Predicting Plasma Olanzapine Concentration Following a Change in Dosage: A Population Pharmacokinetic Study.
BACKGROUND
Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge.


METHODS
Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM(®), using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information.


RESULTS
31 subjects (mean±SD age=56.0±11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p<0.001).


CONCLUSIONS
Plasma olanzapine concentrations following an actual dosage change can be predicted in advance with a high degree of certainty.
Department of Neuropsychiatry, Kyorin University School of Medicine, Tokyo, Japan.
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Tsuboi
Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN, USA.
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Bies
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
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Suzuki
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
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Takeuchi
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
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Nakajima
Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
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Graff-Guerrero
Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
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Mamo
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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Caravaggio
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
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Plitman
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
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Mimura
Geriatric Psychiatry Division, Centre for Addiction and Mental Health, Toronto, ON, Canada.
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Pollock
Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
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Uchida
D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D012559:Schizophrenia / Q000097:blood / Q000188:drug therapy*
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine