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Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting
Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-6041-0744
Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
Department of Clinical Pharmacology, Lund University, Lund, Sweden.
Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.
2002 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 24, no 4, 545-553 p.Article in journal (Refereed) Published
Abstract [en]

When Efexor® (venlafaxine) became available in Sweden, a therapeutic drug monitoring (TDM) service was developed in the authors' laboratory. This analytical service was available to all physicians in the country. From March 1996, to November 1997, 797 serum concentration analyses of venlafaxine (VEN) and its main metabolites, O-desmethylvenlafaxine (ODV), N-desmethylvenlafaxine (NDV), and N,O-didesmethylvenlafaxine (DDV) were requested. These samples, each of which was accompanied by clinical information on a specially designed request form, represented 635 inpatients or outpatients, comprising all ages, treated in a naturalistic setting. The first sample per patient, drawn as a trough value in steady state and with documented concomitant medication, was further evaluated pharmacokinetically (n= 187). The doses prescribed were from 37.5 mg/d to 412.5 mg/d. There was a wide interindividual variability of serum concentrations on each dose level, and the mean coefficient of variation of the dose-corrected concentrations (C/D) was 166% for C/D VEN, 60% for C/D ODV, 151% for C/D NDV, and 59% for C/D DDV. The corresponding CV for the ratio ODV/VEN was 110%. However, within patients over time, the C/D VEN and ODV/VEN variation was low, indicating stability in individual metabolizing capacity. Patients over 65 years of age had significantly higher concentrations of C/D VEN and C/D ODV than the younger patients. Women had higher C/D NDV and C/D DDV, and a higher NDV/VEN ratio than men, and smokers showed lower C/D ODV and C/D DDV than nonsmokers. A number of polycombinations of drugs were assessed for interaction screening, and a trend for lowered ODV/VEN ratio was found, predominantly with concomitant medication with CNS-active drug(s) known to inhibit CYP2D6.

Place, publisher, year, edition, pages
2002. Vol. 24, no 4, 545-553 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-27668DOI: 10.1097/00007691-200208000-00014Local ID: 12406OAI: oai:DiVA.org:liu-27668DiVA: diva2:248220
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Pharmacokinetics of antidepressant drugs: naturalistic and clinical trials
Open this publication in new window or tab >>Pharmacokinetics of antidepressant drugs: naturalistic and clinical trials
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Depression is a major public health problem and it is predicted to be the second leading cause of disease burden by the year 2020. The pharmacological treatment period for major depressive disorder (MDD) is relatively long and sometimes prophylactic over many years. Despite the many drugs introduced on this indication in recent years, details in the drug kinetics linked to the many possible clinical scenarios arising in phase-IV have not been adequately assessed.

The main objective of this thesis was therefore to focus on the posology of the frequently prescribed antidepressant drugs citalopram (CIT), sertraline (SERT), paroxetine (PAR) and venlafaxine (VEN) in terms of trough level serum concentrations of the parent compound and metabolite(s) under steady state conditions. Therapeutic Drug Monitoring (TDM)-based bioanalytical data were to be linked to clinical information obtained on patients in naturalistic or controlled clinical trial phase-IV settings for evaluation of the inter- as well as intraindividual PK (pharmacokinetic) variance. Specific aims were to identifY and analyze subgroups with possibly deviating PK such as adolescents, elderly patients, and the differences between the sexes. From a controlled trial setting during a six months period a possible serum concentration-effect relationship should be searched for, as well as testing the applicability of a novel type ofTDM procedure based on the metabolite/parent compound ratio to explore both total and partial pharmacological noncompliance.

Studies I-III were applied on the naturalistic TDM-based trial design. In brief, study I contained 44 adolescents treated with CIT. Study II evaluated trough values in steady state in 749 patients treated with CIT, and study III describes the same parameters for 187 patients treated with VEN. Results revealed that interindividual PK-variations were pronounced for all compounds on all dose levels, but the intraindividual variations were low. Adolescents seemed to have CIT values similar to adults, but old age was correlated with higher dose-corrected serum concentrations of both CIT and VEN. All studied compounds displayed differences between the sexes. Polypharmacy affected the metabolism of CIT and VEN as did smoking.

Study IV contained 353 patients treated with SERT or PAR in a prospective, randomized multi-center trial with up to eight serum samples each over six months. In study V the TDM-based "compliance method" was tested on the SERT population from the study cohort. Results revealed that no serum concentration - clinical effect relationship could be found for either PAR or SERT. It was observed that the TDM compliance method seemed to detect not only total but also significant partial non-compliance.

In conclusion, the present thesis describes the possibility for making further PK-assessments on antidepressant drugs commonly prescribed. Thus, by building up drug specific TDM databases in naturalistic clinical phase IV-trials, combined with a structured data analysis a detailed retrospective follow up on the PK of the drugs coming into play in real life emerged. Taken together with the PK-data obtained from a prospective, randomized trial, the overall significance of this thesis may be to forward a new strategy for TDM -related postmarketing surveillance studies. This strategy may also be of interest to explore for other psychoactive drugs as well as for other new drugs commonly used on lager patient groups on chronic medications but outside psychiatric indications.

Place, publisher, year, edition, pages
Lund: Bloms i Lund Tryckeri AB, 2003. 70 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 783
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24799 (URN)7063 (Local ID)91-7373-543-4 (ISBN)7063 (Archive number)7063 (OAI)
Public defence
2003-04-25, Berzeliussalen, Hälsouniversitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2013-10-28Bibliographically approved

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Reis, MargaretaLundmark, JönsBengtsson, Finn

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