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Therapeutic Drug Monitoring of Ziprasidone in a Clinical Treatment Setting
Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. (Swedish National Board of Forensic Medicine)ORCID-id: 0000-0002-6041-0744
Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
Vise andre og tillknytning
2008 (engelsk)Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 30, nr 6, s. 682-688Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

There is limited information on the pharmacokinetics of ziprasidone (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 Linkoping, 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)) for ZIP and 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 close-normalized scruin concentrations of ZIP, SMDZ, and SMDZ: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 ZIP concentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.

sted, utgiver, år, opplag, sider
2008. Vol. 30, nr 6, s. 682-688
Emneord [en]
Antipsychotic agents, ziprasidone, therapeutic drug monitoring, serum concentration, naturalistic setting
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-16195DOI: 10.1097/FTD.0b013e31818ac8baOAI: oai:DiVA.org:liu-16195DiVA, id: diva2:133406
Tilgjengelig fra: 2009-01-09 Laget: 2009-01-09 Sist oppdatert: 2017-12-14bibliografisk kontrollert
Inngår i avhandling
1. Therapeutic Drug Monitoring in Psychiatry: Some aspects of utility in clinical practice and research
Åpne denne publikasjonen i ny fane eller vindu >>Therapeutic Drug Monitoring in Psychiatry: Some aspects of utility in clinical practice and research
2009 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Background and objectives: Several new psychoactive drugs for the treatment of psychiatric disorders have been introduced onto the market since the late 1980s. Basic aspects of pharmacodynamics and pharmacokinetics (PK) are investigated before approval for general prescription. Thus, a limited number of subjects are exposed to the drug before it is marketed and only sparse measurements of drug concentration are performed during phases II and III of drug development. The objective of this thesis was to provide further descriptive PK and linked patients data in naturalistic clinical settings. The PK of psychoactive drugs was also studied in the elderly and the young, major risk groups that are exposed in normal everyday clinical practice but that are underrepresented in the phases of drug development. The PK-data were to be assessed by samples sent to the Therapeutic Drug Monitoring (TDM) laboratory service. In a subset of individuals, the genotypes of the cytochrome P450 (CYP) enzymes were described.

Results: Serum concentration of the parent compound and its metabolites was provided from TDM-data on antidepressant escitalopram (Paper I) and antipsychotic ziprasidone (Paper II). A large interindividual PK variability was found. The daily dose of the drug was higher than the defined daily dose (DDD) for both escitalopram and ziprasidone (median dose 20 mg and 120 mg, respectively). The median number of drugs per patient, apart from the studied drug, was 4 and 3, respectively (range 1-18). If repeated eligible TDM-data were available, change in treatment strategies could be seen between the first and second sample for the patient, and the metabolite/parent compound (M/P) ratio had lower intraindividual than interindividual variation in the escitalopram study but opposite results were found in the ziprasidone study.

The prescription of antidepressant drugs (ADs) in the nursing homes studied was 38 % (Paper III). The concentration of the ADs was higher, or much higher, than could be expected from the dose administered in 73 %. The majority of the elderly people were treated with citalopram. No clear time schedule for how long the drug treatment should continue was found in the patients’ current medical record. The median number of drugs per patient apart from the AD was 11 (range 4-19), no monotherapy was found in these patients. The genetically impaired metabolic activity of CYP enzymes correlated to higher drug concentration as expected, in patients medicated with an AD that is substrate for the CYP enzyme genotype.

The concentrations of ADs were as expected from the dose administered in 63 % of the children/adolescents evaluated (Paper IV). The majority of TDM samples requested sertraline. PK outcome of sertraline was similar to the results in adult populations. Monotherapy was documented in 49 % (median number of drugs apart from AD was 1 per patient, range 1-7). Changes in treatment strategies were also shown, if repeated TDM-samples were available. The median variation of the M/P ratio for sertraline between the first and the last samples within the same patient was 20 % (the interindividual variation was 37 %). The poor metabolizers (PM) for CYP2D6 medicated with a CYP2D6 substrate had a lower dose than did non-PM for the same drug.

Conclusion: These studies provide reference data for the evaluation of the therapeutic response, i.e. a reference range of what is to be expected in a normal clinical setting, as well as the toxicological information concerning the psychoactive drugs studied. When available, the M/P ratio between two patients’ samples may assess patient compliance, as well as drug-drug interactions. Thus, the use of TDM can be beneficial for individual dose optimisation and drug safety, above all in the studied populations, elderly people and children/adolescents, when the selection of doses requires a consideration of PK parameters. TDM may be a tool for research, increasing knowledge of the psychoactive drug in TDM service, as well as toxicology. A more frequent clinical use of TDM and pharmacogenetic testing in clinical practice would contribute to a better quality when treating with psychoactive drugs.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2009. s. 84
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1152
Emneord
TDM, psychoactive drug, pharmacokinetics, pharmacogenetics, naturalistic, elderly, child
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-52107 (URN)978-91-7393-537-1 (ISBN)
Disputas
2009-12-18, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2009-12-07 Laget: 2009-12-04 Sist oppdatert: 2020-02-26bibliografisk kontrollert

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