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Pharmacokinetics of antidepressant drugs: naturalistic and clinical trials
Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-6041-0744
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: urn:nbn:se:liu:diva-24799Local ID: 7063ISBN: 91-7373-543-4 (print)OAI: oai:DiVA.org:liu-24799DiVA: diva2:245122
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
List of papers
1. Serum levels of citalopram and its main metabolites in adolescent patients treated in a naturalistic clinical setting
Open this publication in new window or tab >>Serum levels of citalopram and its main metabolites in adolescent patients treated in a naturalistic clinical setting
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2002 (English)In: Journal of Clinical Psychopharmacology, ISSN 0271-0749, E-ISSN 1533-712X, Vol. 22, no 4, 406-413 p.Article in journal (Refereed) Published
Abstract [en]

The prescribing of selective serotonin reuptake inhibitors for adolescents is extensive despite the fact that there are few pharmacokinetic (PK), effi]cacy, safety, or tolerability studies on this group. This study reports the PK findings from two trials in adolescents treated with citalopram (CIT) in naturalistic clinical settings: one retrospective and one prospective. The aim of our study was to describe serum concentrations of CIT, desmethylcitalopram (DCIT), and didesmethylcitalopram (DDCIT) (trough values in steady state) in adolescents in relation to daily dose and clinical information obtained from therapeutic drug monitoring request forms. Altogether, 44 patients younger than 21 years were scrutinized using this combined open-label approach. The main findings were that (1) there was a pronounced interindividual variability of serum CIT, DCIT, and DDCIT concentrations in all doses prescribed, in agreement with previous studies on adults; on correcting for dose, the coefficient of variance was about 50% for CIT, DCIT, and DDCIT; (2) the transformation of CIT to DCIT and of DCIT to DDCIT was similar within the dose range 20 to 60 mg/day; (3) there was a difference between the sexes on comparing the dose-corrected concentrations of CIT and DCIT, with girls presenting significantly higher values than boys; and (4) there was a strong dose-serum concentration relationship in three identified subgroups of adolescents: (a) nonsmokers (CIT, r 2 = 0.71; DCIT, r 2 = 0.81), (b) girls not taking oral contraceptives (CIT, r 2 = 0.75; DCIT, r 2 = 0.71,), and (c) girls in the last 14 days of the menstrual cycle (CIT, r 2 = 0.68; DCIT, r 2 = 0.64). In summary, the present study tentatively supports influences of sex, oral contraceptives, and smoking habits on the disposition of CIT in younger patients. Hence, future studies on CIT should assess these parameters.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26736 (URN)10.1097/00004714-200208000-00012 (DOI)11331 (Local ID)11331 (Archive number)11331 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
2. Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992-1997
Open this publication in new window or tab >>Therapeutic drug monitoring of racemic citalopram: a 5-year experience in Sweden, 1992-1997
2003 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 25, no 2, 183-191 p.Article in journal (Refereed) Published
Abstract [en]

Racemic citalopram (CIT) was introduced in Sweden in 1992 for management of major depression. During a 5-year period, 1992 to 1997, serum samples of CIT and desmethylcitalopram (DCIT) were collected for therapeutic drug monitoring (TDM) from patients from all over Sweden. These samples were accompanied by clinical information on a specially designed TDM request form. They represented men and women of various ages (11-94 years) usually on multiple concomitant medications and treated in a naturalistic setting. The TDM samples eligible for evaluation (n = 749), all trough values at steady state, were studied with respect to inter- and intraindividual pharmacokinetic variability. Extensive, interindividual serum concentration variability was seen on all dose levels. For dose-corrected concentrations (C/D) and for clearance (C1) we found the coefficient of variation (CV) to be approximately 55% for all variables (C/D CIT, C/D DCIT, the ratio DCIT to CIT, and for C1 CIT). The intraindividual variations over time for the same parameters were 30% to 35%. On a population level, signs of a possible saturation of CYP2D6 associated with increasing DCIT-to-CIT ratios with increasing daily doses was observed. Age and gender affected the pharmacokinetics of CIT and DCIT. Women showed significantly higher C/D CIT and C/D DCIT and lower C1 CIT values compared with men, and patients aged more than 65 years had higher C/D CIT and C/D DCIT and lower C1 CIT values compared with younger patients. Finally, concomitant medication affected the outcome of serum concentrations by a general increase in C/D CIT and C/D DCIT but without alteration in the DCIT-to-CIT ratio. Thus, this tendency of changes in the CIT disposition when multiple drugs are used (and multiple diseases are prevailing?) seems more general in character than specific for a certain drug or type of drugs.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-26797 (URN)10.1097/00007691-200304000-00007 (DOI)11405 (Local ID)11405 (Archive number)11405 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
3. Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting
Open this publication in new window or tab >>Therapeutic drug monitoring of racemic venlafaxine and its main metabolites in an everyday clinical setting
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-27668 (URN)10.1097/00007691-200208000-00014 (DOI)12406 (Local ID)12406 (Archive number)12406 (OAI)
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2017-12-13Bibliographically approved
4. Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression
Open this publication in new window or tab >>Serum disposition of sertraline, N-desmethylsertraline and paroxetine: a pharmacokinetic evaluation of repeated drug concentration measurements during 6 months of treatment for major depression
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2004 (English)In: Human Psychopharmacology: Clinical and Experimental, ISSN 0885-6222, E-ISSN 1099-1077, Vol. 19, no 5, 283-291 p.Article in journal (Refereed) Published
Abstract [en]

Sertraline and paroxetine are frequently prescribed SSRIs for long-term treatment of major depression. Nevertheless, continuous follow-ups of drug concentrations prevailing in patients during the whole treatment period are not available. Hence, in a large phase IV clinical trial, a total of 353 patients with major depression were enrolled for a 6-month comparison of sertraline (50–150 mg daily) and paroxetine (20–60 mg daily). The present study reports the pharmacokinetic results of up to eight serum samples per patient.

1 A profound variability was found in the interindividual steady state and trough serum levels of sertraline, desmethylsertraline and paroxetine: the coefficient of variation (CV) was 59% for sertraline, 51% for desmethylsertraline, 27% for the ratio desmethylsertraline/sertraline (50 mg/day), and 71% for paroxetine (20 mg/day). The intraindividual CV for the ratio desmethylsertraline/sertraline was only 19%, indicating intraindividual metabolizing stability over time. Both sertraline and paroxetine displayed sex differences in the dose-concentration correlation.

2 It was possible to predict sertraline, but not paroxetine, steady state levels.

3 The terminal elimination t½ for both drugs after 6 months of treatments was similar to data previously reported from short-term withdrawal studies.

4 No correlation between serum drug concentrations and clinical effect was detected for either sertraline or paroxetine.

For the future, continuous efforts are warranted to perform PK investigations in the natural clinical setting in which the drugs are usually prescribed.

Keyword
sertraline, paroxetine, serum concentrations
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-23758 (URN)10.1002/hup.599 (DOI)3270 (Local ID)3270 (Archive number)3270 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
5. Compliance with SSRI medication during 6 months of treatment for major depression: an evaluation by determination of repeated serum drug concentrations
Open this publication in new window or tab >>Compliance with SSRI medication during 6 months of treatment for major depression: an evaluation by determination of repeated serum drug concentrations
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2004 (English)In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 82, no 3, 443-446 p.Article in journal (Refereed) Published
Abstract [en]

Background: A recent estimation in a psychiatric cohort showed numbers of noncompliance between 10% and 60%. Therapeutic drug monitoring (TDM) is one method assessing compliance by analysis of drug concentration in the blood.

Method: During a 24-week phase IV clinical trial, five repeated serum samples of sertraline (SERT) and N-desmethylsertraline (DSERT), trough values in steady state, were collected per patient. Previous results show that the intraindividual variation over time of the ratio DSERT/SERT is low. Hence, we hypothesized that significant partial noncompliance could be scrutinized further by an assessment of the DSERT/SERT ratio. The main aim was to test the applicability of a novel type of TDM procedure based on repeated metabolite/parent compound ratio measurements.

Result: 9.4% of the per-protocol population in the trial (n=96) were in either hidden total (n=4) or hidden partial (n=5) noncompliance. Only by using the novel TDM ratio screening method could a majority of these patients be identified.

Keyword
SSRI, depression, sertraline
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-23759 (URN)10.1016/j.jad.2004.02.003 (DOI)3271 (Local ID)3271 (Archive number)3271 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved

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