Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting

Abstract

There is limited information on the pharmacokinetics ofziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linköping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20 -320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L(-1) mg(-1) d(-1) forZIPand SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively,with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for dose-normalized serum concentrations of ZIP, SMDZ, andSMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIPconcentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.

Dopamine D2/3 occupancy of ziprasidone across a day: a within-subject PET study

“…The serum ziprasidone levels we observed 13 hours post-dose in this study (150±103 nmol/L; median: 114 nmol/L) are consistent with data reported at trough in a larger therapeutic drug monitoring sample (median: 125 nmol/L for 120 mg/day) (Cherma et al 2008). In contrast, the occupancy at 13 hours (39±26%) was slightly lower than that reported in previous PET studies (Mamo et al 2004; Vernaleken et al 2008), as well as a single photon emission tomography study that found D 2/3 receptor occupancy of 60% at 12 hours post-dose (Corripio et al 2005).…”

“…It has been pointed out that a range of 50–200 ng/ml for ziprasidone may be effective (Hiemke et al 2011) but it has also been identified that heterogeneity in levels is substantial with hits medication, both centrally (Gründer et al 2011) and peripherally (Cherma et al 2008). While this point is highly relevant in trying to translate the results of PET data to peripheral therapeutic drug monitoring (TDM) that is more easily applicable, and efforts are ongoing to better model pharmacokinetics of the medication (Wessels et al 2011) and to predict central occupancy levels using peripheral drug levels (Uchida et al 2011), it has been reported that blood levels of ziprasidone failed to well filter out responders, with no correlations observed between improvements or side effects and doses or serum levels (Vogel et al 2009).…”

Therapeutic drug monitoring of atypical antipsychotic drugs

“…However, great interindividual and intraindividual differences in ziprasidone concentrations were observed. TDM of ziprasidone may be used for individual dose adjustments and monitoring of medication adherence (52,53). The available PET studies with ziprasidone suggest that an antipsychotic effect can be expected above a threshold level at steady-state of approximately 50 ng mL -1 .…”

Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs—Influence of Smoking Behavior and Inflammation on Pharmacokinetics

“…This may be in agreement with the fact that the enzyme CYP1A2 is activated by smoking. However, at the current time it is not possible to make any solid conclusions regarding a possible explanation on the differences of smoking effects on dose-normalized ziprasidone concentrations between males and females [225]. Further research is required to ascertain the role of smoking status on plasma amisulpride and ziprasidone concentration.…”