Narrow Therapeutic Index (narrow + therapeutic_index)

Distribution by Scientific Domains

Selected Abstracts

Metabolic drug interactions with new psychotropic agents

Edoardo Spina
Abstract New psychotropic drugs introduced in clinical practice in recent years include new antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and ,third generation' antidepressants, and atypical antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone and amisulpride. These agents are extensively metabolized in the liver by cytochrome P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with other psychotropic medications or with compounds used for the treatment of concomitant somatic illnesses. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These antidepressants may be involved in clinically significant interactions when coadministered with substrates of these isoforms, especially those with a narrow therapeutic index. Other new antidepressants including sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. The new atypical antipsychotics do not affect significantly the activity of CYP isoenzymes and are not expected to impair the elimination of other medications. Conversely, coadministration of inhibitors or inducers of the CYP isoenzymes involved in metabolism of the various antipsychotic compounds may alter their plasma concentrations, possibly leading to clinically significant effects. The potential for metabolically based drug interactions of any new psychotropic agent may be anticipated on the basis of knowledge about the CYP enzymes responsible for its metabolism and about its effect on the activity of these enzymes. This information is essential for rational prescribing and may guide selection of an appropriate compound which is less likely to interact with already taken medication(s). [source]

Frequently discordant results from therapeutic drug monitoring for digoxin: clinical confusion for the prescriber

N. M. Rogers
Abstract Background: Digoxin remains a commonly prescribed medication for the treatment of congestive cardiac failure or atrial tachyarrhythmias. Its utility is offset by its narrow therapeutic index requiring regular blood concentration monitoring. Recent evidence suggests that a lower therapeutic range (0.5,0.8 g/L, or 0.6,1.0 nmol/L) is associated with reduced mortality in patients with congestive cardiac failure. Therapeutic drug monitoring for digoxin is carried out by immunoassays that are well established in routine clinical practice. Laboratories using different immunoassays may be involved in monitoring individual patients throughout the protracted course of therapy. These results should be concordant to ensure consistent dose individualization and optimum clinical management. We have investigated the discordance in digoxin measurements involving five different laboratories across the Adelaide metropolitan area. Methods: Aliquots from routine digoxin samples (n= 261) were analysed by accredited laboratories using commercially available immunoassays. Results: The results showed that 119 (46%) of 261 samples were so varied that a different clinical outcome was indicated when reviewed by the treating physician. The differences between the highest and lowest readings from any one sample were also substantial, with 45% of the measurements exceeding 0.3 g/L. Conclusions: Our study shows the considerable variation in the routine monitoring of digoxin. This makes therapeutic drug monitoring difficult to interpret and complicates clinical management when treating physicians are endeavouring to avoid toxicity and optimize dosing. These results raise a significant concern for the quality of therapeutic drug monitoring of digoxin and have direct repercussions on patient care. [source]

Is there variability in drug release and physical characteristics of amiodarone chloride from different commercially available tablets?

Possible therapeutic implications
Abstract Objectives, Amiodarone is a low-solubility, high-permeability drug with a narrow therapeutic index and reported bioavailability problems associated with switching formulations. The aim of this study was to identify whether there is variability in drug release and physical characteristics of different commercially available amiodarone hydrochloride formulations in Australia. Methods, Four available formulations (innovator Cordarone (COR) and generic products G1, G2 and G3) were tested for drug dissolution, content uniformity, hardness, weight variation, friability and disintegration in accordance with the US Pharmacopeia specifications. Key findings, The tested formulations exhibited variable dissolution behaviours: G1 and G3 exhibited the fastest dissolution, G2 dissolution was the slowest and Cordarone showed a medium dissolution. After 3 months' exposure to high temperature (40 2C) and relative humidity (75 5%), the products exhibited a higher degree of disparity, with drug-release profiles of the generics being markedly different from that of Cordarone. This suggests possible implications on bioequivalence for patients who live in warm/tropical regional areas. Most products met the US Pharmacopeia specifications for drug-content uniformity and other test physical characteristics. Conclusions, The results suggested that variability in drug release profiles in vitro of amiodarone formulations might be a potential indicator of compromised bioavailability, causing possible interference with the therapeutic response of the drug. [source]

Biowaiver monographs for immediate release solid oral dosage forms: ethambutol dihydrochloride,,

C. Becker
Abstract Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing ethambutol dihydrochloride as the only active pharmaceutical ingredient (API) are reviewed. Ethambutol dihydrochloride is a Biopharmaceutics Classification System (BCS) Class III drug with permeability properties approaching the border between BCS Class I and III. BE problems of ethambutol formulations containing different excipients and different dosages forms have not been reported and hence the risk of bioinequivalence caused by excipients is low. Ethambutol has a narrow therapeutic index related to ocular toxicity. However, as long as the prescribers' information of the test product stipulates the need for regular monitoring of ocular toxicity, the additional patient risk is deemed acceptable. It is concluded that a biowaiver can be recommended for IR solid oral dosage forms provided that the test product (a) contains only excipients present in ethambutol IR solid oral drug products approved in ICH or associated countries, for instance as presented in this paper, (b) complies with the criteria for "very rapidly dissolving" and (c) has a prescribers' information indicating the need for testing the patient's vision prior to initiating ethambutol therapy and regularly during therapy. 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1350,1360, 2008 [source]

A comparative proteomic analysis of HepG2 cells incubated by S(,) and R(+) enantiomers of anti-coagulating drug warfarin

Jing Bai
Abstract Warfarin is a commonly prescribed oral anti-coagulant with narrow therapeutic index. It interferes with vitamin K cycle to achieve anti-coagulating effects. Warfarin has two enantiomers, S(,) and R(+) and undergoes stereoselective metabolism, with the S(,) enantiomer being more effective. We reported that the intracellular protein profile in HepG2 cells incubated with S(,) and R(+) warfarin, using iTRAQ-coupled 2-D LC-MS/MS. In samples incubated with S(,) and R(+) warfarin alone, the multi-task protein Protein SET showed significant elevation in cells incubated with S(,) warfarin but not in those incubated with R(+) warfarin. In cells incubated with individual enantiomers of warfarin in the presence of vitamin K, protein disulfide isomerase A3 which is known as a glucose-regulated protein, in cells incubated with S(,) warfarin was found to be down-regulated compared to those incubated with R(+) warfarin. In addition, Protein DJ-1 and 14-3-3 Protein, were down-regulated in cells incubated with either S(,) or R(+) warfarin regardless of the presence of vitamin K. Our results indicated that Protein DJ-1 may act as an enzyme for expression of essential enzymes in vitamin K cycle. Taken together, our findings provided molecular evidence on a comprehensive protein profile on warfarin,cell interaction, which may shed new lights on future improvement of warfarin therapy. [source]

Pharmacogenetics of Immunosuppressants: Progress, Pitfalls and Promises

D. Cattaneo
Most of the immunosuppressants used in organ transplantation are characterized by a narrow therapeutic index, whereby underdosing is associated with increased risk of rejection episodes and overdosing may exacerbate drug-related toxicity. Pharmacogenetics,complementary to pharmacokinetics,holds the potential to allow individualized dosing of immunosuppressive agents to optimize their therapeutic actions while minimizing adverse effects. Most of the studies have focused on polymorphisms of genes involved in drug metabolism and distribution, but as of now, only thiopurine-S-methyltransferase and cytochrome P 450 3A5 genotypes appear to have sufficiently large influence to have potentialities in guiding drug dosing. This may reflect the fact that available information from other polymorphisms derives almost exclusively from retrospective observations or from studies with important methodological biases. Active investigations aimed at identifying allelic variants of gene encoding for the pharmacologic targets are now ongoing. Recent studies have demonstrated that also donor genotype may play a significant role in immunosuppressive drug pharmacokinetics and pharmacodynamics. As one of the main future tasks, it is mandatory to develop mathematical models able to incorporate multiple gene polymorphisms with pharmacokinetic data and other critical information, providing algorithms able to individualize the best immunosuppressive therapy for each patient before transplantation. [source]

Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients

Marie Antignac
What is already known about this subject , ,In spite of its success in ensuring graft survival, therapeutic use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. , ,Some studies of population pharmacokinetics have already been conducted in liver transplant recipients and in paediatric patients. What this study adds , ,Our work determined population pharmacokinetic parameters, in particular bioavailability, in kidney transplant recipients and the relative importance of factors influencing the disposition of tacrolimus. , ,Clearance was modelled and days postoperation and corticosteroids dose were significant covariates. Aims The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. Tacrolimus population pharmacokinetics, including bioavailability, were investigated in an adult kidney transplant cohort to identify patient characteristics that influence pharmacokinetics. Methods The database (drug monitoring data) included 83 adult kidney transplant recipients and analysis was performed by a population approach with NONMEM. Data were collected during the first months after transplantation. Patients were administered oral or intravenous tacrolimus as part of a triple immunosuppressive regimen that also included mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity as in routine therapeutic drug monitoring. Results A one compartment open model with linear absorption and elimination adequately described the data. The typical value of minimal clearance was 1.8 0.2 l h,1. Clearance increased with time post transplantation to reach 50% of maximal value after 3.8 0.5 days, with a maximal value of 5.6 l h,1. Moreover clearance increased by approximately 1.6 fold (range 0.5,1.6) if the dose of prednisone was >25 mg. The typical value for volume of distribution, V, (98 13 l kg,1) was similar to reported values in kidney transplant patients. The oral bioavailability of tacrolimus was poor and ranged from 11.2 to 19.1%. No covariates significantly influenced V or F. Conclusions The number of days postoperation and corticosteroid dose were significant covariates influencing tacrolimus clearance. [source]

Overview of model-building strategies in population PK/PD analyses: 2002,2004 literature survey

C. Dartois
What is already known about this subject ,,The reviews already published on population pharmacokinetic/pharmacodynamic (PK/PD) analyses have focused on theory and have presented some clinical applications, evaluated validation practices in limited circumstances, defined the interest and sometimes the complexity of this approach in drug development or proposed a list of relevant articles. ,,None of them has exhaustively evaluated published analyses and more precisely the model-building steps. ,,In view of the statistical complexity of population PK/PD methodology, more attention is required to how models are built and how they are reported in the literature. What this study adds ,,With a strict methodology and by establishing a standardized tool, this survey provides an exhaustive, objective and up-to-date review of model-building practices. ,,It reveals deficiencies in information reporting in most articles and the genuine need for guidance in publishing. ,,An initial, minimal list of items is suggested, which can be used by authors and reviewers in pharmacology journals. ,,The value of published peer-reviewed papers could be greatly improved if authors were to address the suggested list of items systematically. Aims A descriptive survey of published population pharmacokinetic and/or pharmacodynamic (PK/PD) analyses from 2002 to 2004 was conducted and an evaluation made of how model building was performed and reported. Methods We selected 324 articles in Pubmed using defined keywords. A data abstraction form (DAF) was then built comprising two parts: general characteristics including article identification, context of the analysis, description of clinical studies from which the data arose, and model building, including description of the processes of modelling. The papers were examined by two readers, who extracted the relevant information and transmitted it directly to a MySQL database, from which descriptive statistical analysis was performed. Results Most published papers concerned patients with severe pathology and therapeutic classes suffering from narrow therapeutic index and/or high PK/PD variability. Most of the time, modelling was performed for descriptive purposes, with rich rather than sparse data and using NONMEM software. PK and PD models were rarely complex (one or two compartments for PK; Emax for PD models). Covariate testing was frequently performed and essentially based on the likelihood ratio test. Based on a minimal list of items that should systematically be found in a population PK,PD analysis, it was found that only 39% and 8.5% of the PK and PD analyses, respectively, published from 2002 to 2004 provided sufficient detail to support the model-building methodology. Conclusions This survey allowed an efficient description of recent published population analyses, but also revealed deficiencies in reporting information on model building. [source]