Studies on Variability in Olanzapine Disposition

Sammanfattning: 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.