A sensitive assay for ZD1839 (Iressa) in human plasma by liquid-liquid extraction and high performance liquid chromatography with mass spectrometric detection: validation and use in Phase I clinical trials.

A specific and sensitive high performance liquid chromatography method for the quantitative determination of ZD1839 ('Iressa') concentrations in treated healthy volunteers and patients with cancer has been developed and validated. Plasma samples (0.5 ml) were extracted, at basic pH, with methyl-t-butyl ether using deuterated ZD1839 as an internal standard. The extracts were chromatographed on an Inertsil ODS3 column eluted with acetonitrile/ammonium acetate and ZD1839 and the internal standard quantified by mass spectrometric detection. The method was validated with respect to linearity, selectivity, precision, accuracy, limit of quantification (LOQ), recovery and stability. The precision and accuracy of the assay were good and the LOQ was 0.5 ng/ml. The assay has been successfully applied to a number of clinical and pharmacokinetic studies and been shown to be robust and reliable during routine use.

Phase I clinical evaluation of ZD6126, a novel vascular-targeting agent, in patients with solid tumors.

BACKGROUND: ZD6126 is a novel vascular-targeting agent that disrupts the endothelial tubulin cytoskeleton causing selective occlusion of tumor vasculature and extensive tumor necrosis. This Phase I clinical study was conducted to evaluate the dose and administration schedule of ZD6126. METHODS: Adult patients with solid tumors refractory to existing treatments received a 10-min, single-dose intravenous infusion of ZD6126 every 14 or 21 days. Subsequent dose escalation was performed, based on the incidence of adverse events (AEs) within the first cycle of drug administration. Blood samples were obtained for pharmacokinetic analysis, and the effects of ZD6126 on tumor vasculature were visualized using DCE-MRI technology. RESULTS: Forty-four patients received ZD6126 (5-112 mg/m2 in the 21-day schedule, n=35; 40-80 mg/m2 in the 14-day schedule, n=9). Common AEs were similar in both groups and included abdominal pain, nausea and vomiting, which appeared to be dose related. The incidence of abdominal pain at 112 mg/m2 in the 21-day study prevented further dose escalation. Pharmacokinetic studies confirmed that ZD6126 is rapidly hydrolyzed to ZD6126 phenol. There was no difference in the pharmacokinetics of ZD6126 phenol upon repeat administration or between the two dosing regimens. DCE-MRI evaluation has demonstrated the antivascular effects of ZD6126. CONCLUSIONS: This study identified that ZD6126 administered every 2 or 3 weeks at 80 mg/m2 was well tolerated, with mild but manageable gastrointestinal AEs. In approximately 11% (5 out of 44) of patients, ZD6126 was associated with cardiac events categorized as dose limiting toxicities (one patient with asymptomatic decreased left ventricular ejection fraction (LVEF), two with increased troponin concentrations, one with myocardial ischemia, and one with ECG signs of myocardial ischemia).