Abstract 3358: Pharmacokinetic investigation of unbound vandetanib in patients with medullary thyroid carcinoma using liquid chromatography-tandem mass spectrometry.
Authors: Sophie Broutin, Marjorie Salles, Sophie Leboulleux, Alain Deroussent, Cécile N. Chougnet, Eric Baudin, Jean-Michel Bidart, Martin Schlumberger, Angelo Paci
Journal: Cancer Research (2013)

Abstract Introduction: Vandetanib is a once-daily oral multikinase inhibitor with antitumoral activity in patients with advanced medullary thyroid carcinoma (MTC). Previously, we reported a relationship between high serum levels of vandetanib and serious toxicity. A significant impact of the unbound concentration of kinase inhibitors on clinical response and/or toxicity has been suggested. Here, we report the application of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the measurement of unbound serum vandetanib level in MTC patients. Materials and Methods: Serum from 13 MTC patients was prospectively collected during each course of vandetanib treatment (starting dose 300 mg/day) from 1 week up to 24 months and stored at -20°C before analysis. Total and unbound exposure monitoring was investigated on 134 and 90 samples respectively. Unbound serum fraction was obtained by conventional ultrafiltration with Centrifree® YM-30 device. The previously described LC-MS/MS method was used to quantify total and unbound vandetanib. Results: We developed and validated a fast and sensitive LC-MS/MS assay allowing the quantitation of the unbound fraction of vandetanib in human serum. The calibration curve was linear from 2.5 to 250 ng/mL with a lower limit of quantitation at 5.7 ng/mL. Intraday and interday CV (%) for unbound vandetanib ranged from 2.7 to 6.5% and from 5.6 to 6.9%, respectively. Median unbound vandetanib serum levels evaluated in MTC patients indicated a progressive rise from ∼50 ng/ml (at 1 week) to ∼70 ng/ml (at 3 months) that persisted over time. Mean percentage of unbound vandetanib was 8%, in agreement with literature. Six of the 13 patients presented serious adverse events that required treatment interruption and/or dose reduction within 3 months of treatment. As expected, 3 patients with adverse events had a serum vandetanib level higher by more than 20% above the median level during the first 3 months of treatment. Interestingly, one patient with serious adverse event presented higher unbound vandetanib levels than the other patients, but its total vandetanib level was not increased. Conclusion: The steady state unbound vandetanib level is close to 70 ng/mL and total and unbound fraction may be relevant for therapeutic monitoring. Relationship between free fraction levels and adverse events is currently under investigation on a larger cohort of patients. Citation Format: Sophie Broutin, Marjorie Salles, Sophie Leboulleux, Alain Deroussent, Cécile N. Chougnet, Eric Baudin, Jean-Michel Bidart, Martin Schlumberger, Angelo Paci. Pharmacokinetic investigation of unbound vandetanib in patients with medullary thyroid carcinoma using liquid chromatography-tandem mass spectrometry. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3358. doi:10.1158/1538-7445.AM2013-3358