摘要:

Tuberculosis is re-emerging in patients with altered immune status, such as those with chronic renal failure. Clinicians should thus be aware of the pharmacokinetics and dosage adjustment of antitubercular drugs in patients with renal insufficiency. Among patients with renal insufficiency, those who are dialysed should be treated with special care. Indeed, dosage should always be closely adjusted in these patients and potential removal by dialysis must be taken into account.However reliable the dosage adjustment recommendations are for these drugs in patients with renal failure, further pharmacokinetic investigations need to be performed, especially in dialysis patients in whom the influence of haemodialysis and continuous ambulatory peritoneal dialysis on drug pharmacokinetics needs to be detailed. In the meantime, it could be generally advised to administer all antitubercular drugs after the haemodialysis session, even though some drugs are known to be non-dialysable.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

The pharmacokinetics of almotriptan are linear over a range of oral doses up to 200mg in healthy volunteers. The compound has a half-life of approximately 3 hours. Almotriptan is well absorbed after oral administration and the mean absolute bioavailability is 69.1%. Maximal plasma concentrations are achieved between 1.5 and 4 hours after dose administration; however, within 1 hour after administration, plasma concentrations are approximately 68% of the value at 3 hours after administration. Food does not significantly affect almotriptan absorption.Almotriptan is not highly protein bound and is extensively distributed in the body. Approximately 50% of an almotriptan dose is excreted unchanged in the urine; this is the predominant single mechanism of elimination. Renal clearance is mediated, in part, through active tubular secretion, while the balance of the almotriptan dose is metabolised to inactive compounds. The predominant route of metabolism is via monoamine oxidase-A, and cytochrome P450 (CYP) mediated oxidation (via CYP3A4 and CYP2D6) occurs to a minor extent.Almotriptan clearance is moderately reduced in elderly subjects, but the magnitude of this effect does not warrant a dose reduction. Sex has no significant effect on almotriptan pharmacokinetics. Almotriptan pharmacokinetic parameters do not differ between adolescents and adults, and absorption is not affected during a migraine attack. As expected, renal dysfunction results in reduced clearance of almotriptan. Patients with moderate-to-severe renal dysfunction should use the lowest dose of almotriptan and the total daily dose should not exceed 12.5mg. Similar dosage recommendations are valid for patients with hepatic impairment, based on the clearance mechanisms for almotriptan.Drug-drug interaction studies were conducted between almotriptan and the following compounds: fluoxetine, moclobemide, propranolol, verapamil and ketoconazole. No significant pharmacokinetic or pharmacodynamic interactions with  almotriptan  were  observed  for  fluoxetine  or  propranolol.  Almotriptan clearance  was  reduced,  to  a  modest  degree,  by  moclobemide  and  verapamil, which was consistent with the contribution of monoamine oxidase-A and CYP3A4 to the metabolic clearance of almotriptan. Although ketoconazole has a greater effect on almotriptan clearance than verapamil, no dosage adjustment is required when almotriptan is given with these drugs.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Ciclosporin is a potent immunomodulator that acts selectively and locally when administered at the ocular surface. 0.05% ciclosporin ophthalmic emulsion has recently been approved by the US FDA for treatment of keratoconjunctivitis sicca (KCS) [dry-eye disease].After topical application, ciclosporin accumulates at the ocular surface and cornea, achieving concentrations (≥0.236 μg/g) that are sufficient for immunomodulation. Very little drug penetrates through the ocular surface to intraocular tissues. Ciclosporin is not metabolised in rabbit or dog eyes and may not be prone to metabolism in human eyes. Cultured human corneal endothelial and stromal cells exposed to ciclosporinin vitroexhibited no adverse effects and only minor effects on DNA synthesis. No ocular or systemic toxicity was seen with long-term ocular administration of ciclosporin at concentrations up to 0.4%, given as many as six times daily for 6 months in rabbits and 1 year in dogs. Systemic blood ciclosporin concentration after ocular administration was extremely low or undetectable in rabbits, dogs and humans, obviating concerns about systemic toxicity. In 12-week and 1-year clinical safety studies in dry-eye patients, the most common adverse event associated with the ophthalmic use of ciclosporin emulsion was ocular burning. No serious drug-related adverse events occurred.These data fromin vitro, nonclinical and clinical studies indicate effective topical delivery of ciclosporin to desired target tissues along with a favourable safety profile, making 0.05% ciclosporin ophthalmic emulsion a promising treatment for KCS.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Several particle engineering technologies have recently emerged, which have enabled inhaled microspheres to seek to manipulate pulmonary biopharmaceuticals, and to improve therapeutic efficacy for both local and systemic treatments. These microspheres may be designed to sustain drug release, to prolong lung retention, to achieve drug targeting and/or to enhance drug absorption and thereby, to seek the potentials of reducing dosing frequency and/or drug dose, while maintaining therapeutic efficacy and/or reducing adverse effects. While product development is still in process, in many cases, considerable therapeutic benefits and/or new therapeutic opportunities can be envisaged. ‘Proof-of-concept’ results are now available for various drug classes including β2-adrenoceptor agonists, corticosteroids, antimycobacterial antibacterials, estradiol and therapeutic macromolecules such as insulin. Nevertheless, their development success must overcome several critical and unique challenges including toxicological evaluations of microsphere materials, and, clearly, successful products should meet the needs of the patient and the market place. Unfortunately, such issues have not always been addressed or examined adequately in the current studies, and thus we may anticipate paradigm shifts in the research of several groups seeking to develop products with improved therapeutic profiles. Nevertheless, it seems likely that improved inhalation products, with greater therapeutic efficacy and reduced adverse effects, will result from next-generation respirable microspheres. These may be expected to contain drugs intended for both local and systemic activity.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches usingin vitro,in silicoandin vivomodels can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (KI) and the maximal rate of inactivation at saturation (kinact).Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs.Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of itsKI,kinactand partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confoundingin vitro-in vivoextrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveTo evaluate the efficacy of antimicrobial therapy in oral odontogenic infections using estimated pharmacokinetic/pharmacodynamic parameters or efficacy indices, and to compare pharmacokinetic/pharmacodynamic breakpoints with National Committee for Clinical Laboratory Standards’ (NCCLS) breakpoints.Study designRetrospective literature search to obtain minimum inhibitory concentration (MIC) values, pharmacokinetic parameters of antimicrobials and NCCLS breakpoints. Pharmacokinetic simulations were carried out using WinNonlin software (Pharsight Corporation, Mountain View, CA, USA).MethodsFor antimicrobials with time-dependent activity, the time that the plasma drug concentration exceeds the MIC as the percentage of dose interval at steady state was calculated. For antimicrobials with concentration-dependent activity, the total area under the plasma concentration-time curve over 24 hours at steady state divided by the MIC was calculated. Pharmacokinetic/pharmacodynamic breakpoints were calculated according to these parameters.ResultsOnly amoxicillin/clavulanic acid and clindamycin showed adequate efficacy indices against the most commonly isolated bacteria in odontogenic infections. Metronidazole reached good indices against anaerobes only. Pharmacokinetic/pharmacodynamic susceptibility breakpoints do not coincide exactly with NCCLS breakpoints.ConclusionOwing to the scarcity of double-blind, clinical trials on the use of antimicrobials in endodontics, this study may be useful in determining the best antimicrobial treatment in these infections. However, as we have not used concentration data in infected tissue to determine pharmacokinetic/pharmacodynamic indices, it would be necessary to design clinical trials in order to confirm these results.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background and objectiveTelithromycin, a ketolide antibacterial, demonstrates concentration-dependent bactericidal activity against the major pathogens causing community-acquired respiratory tract infections. The objective of this study was to explore the relationships between pharmacokinetic/pharmacodynamic predictor variables, such as area under the plasma concentration-time curve (AUC) over minimum inhibitory concentration (MIC) [AUC/MIC], maximum plasma concentration (Cmax) over MIC (Cmax/MIC) and microbiological outcome from telithromycin therapy for community-acquired pneumonia (CAP).Patients and methodsData were pooled from five phase III studies of oral telithromycin (800mg once daily for 7–10 days) for the outpatient treatment of adults with CAP. Only subjects with a single pathogen isolated at baseline, a telithromycin MIC determination and at least one plasma pharmacokinetic sample were included. Bacteriologically modified intent-to-treat (bmITT) and bacteriologically evaluable per protocol (PPb) populations were analysed. Individual AUC and CmaxBayesian estimates were obtained with a population pharmacokinetic model. Logistic regression, nonparametric smoothing, and classification analysis and regression tree (CART) were used to assess the relationship between AUC/MIC and Cmax/MIC and microbiological outcome by pathogen.ResultsThe bmITT population included 224 patients (Streptococcus pneumoniaein 113,Haemophilus influenzaein 89 andStaphylococcus aureusin 22). Median telithromycin MIC was 0.015 µg/mL forS. pneumoniae, 2.0 µg/mL forH. influenzaeand 0.12 µg/mL forS. aureus, with median AUC/MIC of 907.1, 6.9 and 98.4, and median Cmax/MIC of 172.0, 1.3 and 20.4 for the three pathogens, respectively. Both logistic regression and nonparametric smoothing showed the probability of microbiological cure to be consistently greater than 90% over the observed range of predictor variables. No reliable AUC/MIC or Cmax/MIC breakpoints were identified by CART.ConclusionTelithromycin exhibits near-maximal efficacy against three major pathogens causing CAP at a dose of 800mg once daily.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS