期刊
INVESTIGATIONAL NEW DRUGS
卷 30, 期 3, 页码 1055-1064出版社
SPRINGER
DOI: 10.1007/s10637-011-9637-1
关键词
Axitinib; Fatigue; Thyroid dysfunction; Biomarker; Pharmacokinetics; Vascular endothelial growth factor receptor
资金
- Pfizer Inc
- Pfizer Medical Affairs
- Pfizer Japan Inc.
Background Axitinib is an oral, potent and selective inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2 and 3. We report on data obtained from 18 Japanese patients with advanced solid tumors in two phase I trials that evaluated the safety, pharmacokinetics and antitumor activity of axitinib and also examined potential biomarkers. Methods Six patients received a single 5-mg dose of axitinib followed by 5 mg twice daily (BID), and an additional six patients received axitinib 5 mg BID only. Another six patients received axitinib at 5-mg, 7-mg and 10-mg single doses followed by 5 mg BID. Results Plasma pharmacokinetics following single doses of axitinib was generally linear. Common treatment-related adverse events were fatigue (83%), anorexia (72%), diarrhea (67%), hand-foot syndrome (67%) and hypertension (61%). Sixteen patients (89%) experienced thyroid-stimulating hormone (TSH) elevation. Grade 3/4 toxicities included hypertension (33%) and fatigue (28%). No grade 3/4 fatigue occurred in patients who started thyroid hormone replacement therapy when TSH was elevated. Thyroglobulin elevation was observed in all patients who continued treatment with axitinib for >= 3 months. Abnormal TSH correlated with exposure to axitinib (r=0.72). Decrease in soluble (s) VEGFR-2 levels significantly correlated with exposure to axitinib (r=-0.94). Axitinib showed antitumor activity across multiple tumor types. Conclusions Axitinib-related thyroid dysfunction could be due to a direct effect on the thyroid gland. Grade 3/4 fatigue and hypothyroidism appear to be controllable with use of thyroid hormone replacement therapy. sVEGFR-2 and TSH may act as biomarkers of axitinib plasma exposure.
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