Population pharmacokinetics of nortriptyline during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6‐an evaluation with the nonparametric maximum likelihood method.

Jerling, Markus; Merlé, Yann; Mentré, France; Mallet, Alain

doi:10.1111/j.1365-2125.1994.tb04382.x

Cited by 37 publications

(15 citation statements)

References 46 publications

(70 reference statements)

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“…The most likely explanation for these observations is medication noncompliance. However, it is also possible some of these subjects were ultra-rapid nortriptyline metabolizers [24].In our sample, we observed significantly higher normalized plasma nortriptyline concentrations in Asians and Blacks compared to Whites (see Figure 2). Ethnic differences in the metabolism of tricyclic antidepressants have been observed in Asians as well as in Africans and African-Americans [25,26].…”

supporting

confidence: 53%

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Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis

Mooney

Reus

Gorecki

et al. 2007

Clin Pharmacol Ther

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Multiple controlled clinical trials support the efficacy of nortriptyline as a smoking cessation agent. While therapeutic plasma nortriptyline concentrations (PNCs) are known for the treatment of depression, little is known about PNCs in smoking cessation treatment. PNCs from three randomized, placebo-controlled smoking cessation trials (N = 244) were analyzed, both pooled and separately. PNCs normalized for dose and weight were not associated with sex or age, but were associated with cigarettes/day and race. Greater smoking was associated with decreased normalized PNCs. In addition, both Asians and Blacks had significantly higher normalized PNCs than Whites. Weak and inconsistent associations between PNCs and self-reported side effects were observed. PNCs were linearly related to end of treatment and long-term biochemically verified smoking abstinence. Maximum therapeutic effects were observed at a range of plasma concentrations somewhat lower than those found effective for the treatment of depression. Keywordsnortriptyline; smoking cessation; plasma nortriptyline concentration; therapeutic drug monitoring The tricyclic antidepressant, nortriptyline, has shown consistent efficacy as a smoking cessation agent [1,2]. Unlike other smoking cessation pharmacotherapies, therapeutic drug monitoring (TDM) has played an important role in nortriptyline therapy. A given dose of nortriptyline may produce plasma concentrations of the drug that differ by as much as 30-fold [3]. Based on a known therapeutic range or window for depression of 50 to 150 ng/mL [4], most nortriptyline smoking cessation studies have measured drug concentrations and titrated dosage to place smokers in this range [5][6][7][8][9].Using depression dosing guidelines for these initial nortriptyline smoking cessation studies was reasonable. However, a database now exists to empirically address several important topics concerning plasma nortriptyline concentrations (PNCs) in smokers, including describing variability in PNCs by dosage, identifying patient characteristics associated with PNCs, relating PNCs to self-reported side effects, and defining a smoking-cessation specific therapeutic range for nortriptyline. With respect to the last point, defining a separate nortriptyline therapeutic range for smokers may be necessary for several reasons. The original work that informed the therapeutic range for depression was conducted in a relatively small set of patients, most of whom experienced severe endogenous depression [10,11]. The degree of affective dysregulation observed in smoking cessation is comparatively mild and transient relative to major depression [12,13], so lower PNCs may be sufficient to achieve smoking abstinence. At the same time, lower PNCs would help to decrease the frequency and severity of side effects common to tricyclics including dry mouth, blurred vision, weight gain, constipation, and orthostatic hypotension.The current paper uses data from three randomized, placebo-controlled trials that evaluated nortriptyline for smoking c...

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supporting

confidence: 53%

“…The most likely explanation for these observations is medication noncompliance. However, it is also possible some of these subjects were ultra-rapid nortriptyline metabolizers [24].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis

Mooney

Reus

Gorecki

et al. 2007

Clin Pharmacol Ther

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“…In addition, olanzapine at daily dosages of 20 mg or over can prolong the PR interval, resulting in arrhythmia (23) (26); combination with hepatic drug enzyme inhibitors, potentially resulting in markedly increased plasma levels of psychotropic drugs (27); ionic disturbances, such as hypokalemia and hypomagnesemia (28); and dosage (29). The predisposing role of myocardial ischemia is well recognized.…”

Section: Discussionmentioning

confidence: 99%

Hidden Cardiac Lesions and Psychotropic Drugs as a Possible Cause of Sudden Death in Psychiatric Patients: A Report of 14 Cases and Review of the Literature

et al. 2004

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Objective: To confirm the hypothesis that psychotropic drugs, especially neuroleptics, lithium, and antidepressants, are implicated as a cause of unexpected sudden death in psychiatric patients because of their cardiotoxicity, especially when hidden cardiac lesions are present. Method:We performed a full pathological examination of 14 psychiatric patients who unexpectedly and suddenly died between 1980 and 1999.

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“…A recent clinical study indicates that the CYP2D6 gene could be important for the development of depression. A population of 578 depressives was found to be totally lacking in individuals belonging to the subgroup of the population deficient in CYP2D6 [Jerling et al, 1994]. (There should have been around 40, since the incidence in Caucasian populations is circa 7%.)…”

Section: Involvement Of Cytochrome P 450 2d6 and Neuronal K + Channelsmentioning

confidence: 99%

Toward a better understanding of depression: New mechanistic considerations of antidepressant action provide a basis for development of delay-free drugs

Gittos¹

2000

Drug Dev. Res.

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Population pharmacokinetics of nortriptyline during monotherapy and during concomitant treatment with drugs that inhibit CYP2D6‐an evaluation with the nonparametric maximum likelihood method.

Cited by 37 publications

References 46 publications

Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis

Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis

Hidden Cardiac Lesions and Psychotropic Drugs as a Possible Cause of Sudden Death in Psychiatric Patients: A Report of 14 Cases and Review of the Literature

Toward a better understanding of depression: New mechanistic considerations of antidepressant action provide a basis for development of delay-free drugs

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