patient; Malignant tumor; Liver failure; Dynamics; Cytoskeleton; Digestive diseases; Inhibitor; Microtubule; Child; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-012-1976-x

Purpose
The aim of this study was to determine the plasma pharmacokinetics of eribulin mesylate in patients with solid tumors with mild and moderate hepatic impairment.
Patients and methods
A phase I, pharmacokinetic study was performed in patients with advanced solid tumors and normal hepatic function or Child-Pugh A (mild) or Child-Pugh B (moderate) hepatic impairment. Treatments were given on day 1 and 8 of a 21-day cycle and consisted of 1.4, 1.1 and 0.7 mg/m
2
eribulin mesylate, for normal hepatic function, Child-Pugh A and B hepatic impairment, respectively. Also safety and anti-tumor activity were determined.
Results
Hepatic impairment increased exposure to eribulin. In patients with Child-Pugh A (
N
 = 7) and Child-Pugh B (
N
 = 5), mean dose-normalized AUC
0–∞
was 1.75-fold (90 % confidence intervals (CI): 1.16–2.65) and 2.48-fold (90 % CI: 1.57–3.92) increased, respectively, compared with patients who have normal function (
N
 = 6). The most frequently reported treatment-related events were alopecia (12/18) and fatigue (7/18) and these were observed across all groups. Nine patients (50 %) had stable disease as best response.
Conclusions
A reduced dose of 1.1 and 0.7 mg/m
2
of eribulin mesylate is recommended for patients with Child-Pugh A or B hepatic impairment, respectively.