Antidepressive effect of amitriptyline treatment with plasma drug levels controlled within three different ranges

Burch, Jane; Ahmed, Osama M.; Hullin, R. P.; Mindham, Richard

doi:10.1007/bf00176845

Cited by 15 publications

(7 citation statements)

References 46 publications

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“…Data fromthese studiesdidnot reveal any correlation between steady-state plasma concentrations of paroxetine achieved and either efficacy or occurrence of adverse events (21). This observation is in keeping with the results of another study (12) and with the majority of published data on other antidepressant drugs (9,22,23,24). Changes or differences in the pharmacokinetics of paroxetine should be viewed in the context of this lack of correlation.…”

Section: Relationship Between Plasma Concentration and Clinical Effectsupporting

confidence: 81%

A review of the metabolism and pharmacokinetics of paroxetine in man

Kaye

Haddock

Langley

et al. 1989

Acta Psychiatr Scand

244

159

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Acta psychiatr. scand: 80 (supp. 350): 60-75 ABSTRACT -Paroxetine is well absorbed from the gastrointestinal tract, and appears to undergo first-pass metabolism which is partially saturable. Consistent with its lipophilic amine character, paroxetine is extensively distributed into tissues. Its plasma protein binding at therapeuticallyrelevant concentrations is about 95%. Paroxetine is eliminated by metabolism involving oxidation, methylation, and conjugation. All of these factors lead to wide interindividual variation in the pharmacokinetics of paroxetine. Renal clearance of the compound is negligible. The major metabolites of paroxetine are conjugates which do not compromise its selectivity nor contribute to theclinical response. Ascending single-dose studies reveal that the pharmacokinetics of paroxetine are non-linear to a limited extent in most subjects and to a marked degree in only a few. Also, steady-state pharmacokineticparameters are not predictable from single-dose data. In many subjects, daily administration of 20-50mg of paroxetine leads to little or no disproportionality in plasma levels with dose, although in a few subjects this phenomenon is evident. Steady-state plasma concentrations are generally achieved within 7 to 14 days. The terminal half-life is about one day, although there is a wide intersubject variability (e.g. with 30mg, a range of 7-65 hours was observed in a group of 28 healthy young subjects). In elderly subjects there is wide interindividual variation in steady-state pharmacokinetic parameters, with statistically significantly higher plasma concentrations and slower elimination than in younger subjects, although there is a large degree of overlap in the ranges of corresponding parameters. In severe renal impairment higher plasma levels of paroxetine are achieved than in healthy individuals after single doses. In moderate hepatic impairment the pharmacokinetics after single doses are similar to those of normal subjects. Paroxetine is not a general inducer or inhibitor of hepatic oxidation processes, and has little or no effect on the pharmacokinetics of other drugs examined. Its metabolism and pharmacokinetics are to some degree affected by the induction or inhibition of drug metabolizing enzyme(s). From a pharmacokinetic standpoint, drug interactions involving paroxetine are considered unlikely to be a frequent occurrence. Data available have failed to reveal any correlation between plasma concentrations of paroxetine and its clinical effects (either efficacy or adverse events). Paroxetine (Fig. l), a potent, selective 5-HT uptake inhibitor, currently being developed as a n antidepressant d r u g (1,2), has been review are in terms of the pure free base. extensively studied in man to examine its metabolism andpharmacokinetics. This review provides a summary of the key findings to date, extending earlier observations (3,4). Paroxetine is administered as its hydrochloride salt (BRL 29060A), but doses quoted throughout this Analytical methodology Paroxetinecan be determined in biologi...

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Section: Relationship Between Plasma Concentration and Clinical Effectsupporting

confidence: 81%

A review of the metabolism and pharmacokinetics of paroxetine in man

Kaye

Haddock

Langley

et al. 1989

Acta Psychiatr Scand

244

159

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“…The r value for amitriptyline CSS vs age was 0.42 (p < 0.05). Burch et al (1988) included 18 patients >65 years of age in a study of amitriptyline plus nortriptyline plasma concentrations in relation to therapeutic effect. Amitriptyline Cmax values varied considerably from 73 to 247 f.Lg/L.…”

Section: Amitriptylinementioning

confidence: 99%

Clinical Pharmacokinetics of Antidepressants in the Elderly

Moltke

Greenblatt

Shader

1993

Clinical Pharmacokinetics

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The prevalence of depression in the elderly suggests that a substantial number of older patients will be treated with an antidepressant medication such as one of the tricyclics, trazodone, fluoxetine or lithium. The physiological changes that accompany aging raise the possibilities of altered pharmacokinetics, patterns of efficacy and adverse effect profiles. The literature addressing the subject of antidepressant use in the elderly has not provided a clear, consistent picture of how these drugs behave in this population in comparison with younger patients. Particularly in the case of the tricyclic antidepressants (TCAs), a large degree of interindividual variation in drug clearance (CL) confounds attempts to find differences attributable to age per se. Study design, however, is also a problem in that very few investigators include a young control group, choosing instead to compare their data with previously reported outcomes. Designations of statistical significance and positive correlation also differ among investigators, and the clinical significance of any finding is not always addressed. The available data suggest that imipramine CL is reduced in the elderly and that amitriptyline CL may be reduced. Desipramine CL does not appear to be affected by age, although decreased renal function in the elderly may lead to accumulation of the hydroxylated metabolite, the clinical importance of which is not known. Nortriptyline is the most thoroughly studied TCA in the elderly. CL seems decisively lower only in elderly patients with concurrent medical illness. The hydroxylated metabolite probably accumulates with diminishing renal function. Not enough data are available on doxepin to make a conclusion. Trazodone CL is diminished somewhat in elderly men. Lithium CL appears to diminish with the declining renal function associated with aging. Fluoxetine data are sparse. Available data do not show any decrease in CL of the parent drug; more information is needed on the metabolite norfluoxetine. Although knowledge of CL changes with aging can help the clinician more accurately achieve the desired steady-state concentration of a drug during long term therapy, much work is still needed to evaluate the relationships among drug concentrations at steady-state, efficacy and adverse effects in the elderly.

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“…A MEDLINE search of clinical studies with an RCCT design [9–46] shows that most RCCTs were analysed with a traditional statistical approach. Since model‐based drug development is becoming more popular and is even being advocated by some regulatory authorities [4, 47], it is of interest to investigate the consequences of different randomization schemes under the assumption of a model‐based analysis.…”

Section: Introductionmentioning

confidence: 99%

Randomized exposure‐controlled trials; impact of randomization and analysis strategies

Karlsson

Grahnén

Karlsson

et al. 2007

Brit J Clinical Pharma

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What is already known about this subject • When characterizing an exposure–response relationship it has been suggested that the randomized concentration‐controlled trial (RCCT) is potentially a more informative design than a randomized dose‐controlled trial design (RDCT). • Traditionally, these trials have been analysed by group‐wise comparison or similar statistics. • The aim of this study was to compare different randomization schemes when a model‐based analysis has been performed. What this study adds • Alternative randomization schemes may not have the proposed advantages if a model‐based analysis is employed. Aims In the literature, five potential benefits of randomizing clinical trials on concentration levels, rather than dose, have been proposed: (i) statistical study power will increase; (ii) study power will be less sensitive to high variability in the pharmacokinetics (PK); (iii) the power of establishing an exposure–response relationship will be robust to correlations between PK and pharmacodynamics (PD); (iv) estimates of the exposure–response relationship are likely to be less biased; and (v) studies will provide a better control of exposure in situations with toxicity issues. The main aim of this study was to investigate if these five statements are valid when the trial results are evaluated using a model‐based analysis. Methods Quantitative relationships between drug dose, concentration, biomarker and clinical end‐point were defined using pharmacometric models. Three randomization schemes for exposure‐controlled trials, dose‐controlled (RDCT), concentration‐controlled (RCCT) and biomarker‐controlled (RBCT), were simulated and analysed according to the models. Results (i) The RCCT and RBCT had lower statistical power than RDCT in a model‐based analysis; (ii) with a model‐based analysis the power for an RDCT increased with increasing PK variability; (iii) the statistical power in a model‐based analysis was robust to correlations between CL and EC50 or Emax; (iv) under all conditions the bias was negligible (<3%); and (v) for studies with equal power RCCT could produce either more or fewer adverse events compared with an RDCT. Conclusion Alternative randomization schemes may not have the proposed advantages if a model‐based analysis is employed.

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Antidepressive effect of amitriptyline treatment with plasma drug levels controlled within three different ranges

Cited by 15 publications

References 46 publications

A review of the metabolism and pharmacokinetics of paroxetine in man

A review of the metabolism and pharmacokinetics of paroxetine in man

Clinical Pharmacokinetics of Antidepressants in the Elderly

Randomized exposure‐controlled trials; impact of randomization and analysis strategies

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