Abstract 1671: A simple HPLC method to measure plasma mitotane and its two main metabolites in adrenocortical cancer patients

Abstract

Abstract Adrenocortical carcinoma (ACC) is a rare, aggressive tumour which is often detected in advanced stage. Mitotane (o,p’-DDD) is the drug of choice for unresectable, recurrent and metastatic ACC. Intraadrenal metabolic transformation is essential for its therapeutic effects but the metabolite responsible is unknown (o,p’-DDE or o,p’-DDA). Benefit depends on maintenance of adequate plasma drug levels >14μg/ml and toxicity occurs at >20μg/ml. The relationship between dose administered and steady state plasma level is variable, with up to 5-10 fold inter-patient variation. Plasma level monitoring during treatment allows more rapid and consistent attainment of levels between 14-20μg/ml. Measurement of o,p’-DDD and metabolites o,p'-DDE and o,p’-DDA could provide a better understanding of mitotane pharmacokinetics and pharmacodynamics. We have developed and validated a simple HPLC method to measure plasma mitotane and its two principal metabolites using an internal standard (p,p’-DDD), which involves an isocratic elution and separation through a reversed phase phenyl HPLC column with UV detection (λ 226nm). All these compounds are well separated from each other and from other interfering peaks with a total run time of 21min. The method has been evaluated using 63 plasma samples from 11 patients on mitotane therapy, median age 53 years (range13-73) with start dose of 1-4.5 gm/day. Trough o,p’-DDD levels ranged between 0.9-37.7μg/ml, o,p'-DDE levels 0-4.4μg/ml and o,p’-DDA levels 8.5-90.8μg/ml indicating o,p’-DDA levels in patient plasma are about 1.2-18.1 times higher than the parent compound. 37 samples with o,p’-DDD levels <14μg/ml were recommended to steadily increase dose up to 12 gm/day to achieve target level and then continue at that dose. 10 samples with o,p’-DDD levels >20μg/ml were recommended to decrease dose. Correlation with clinical data would allow us to confirm a relationship between plasma level of o,p’-DDD, o,p'-DDE and o,p’-DDA and clinical outcome, including tumour response or stablisation and toxicity. We aim to establish a therapeutic drug monitoring facility for assessment of plasma mitotane and metabolite levels in patients in the Asia Pacific region. A result and dosing recommendation could be available within 7 days of receipt of sample. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1671.