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Studies on Variability in Olanzapine Disposition
Linköping University, Department of Clinical and Experimental Medicine, Psychiatry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
2011 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Schizophrenia and schizoaffective disorders are chronic conditions with a significant impact on many functions. Positive, negative, cognitive and motor symptoms appear in different degrees and constellations. Antipsychotics are of fundamental importance to reduce symptoms. However, insufficient clinical effect and adverse drug reactions (ADRs) are important limitations of this drug therapy. Olanzapine (OLA) is a second-generation antipsychotic (SGA) drug widely used in the treatment of schizophrenia and schizoaffective disorder. The drug has well-documented effects against positive symptoms and has been claimed to be efficacious also against negative symptoms.

This thesis comprises of two studies. The aim of study 1 was to investigate factors that may influence the inter- and intra-individual variability of steady-state trough concentrations of OLA and its N-desmethyl metabolite (DMO) in serum. This was done in a cohort of patients treated with oral OLA in a routine clinical setting. In study 2 steady-state trough serum OLA and DMO concentrations were studied in relation to cerebrospinal fluid (CSF) OLA and DMO concentrations in patients with schizophrenia or schizoaffective disorder, medicated with oral OLA as the only antipsychotic drug. We also analysed the effects of age, gender smoking and concomitant medication in both studies and in study 2 we also analysed polymorphisms in genes with suggested importance for OLA disposition. The drug metabolizing enzymes CYP1A2 and CYP2D6 have earlier been found to be of importance for OLA metabolism and one animal study has suggested a role for P-gp for the transport of OLA into the brain. Therefore we analysed the influence of single nucleotide polymorphisms in the CYP1A2 gene (-3860G>A, -2467T>delT, -739T>G, -729C>T, -163C>A, and in the CYP2D6 gene (*3, *4, *5,*6, and*41) and in the ABCB1 gene (1236C>T, 3435C>T, and 2677G>A/T).

Study 1 started as a post-marketing surveillance project. In 1997 a high-performance liquid chromatography (HPLC)-based therapeutic drug monitoring (TDM) routine for serum OLA and DMO was established. During 1997–1999, a total of 753 TDM requests for a total of 545 Swedish patients were analysed. Additional patient information on certain clinical variables was collected on a specifically designed TDM request form. Samples from 194 patients were found to be eligible for further scrutiny. We found that the concentration-to-dose ratio (C/D) for OLA varied 25-fold and that of DMO 22-fold between individuals. The intraindividual variability over time was lower. Women had significantly higher median C/D ratio for OLA than men. However, the higher C/D ratio for OLA in women was statistically significant only in the non-smoking group. Non-smokers had significantly higher C/D ratio for OLA than smokers. Smokers received significantly higher daily doses of OLA than non-smokers. In the group with reported ADRs, the serum OLA concentration was 22% higher than in the group without ADRs. Patients co-medicated with carbamazepine had a 71% lower C/D ratio for OLA than patients who did not co-medicate with carbamazepine.

Study 2 included 37 Caucasian outpatients (10 smokers and 27 non-smokers). CSF was collected from 29 out of them. Because of very low OLA and DMO concentrations in CSF, a new liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for determination of OLA and DMO in serum and CSF was developed. We found a strong correlation between serum and CSF concentrations of OLA and a somewhat weaker corresponding correlation regarding DMO. The median CSF concentrations of OLA and DMO were on an average 13% and 16% of the serum levels. Non-smokers had higher (P <0.01) C/D ratio for OLA in serum and in CSF than smokers. Extensive metabolizers (EM) of CYP2D6 had higher daily OLA dosages than poor metabolizers (PM) when the influence of smoking was taken into account. EM smokers also showed lower CSF C/D for DMO than PM smokers. The DMO/OLA ratio in CSF showed a similar pattern, with a statistically significant combined effect of smoking and CYP2D6 genotype, EM smokers having the lowest and PM smokers the highest ratio. The combination of smoking and CYP2D6 genotype also affected the CSF/serum DMO ratio, PM smokers having the highest and EM smokers the lowest ratio (mean 20%, vs 9.5%). Patients co-medicating with benzodiazepines also showed higher CSF DMO/OLA ratio than patients without benzodiazepines. Moreover, DMO concentrations in CSF in relation to serum were higher in benzodiazepine users than in patients not comedicating with benzodiazepines (mean 24% vs 14.4%). Smoking habits did not affect these results. Carriers of the ABCB1 1236T/2677T/3435T haplotype had higher serum and CSF OLA concentrations than patients without this haplotype. The C/D ratios for serum DMO decreased with increasing age (P < 0.05).

In summary, smoking habits and co-medication with carbamazepine should be taken into consideration when dosing OLA. In study 1 we noted that women had higher serum C/D OLA ratio than men among non-smokers. This could not be confirmed in study 2, probably due to the small study population. Polymorphisms in genes of importance for OLA metabolism (CYP1A2 and CYP2D6) and transport (ABCB1) over membranes have some, but probably a minor, effect on serum and CSF concentrations. Larger studies are needed to confirm these observations. Smoking in combination with CYP2D6 polymorphism and the use of benzodiazepines affected the DMO metabolism in the brain in this study. However, because of low precision in the method at low DMO concentrations and a low number of patients, these results must also be confirmed in larger studies. The strong correlation between serum and CSF OLA concentrations established in study 2 indicates that factors influencing serum concentrations (such as smoking) also influence these concentrations in CSF. When patients are non-responsive to treatment, not compliant, vulnerable to ADRs on standard doses, or when drug interactions are suspected, TDM serum-OLA concentrations can be used as a diagnostic tool. Therapeutic drug monitoring is also of value to optimize long-term treatment of patients as environmental factors such as smoking and drug interactions may differ over time and could markedly interact with a patient´s metabolic capacity and thereby the therapeutic outcome.

Abstract [sv]

Schizofreni och schizoaffektiv sjukdom är livslånga tillstånd som oftast medför påtaglig funktionsnedsättning och betydande lidande både för patienten och närstående. Trots att antipsykotika är avgörande för behandlingsframgång vid dessa sjukdomar förekommer inte sällan problem med bristande behandlingseffekt och/eller biverkningar. Olanzapin (OLA) är ett läkemedel godkänt för akut- och underhållsbehandling av schizofreni och schizoaffektiv sjukdom. OLA blev godkänt för allmän förskrivning i Sverige 1996.

Det övergripande syftet med detta projekt var att undersöka variation i omsättningen av OLA och dess metabolit N-desmetylolanzapin (DMO) vid behandling av patienter med schizofreni eller schizoaffektiv sjukdom. Projektet utgörs av två delstudier. Studie 1 syftade till att klargöra hur OLA- och DMO-koncentrationer varierar i blodet mellan individer och inom individer vid upprepade mätningar. Syftet med studie 2 var att utforska om det fanns någon korrelation mellan OLA- och DMO-koncentrationer i serum och i likvor hos patienter som behandlades med enbart OLA som antipsykotiskt läkemedel. Effekten av rökning, kön, ålder och eventuell annan pågående medicinering undersöktes i båda studierna. I arbete 2 analyserades även samband till varianter av gener som kodar för läkemedelsmetabolism (CYP2D6, CYP1A2) och läkemedelstransport (ABCB1).

Materialet till studie 1 insamlades under 1997-1999. Med vätskekromatografi analyserades OLA- och DMO-koncentrationer i 753 serumprover från 545 patienter. Kliniska data registrerades enligt ett strukturerat protokoll. För de 194 patienter där provet var korrekt taget (jämvikt, dalvärde) och där relevant klinisk information fanns tillgänglig gjordes ytterligare dataanalys. Vi fann att förhållandet mellan serumkoncentration och OLA dos (C/D OLA) varierade 25-faldigt och C/D DMO varierade 22-faldigt mellan individer. Kvinnor hade signifikant högre C/D OLA än män och icke-rökare hade högre C/D OLA än rökare. Rökare ordinerades högre doser av OLA än icke-rökare. I gruppen med rapporterade biverkningar var medianvärdet av OLA i serum 22 % högre än i gruppen utan biverkningar. Patienter som samtidigt medicinerade med karbamazepin hade ett 71% lägre medianvärde av C/D OLA än patienter utan karbamazepinmedicinering. Variabiliteten av C/D OLA var lägre inom individer vid upprepade mätningar vid olika tillfällen än mellan individer.

I studie 2 inkluderades 37 svenska polikliniska patienter (10 rökare och 27 icke-rökare). Från 29 avdessa erhölls likvor via lumbalpunktion. Vi fann stark korrelation mellan OLA-koncentration iserum och likvor och något svagare korrelation mellan serum- och likvorkoncentration av DMO. Likvorkoncentrationerna av OLA och DMO var i genomsnitt 12% respektive 16% avkoncentrationerna i serum. Icke-rökare hade högre C/D OLA i serum och likvor än rökare.Snabba metaboliserare via CYP2D6 förskrevs högre dagliga doser än långsammametaboliserare när hänsyn togs till rökvanor. Rökande långsamma metaboliserare hade högreC/D DMO i likvor, högre DMO/OLA ratio och högre likvor/serum DMO än rökande snabbametaboliserare. Även patienter som samtidigt medicinerade med bensodiazepiner hade högreCSF DMO/OLA ratio och högre likvor/serum DMO än patienter som inte medicinerade medbensodiazepiner. Bärare av haplotypen 1236T/2677T/3435T för ABCB1 hade högre serumochlikvorkoncentrationer av OLA än patienter utan denna haplotyp. C/D DMO minskademed ökande ålder.

Sammanfattningsvis fann vi att rökvanor och samtidig medicinering med karbamazepin påverkar metabolismen av OLA, vilket ska beaktas vid dosering av OLA. I studie 1 visade serumanalyser högre C/D OLA hos kvinnor än hos män. Denna könsskillnad var statistiskt signifikant enbart för icke rökare. Genetiska varianter av de metaboliserande enzymerna CYP2D6 och CYP1A2 hade en viss, men till synes underordnad, effekt. De effekter vi noterade avseende likvoromsättningen av DMO hos rökande långsamma metaboliserare samt hos patienter som använde bensodiazepiner måste undersökas närmare i framtida studier pga. viss metodosäkerhet vid låga DMO-koncentrationer. Det fanns en stark korrelation mellan serum- och likvorkoncentrationer av OLA och en något svagare motsvarande korrelation för DMO. Resultaten talar för att koncentrationer av OLA i serum reflekterar dem i likvor. Den intraindividuella variabiliteten av C/D OLA var som väntat lägre än den interindividuella variabiliteten. OLA-behandling kan betraktas som förutsägbart i så måtto att vid ökad dosering ökar likvorkoncentrationen linjärt med koncentrationen i serum. Serumkoncentrationsmätning av OLA kan, förutom att vara vägledande avseende ordinationsföljsamhet, användas för optimering av OLA-behandling och för långsiktig individuell uppföljning. Omgivningsfaktorer, som t.ex. rökning eller samtidig medicinering med vissa andra läkemedel, kan interagera med genetiska faktorer avseende läkemedelsmetabolism. Detta kan i sin tur markant påverka individuell variation över tid. Ändrade rök- och medicineringsvanor kan därför kräva betydande justeringar av OLAdosering.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 62 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 116
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-71231ISBN: 978‐91‐7393‐146‐5 OAI: oai:DiVA.org:liu-71231DiVA: diva2:446445
Presentation
2011-10-14, Consensussalen, psyk US, pl 10, ingång 27, Campus US, Linköpnigs universitet, Linköping, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2011-10-07 Created: 2011-10-07 Last updated: 2011-10-07Bibliographically approved
List of papers
1. Therapeutic drug monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting
Open this publication in new window or tab >>Therapeutic drug monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting
Show others...
2002 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, Vol. 24, no 4, 518-526 p.Article in journal (Refereed) Published
Abstract [en]

Olanzapine (Zyprexa«) was approved for general prescription in Sweden in November 1996, and an HPLC-based therapeutic drug monitoring (TDM) routine for serum olanzapine (OLA) and its major metabolite, N-demethylolanzapine (DMO) was established in February 1997. During 1997 to 1999, a total of 753 TDM requests for a total of 545 Swedish patients was analyzed. Additional patient information on certain clinical variables was collected on specifically designed TDM request forms. After the exclusion process, samples from 194 patients were found to be eligible for further scrutiny. The concentration-to-dose (C/D) ratio for OLA varied 25-fold and that of DMO 22-fold. Women had a higher (P < 0.01) median C/D ratio for OLA than men (median, 7.2 nmol/L/mg vs 5.2 nmol/L/mg). Nonsmokers had a higher (P < 0.001) C/D ratio for OLA than smokers (median, 9,2 nmol/L/mg vs 4.0 nmol/L/mg). Smokers got higher prescribed (P < 0.05) doses of OLA than nonsmokers did. In the group with reported side effects, the median serum OLA concentration was 22% higher (P < 0.05) than in the group without side effects. Patients co-medicated with carbamazepine had a 71% lower median C/D ratio for OLA than patients on OLA monotherapy. The present TDM-based follow-up suggests that the influence of gender, smoking habits, and certain drug interactions may need to be considered for optimal dosage of OLA. TDM may be used for this purpose more readily in the future.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27669 (URN)10.1097/00007691-200208000-00010 (DOI)12407 (Local ID)12407 (Archive number)12407 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-10-28
2. High Correlation Between Serum and Cerebrospinal Fluid Olanzapine Concentrations in Patients With Schizophrenia or Schizoaffective Disorder Medicating With Oral Olanzapine as the Only Antipsychotic Drug
Open this publication in new window or tab >>High Correlation Between Serum and Cerebrospinal Fluid Olanzapine Concentrations in Patients With Schizophrenia or Schizoaffective Disorder Medicating With Oral Olanzapine as the Only Antipsychotic Drug
2011 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 31, no 1, 4-9 p.Article in journal (Refereed) Published
Abstract [en]

The primary aim of the present study was to investigate the relationship between steady state serum and cerebrospinal fluid (CSF) concentrations of olanzapine (OLA) and its metabolite 4-N-desmethylolanzapine (DMO) in patients with schizophrenia or schizoaffective disorder treated with oral OLA as the only antipsychotic drug. The influence of smoking, gender, age, as well as polymorphisms in cytochrome P450 CYP2D6, CYP1A2, and ABCB1 genes on the serum and CSF drug levels was also analyzed. Thirty-seven white outpatients (10 smokers and 27 nonsmokers) were included. From 29 of them, CSF was collected successfully. A strong correlation (Spearman rank correlation [r(s)] = 0.93; P = 0.05) was found between serum and CSF concentrations of OLA and a somewhat weaker correlation (r(s) = 0.5; P = 0.05) between those of DMO. The CSF concentrations of OLA and DMO were on average 12% and 16% of those in serum. Extensive metabolizers of CYP2D6 had higher (P = 0.05) daily doses than poor metabolizers when the influence of smoking was taken into account. Smokers had lower (P = 0.01) concentration-to-dose ratios of OLA in serum (mean, 2.23 ng/mL per mg vs 3.32 ng/mL per mg) and CSF (0.27 ng/mL per mg vs 0.41 ng/mL per mg) than nonsmokers. The concentration-to-dose ratio for serum DMO decreased with increasing age (r(s) = -0.41; P = 0.05). Carriers of ABCB1 1236T/2677T/3435T haplotype had higher serum (mean, 37.7 ng/mL vs 22.5 ng/mL; P = 0.035) and CSF (4.7 ng/mL vs 2.6 ng/mL; P = 0.018) OLA concentrations than patients without this haplotype. The present study shows a strong correlation between serum and CSF concentrations of OLA, indicating that concentrations of OLA in serum reflect those in CSF.

Place, publisher, year, edition, pages
Williams and Wilkins, 2011
Keyword
olanzapine, smoking, serum concentration, cerebrospinal fluid, pharmacogenetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-64762 (URN)10.1097/JCP.0b013e318204d9e2 (DOI)000285771000002 ()
Available from: 2011-02-04 Created: 2011-02-04 Last updated: 2017-12-11Bibliographically approved

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