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Prediction of olanzapine exposure in individual patients using physiologically based pharmacokinetic modelling and simulation

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dc.contributor.authorPolasek, T.M.
dc.contributor.authorTucker, G.T.
dc.contributor.authorSorich, M.J.
dc.contributor.authorWiese, M.D.
dc.contributor.authorMohan, T.
dc.contributor.authorRostami Hodjegan, A.
dc.contributor.authorKorprasertthaworn, P.
dc.contributor.authorPerera, V.
dc.contributor.authorRowland, A.
dc.date.issued2018
dc.description.abstractAim: The aim of the present study was to predict olanzapine (OLZ) exposure in individual patients using physiologically based pharmacokinetic modelling and simulation (PBPK M & S). Methods: A 'bottom-up' PBPK model for OLZ was constructed in Simcyp® (V14.1) and validated against pharmacokinetic studies and data from therapeutic drug monitoring (TDM). The physiological, demographic and genetic attributes of the 'healthy volunteer population' file in Simcyp® were then individualized to create 'virtual twins' of 14 patients. The predicted systemic exposure of OLZ in virtual twins was compared with measured concentration in corresponding patients. Predicted exposures were used to calculate a hypothetical decrease in exposure variability after OLZ dose adjustment. Results: The pharmacokinetic parameters of OLZ from single-dose studies were accurately predicted in healthy Caucasians [mean-fold errors (MFEs) ranged from 0.68 to 1.14], healthy Chinese (MFEs 0.82 to 1.18) and geriatric Caucasians (MFEs 0.55 to 1.30). Cumulative frequency plots of trough OLZ concentration were comparable between the virtual population and patients in a TDM database. After creating virtual twins in Simcyp®, the R2 values for predicted vs. observed trough OLZ concentrations were 0.833 for the full cohort of 14 patients and 0.884 for the 7 patients who had additional cytochrome P450 2C8 genotyping. The variability in OLZ exposure following hypothetical dose adjustment guided by PBPK M&S was twofold lower compared with a fixed-dose regimen - coefficient of variation values were 0.18 and 0.37, respectively. Conclusions: Olanzapine exposure in individual patients was predicted using PBPK M&S. Repurposing of available PBPK M&S platforms is an option for model-informed precision dosing and requires further study to examine clinical potential.
dc.identifier.citationBritish Journal of Clinical Pharmacology, 2018; 84(3):462-476
dc.identifier.doi10.1111/bcp.13480
dc.identifier.issn0306-5251
dc.identifier.issn1365-2125
dc.identifier.urihttps://hdl.handle.net/11541.2/130731
dc.language.isoen
dc.publisherWiley-Blackwell Publishing Ltd.
dc.relation.fundingSimcyp Ltd
dc.relation.fundingCertara
dc.rightsCopyright 2017 British Pharmacological Society Access Condition Notes: Accepted manuscript available after 1 January 2019
dc.source.urihttps://doi.org/10.1111/bcp.13480
dc.subjectdose prediction
dc.subjectolanzapine
dc.subjectPBPK
dc.subjectpersonalized medicine
dc.subjectphysiologically based pharmacokinetics
dc.subjectHumans
dc.subjectAntipsychotic Agents
dc.subjectDrug Monitoring
dc.subjectGenotype
dc.subjectModels, Biological
dc.subjectComputer Simulation
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectAsian Continental Ancestry Group
dc.subjectEuropean Continental Ancestry Group
dc.subjectFemale
dc.subjectMale
dc.subjectYoung Adult
dc.subjectCytochrome P-450 CYP2C8
dc.titlePrediction of olanzapine exposure in individual patients using physiologically based pharmacokinetic modelling and simulation
dc.typeJournal article
pubs.publication-statusPublished
ror.fileinfo12156386740001831 13156386730001831 Polasek_et_al-2017-British_Journal_of_Clinical_Pharmacology.pdf
ror.mmsid9916171191701831

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