Olanzapine is one of the most commonly used antipsychotic drugs in treatment of schizophrenia and bipolar disorder. The interindividual variability in pharmacokinetics of olanzapine is extensive, with a 10-20-fold difference in serum concentration despite equivalent dosing. The aim of this thesis was to identify and evaluate factors that influence the pharmacokinetics of olanzapine, and thereby provide knowledge that can be applied in order to individualize treatment with olanzapine.
Therapeutic drug monitoring samples from patients treated with olanzapine were used as data material in all four studies of the thesis. The serum concentration of olanzapine and metabolites were quantified with liquid chromatography-mass spectrometry (LC-MS) analyses. Overall, cigarette smoking, age and gender were shown to be significant determinants of olanzapine variability. Non-smokers generally obtained a two-fold higher dose-adjusted serum concentration (C/D ratio) compared to smokers. Age and gender were also shown to be significant determinants of olanzapine C/D ratio, but the numerical effects of these factors were less than those mentioned above. Furthermore, it was shown that comedication with the antiepileptic drugs valproic acid and carbamazepine substantially affected C/D ratio of olanzapine. The estimated reductions were approximately 30% and 50%, respectively. Concurrent use of ethinyl-estradiol containing contraceptives and a mutation in the gene encoding uridine diphosphate glycosyl transferase 1A4 (UGT1A4) did not affect serum concentration of olanzapine significantly, but both were shown to have significant impact on metabolic pathways of olanzapine.
In conclusion, the present thesis reveals that cigarette smoking, age, gender and comedication with valproic acid or carbamazepine are significant factors which contribute to the variability in pharmacokinetics of olanzapine. Summarized, a female, non-smoking patient ≥60 years receiving olanzapine monotherapy, would on average obtain a more than 3-fold higher C/D ratio compared to a male, smoking patient <60 years comedicated with valproic acid or carbamazepine. To improve the therapeutic effect and reduce the risk of side effects, these factors should be considered as a basis for individualized dosing of olanzapine in clinical practice.
List of papers. The papers are removed from the thesis due to copyright restrictions.
The effect of variable cigarette consumption on the interaction with clozapine and olanzapine.
Haslemo T, Eikeseth PH, Tanum L, Molden E, Refsum H.
Eur J Clin Pharmacol. 2006 Dec;62(12):1049-53.
The effect of ethinylestradiol-containing contraceptives on the serum concentration of olanzapine and N-desmethyl olanzapine.
Haslemo T, Refsum H, Molden E.
Br J Clin Pharmacol. 2011 Apr;71(4):611-5.
UGT1A4*3 Encodes Significantly Increased Glucuronidation of Olanzapine in Patients on Maintenance Treatment and in Recombinant Systems
T Haslemo, I Loryan, N Ueda, B Mannheimer, L Bertilsson, M Ingelman-Sundberg, E Molden and E Eliasson
Clin Pharmacol Ther. 2012 Aug;92(2):221-7.
Valproic acid significantly lowers serum concentration of olanzapine – an interaction effect comparable to smoking.
Haslemo T, Olsen K, Lunde H, Molden E.
Ther Drug Monit. 2012 Oct;34(5):512-7. Submitted version.