Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model

Sheila Botts; Francisco J. Diaz; Vincenza Santoro; Edoardo Spina; Maria R. Muscatello; Myladis Cogollo; Fidel E. Castro; Jose de Leon

doi:10.1016/j.pnpbp.2008.04.018

Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model

Sheila Botts, Francisco J. Diaz, Vincenza Santoro, Edoardo Spina, Maria R. Muscatello, Myladis Cogollo, Fidel E. Castro, Jose de Leon

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age ≥ 18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial "noise" that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites.

Original language	English
Pages (from-to)	1453-1458
Number of pages	6
Journal	Progress in Neuro-Psychopharmacology and Biological Psychiatry
Volume	32
Issue number	6
DOIs	https://doi.org/10.1016/j.pnpbp.2008.04.018
State	Published - Aug 1 2008

Bibliographical note

Funding Information:
The studies were conducted at the Department of Clinical and Experimental Medicine and Pharmacology, University of Messina and IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy. In the last year, Dr. Botts has been on the advisory board of Eli Lilly and received a researcher-initiated grant from Eli Lilly to study olanzapine drug–drug interactions, and served on the speakers' bureau for Bristol-Myers Squibb. Dr. Diaz was partially supported by Dr. Botts's grant to conduct these analyses. In the last year, Dr. Spina has lectured supported by Eli Lilly, Janssen, AstraZeneca and Bristol-Myers Squibb. Miss Cogollo was partially supported by grant “Apoyo a Estudiantes Sobresalientes de Posgrado” from the Universidad Nacional, Colombia. In the past year (2007), Dr. de Leon has received a researcher-initiated grant from Roche Molecular Systems, Inc., and was co-investigator in Dr. Botts's Eli Lilly grant. Before the last year, Dr. de Leon received one researcher-initiated grant from Eli Lilly, and his lectures have been supported two times by Eli Lilly (2003 and 2006). He personally develops his presentations for lecturing in academic institutions and has never lectured using Eli Lilly presentations or any other pharmaceutical company presentations. He has never been a consultant for Eli Lilly, has no other financial arrangements with this company nor owns any of its stocks. Lorraine Maw, M.A., helped in editing the article.

Keywords

Drug-drug interactions
Lamotrigine
Smoking
Valproic acid
carbamazepine

ASJC Scopus subject areas

Pharmacology
Biological Psychiatry

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10.1016/j.pnpbp.2008.04.018

Cite this

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title = "Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model",

abstract = "The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age ≥ 18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial {"}noise{"} that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites.",

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author = "Sheila Botts and Diaz, {Francisco J.} and Vincenza Santoro and Edoardo Spina and Muscatello, {Maria R.} and Myladis Cogollo and Castro, {Fidel E.} and {de Leon}, Jose",

note = "Funding Information: The studies were conducted at the Department of Clinical and Experimental Medicine and Pharmacology, University of Messina and IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy. In the last year, Dr. Botts has been on the advisory board of Eli Lilly and received a researcher-initiated grant from Eli Lilly to study olanzapine drug–drug interactions, and served on the speakers' bureau for Bristol-Myers Squibb. Dr. Diaz was partially supported by Dr. Botts's grant to conduct these analyses. In the last year, Dr. Spina has lectured supported by Eli Lilly, Janssen, AstraZeneca and Bristol-Myers Squibb. Miss Cogollo was partially supported by grant “Apoyo a Estudiantes Sobresalientes de Posgrado” from the Universidad Nacional, Colombia. In the past year (2007), Dr. de Leon has received a researcher-initiated grant from Roche Molecular Systems, Inc., and was co-investigator in Dr. Botts's Eli Lilly grant. Before the last year, Dr. de Leon received one researcher-initiated grant from Eli Lilly, and his lectures have been supported two times by Eli Lilly (2003 and 2006). He personally develops his presentations for lecturing in academic institutions and has never lectured using Eli Lilly presentations or any other pharmaceutical company presentations. He has never been a consultant for Eli Lilly, has no other financial arrangements with this company nor owns any of its stocks. Lorraine Maw, M.A., helped in editing the article.",

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N1 - Funding Information: The studies were conducted at the Department of Clinical and Experimental Medicine and Pharmacology, University of Messina and IRCCS Centro Neurolesi “Bonino-Pulejo”, Messina, Italy. In the last year, Dr. Botts has been on the advisory board of Eli Lilly and received a researcher-initiated grant from Eli Lilly to study olanzapine drug–drug interactions, and served on the speakers' bureau for Bristol-Myers Squibb. Dr. Diaz was partially supported by Dr. Botts's grant to conduct these analyses. In the last year, Dr. Spina has lectured supported by Eli Lilly, Janssen, AstraZeneca and Bristol-Myers Squibb. Miss Cogollo was partially supported by grant “Apoyo a Estudiantes Sobresalientes de Posgrado” from the Universidad Nacional, Colombia. In the past year (2007), Dr. de Leon has received a researcher-initiated grant from Roche Molecular Systems, Inc., and was co-investigator in Dr. Botts's Eli Lilly grant. Before the last year, Dr. de Leon received one researcher-initiated grant from Eli Lilly, and his lectures have been supported two times by Eli Lilly (2003 and 2006). He personally develops his presentations for lecturing in academic institutions and has never lectured using Eli Lilly presentations or any other pharmaceutical company presentations. He has never been a consultant for Eli Lilly, has no other financial arrangements with this company nor owns any of its stocks. Lorraine Maw, M.A., helped in editing the article.

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N2 - The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age ≥ 18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial "noise" that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites.

AB - The purpose of this study was to estimate the effect sizes of drug interactions on plasma olanzapine concentrations while adjusting for potentially confounding factors such as smoking. The estimation was performed by using a mixed model, data from a series of previously published studies of lamotrigine, oxcarbazepine, topiramate, and mirtazapine, and unpublished data from patients under clinical therapeutic drug monitoring (TDM). The total sample included 163 adult patients (age ≥ 18 years) who provided both steady-state plasma olanzapine concentrations and smoking information. They provided a total of 360 olanzapine concentrations (1 to 11 measures per patient). Smoking and concomitant carbamazepine or lamotrigine use were found to have significant effects on median plasma olanzapine concentrations. The effects of lamotrigine on plasma olanzapine concentrations were modified by smoking. After adjusting for olanzapine dose and carbamazepine intake, plasma olanzapine concentrations were 10% lower in non-smokers who were taking lamotrigine than in non-smokers who were not taking lamotrigine; olanzapine concentrations were 35% higher in smokers who were taking lamotrigine than in smokers who were not taking lamotrigine; olanzapine concentrations were 41% lower in smokers who were not taking lamotrigine than in non-smokers who were not taking lamotrigine; and olanzapine concentrations were 11% lower in smokers who were taking lamotrigine than in non-smokers who were taking lamotrigine. After adjusting for olanzapine dose and taking carbamazepine, the correction factor comparing smokers taking lamotrigine versus non-smokers who were not taking lamotrigine was 1.3. Gender, age, and concomitant use of mirtazapine, valproic acid, lamotrigine, topiramate, lorazepam, citalopram or oxcarbazepine did not have significant effects on olanzapine concentrations. The main limitation of this clinical design is the unavoidable substantial "noise" that characterizes (uncontrolled) clinical environments, which may make it difficult to detect the effects of some variables. Other limitations were the small sample size of some drug sub-samples and the lack of testing for plasma olanzapine metabolites.

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Estimating the effects of co-medications on plasma olanzapine concentrations by using a mixed model

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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