Therapeutic drug monitoring (TDM) of the recent antipsychotic ziprasidone in dried blood spots (DBS) and plasma

Introduction: Ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazine-yl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one) is the most recent atypical antipsychotic introduced in the market. It probably has the highest selectivity of any antipsychotic agent toward 5-HT_2A receptors relative to D₂ and 5-HT_2C receptors [1]. The main clinical advantage of ziprasidone compared to other atypical antipsychotics seems to be its low incidence of metabolic side effects. However, the drug can cause severe undesired effects, mainly QTc prolongation and orthostatic hypotension. For this reason, an accurate TDM of patients is advised during ziprasidone therapy. Aim of this study is the development of an original analytical method for the determination of ziprasidone in dried blood spots (DBS) and plasma of psychotic patients, based on HPLC with spectrofluorimetric and spectrophotometric detection. DBS testing has the advantage of being a minimally invasive procedure; moreover, DBS can be easily stored and transported without the need for refrigeration. Methods: The analysis is carried out on a C8 reversed phase column, using a phosphate buffer/acetonitrile mixture as the mobile phase. Ziprasidone is natively fluorescent under the chromatographic conditions used, therefore fluorimetric detection is suitable for its dosage, granting satisfactory sensitivity and selectivity to the assay. The sample pre-treatment of DBS is based on a very fast and feasible solvent extraction procedure, while plasma sample cleaning is achieved by solid phase extraction. Results: The results obtained until now are satisfactory in terms of precision and extraction yield on both matrices. Conclusions: Method validation is currently in progress. From preliminary assays, the method seems to be suitable for the TDM of ziprasidone in DBS and plasma. References: [1] G.J. Marek, L.L. Carpenter, C.J. McDougle, L.H. Price, Synergistic action of 5-HT_2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology 28, 402–412 (2003).