摘要:

The context-sensitive half-time is the time required for blood or plasma concentrations of a drug to decrease by 50% after discontinuation of drug administration. The context-sensitive half-time often cannot be predicted by the elimination half-life (a measure of the time needed for actual drug metabolism or elimination) since it also depends on drug distribution. The context-sensitive half-time is a function of the duration of drug administration and may only be estimated by computer simulation. It is more relevant than other isolated pharmacokinetic parameters to understanding the kinetics of drug concentrations. However, understanding the kinetics of drug effect requires concomitant consideration of pharmacodynamics.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

A substantial proportion of migraine patients have gastric stasis and suffer severe nausea and/or vomiting during their migraine attack. This may lead to erratic absorption from the gastrointestinal tract and make oral treatment unsatisfactory. For such patients, an intranasal formulation may be advantageous. Sumatriptan is a potent serotonin 5HT1B/1Dagonist widely used in the treatment of migraine; the effectiveness of the intranasal formulation (20mg) has been well established in several clinical studies. This article reviews the pharmacokinetics of intranasal sumatriptan and includes comparisons with oral and subcutaneous administration.After intranasal administration, sumatriptan is directly and rapidly absorbed, with 60% of the maximum plasma concentration (Cmax) occurring at 30 minutes after administration of a single 20mg dose. Following intranasal administration, approximately 10% more sumatriptan is absorbed probably via the nasal mucosa when compared with oral administration. Mean Cmaxafter a 20mg intranasal dose is approximately 13.1 to 14.4 ng/mL, with median time to Cmaxapproximately 1 to 1.75 hours. When given as a single dose, intranasal sumatriptan displays dose proportionality in its extent of absorption and Cmaxover the dose range 5 to 10mg, but not between 5 and 20mg for Cmax. The elimination phase half-life is approximately 2 hours, consistent with administration by other routes.Sumatriptan is metabolised by monoamine oxidase (MAO; predominantly the A isozyme, MAO-A) to an inactive metabolite. Coadministration with a MAO-A inhibitor, moclobemide, leads to a significant increase in sumatriptan plasma concentrations and is contraindicated.Single-dose pharmacokinetics in paediatric and adolescent patients following intranasal sumatriptan were studied to determine the effect of changes in nasal morphology during growth, and of body size, on pharmacokinetic parameters. The pharmacokinetic profile observed in adults was maintained in the adolescent population; generally, factors such as age, bodyweight or height did not significantly affect the pharmacokinetics. In children below 12 years, Cmaxis comparable to that seen in adolescents and adults, but total exposure (area under the concentration-time curve from zero to infinity) was lower in children compared with older patients, especially in younger children treated with 5mg.Clinical experience suggests that intranasal sumatriptan has some advantages over the tablet (more rapid onset of effect and use in patients with gastrointestinal complaints) or subcutaneous (noninvasive and fewer adverse events) formulations.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The clinical management of tacrolimus, a macrolide used as immunosuppressant after transplantation, is complicated by its narrow therapeutic index in combination with inter- and intraindividually variable pharmacokinetics. As a substrate of cytochrome P450 (CYP) 3A enzymes and P-glycoprotein, tacrolimus interacts with several other drugs used in transplantation medicine, which also are known CYP3A and/or P-glycoprotein inhibitors and/or inducers. In clinical studies, CYP3A/P-glycoprotein inhibitors and inducers primarily affect oral bioavailability of tacrolimus rather than its clearance, indicating a key role of intestinal P-glycoprotein and CYP3A. There is an almost complete overlap between the reported clinical drug interactions of tacrolimus and those of cyclosporin. However, in comparison with cyclosporin, only few controlled drug interaction studies have been carried out, but tacrolimus drug interactions have been extensively studiedin vitro. These results are inconsistent and are of poor predictive value for clinical drug interactions because of false negative results. P-glycoprotein regulates distribution of tacrolimus through the blood-brain barrier into the brain as well as distribution into lymphocytes. Interaction of other drugs with P-glycoprotein may change tacrolimus tissue distribution and modify its toxicity and immunosuppressive activity. There is evidence that ethnic and gender differences exist for tacrolimus drug interactions.Therapeutic drug monitoring to guide dosage adjustments of tacrolimus is an efficient tool to manage drug interactions. In the near future, progress can be expected from studies evaluating potential pharmacokinetic interactions caused by herbal preparations and food components, the exact biochemical mechanism underlying tacrolimus toxicity, and the potential of inhibition of CYP3A and P-glycoprotein to improve oral bioavailability and to decrease intraindividual variability of tacrolimus pharmacokinetics.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The relationship between serum concentration (Cs) of amitriptyline and its therapeutic effect in depression has been investigated frequently over the last 3 decades; however, the results were controversial and no consensus was reached. Therefore, we have performed a comprehensive survey and meta-analysis of the subject. All relevant literature was included, and the design of studies on the serum concentration−therapeutic effect relationship (SCTER) of amitriptyline was evaluated. Pooled original data from SCTER studies with adequate design were analysed by various statistical methods: regression analysis of therapeutic effect and Cs; comparison of the mean therapeutic effect in various ranges of Cs; dichotomisation of outcome and analysis according to sensitivity of receiver operation curves; frequency of responders and nonresponders in ranges determined by points of sensitivity; analysis of the distribution of Csin responders and nonresponders; logistic regression of responders and nonresponders with Csand other independent variables; calculation of effect size (g) and mean effect size (gm).Forty-five SCTER studies of amitriptyline were identified, and 27 studies met the minimum criteria of adequate study design. Inadequate study design predicted the finding of no SCTER. Analysis of the pooled data from studies with adequate design confirmed a therapeutic window of the sum of Csof amitriptyline and its active metabolite nortriptyline of about 80 to 200 μg/L. A moderate and significant positive gm(0.538, 95% confidence interval 0.167 to 0.909) was calculated for treatment with Cswithin the therapeutic window in comparison with treatment with Csoutside the therapeutic window (19 studies with adequate design and original data available, n = 583).In conclusion, the evidence for a biphasic SCTER of amitriptyline in depression is considerably improved, and the results may help to find a consensus in the future. However, the clinical benefit of therapeutic drug monitoring of amitriptyline can only be demonstrated in a controlled and randomised study. Furthermore, the results provide further evidence that antidepressants at optimum Csare superior to placebo in the treatment of depression.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The clinical development of new drugs is often terminated because of unfavourable pharmacokinetic properties such as poor intestinal absorption after oral administration. Intestinal permeability and solubility are two of the most important factors that determine the absorption properties of a compound. Efficient and reliable computational models that predict these properties as early as possible in drug discovery and development are therefore desirable.In this review, we first discuss the implementation of predictive models of intestinal drug permeability and solubility in drug discovery and development. Secondly, we discuss the mechanisms of intestinal drug permeability and computational methods that can be used to predict it. We then discuss factors influencing drug solubility and models for predicting it. We finally speculate that once these and other predictive computational models are implemented in drug discovery and development, these processes will become much more effective. Further, an increased fraction of drug candidates that are less likely to fail during clinical development will be selected.

ISSN:0312-5963    

出版商:ADIS    

年代:2002

数据来源: ADIS