摘要:

The pharmacokinetic properties of amoxicillin and clavulanic acid when used alone or in combination are extensively reviewed and discussed in this article. The reported data support a nonlinear absorption process for amoxicillin. Saturable transport mechanisms, limited solubility and the existence of an absorption window are possibly involved in the gastrointestinal absorption of this antibacterial, all leading to a decrease in the peak plasma concentration (Cmax)/dose ratio, a prolongation of the time to reach Cmax, and broad variability for high doses of amoxicillin. Data available in the literature also suggest a possible interaction between amoxicillin and clavulanic acid that might decrease the absolute bioavailability of clavulanic acid. In the present review the intrinsic pharmacodynamics of each drug, together with the synergism produced by the amoxicillin/clavulanic acid association, are also reviewed and analysed. Not only β-lactamase-producing strains, but alsoStreptococcus pneumoniaestrains, seem to be more efficiently eradicated by the association of amoxicillin and clavulanic acid, and a relevant post-antibacterial effect and post-β-lactamase inhibitor effect are likely to operate when amoxicillin is administered together with clavulanic acid.The principles of pharmacokinetic/pharmacodynamic analysis applied to amoxicillin are reviewed, with special emphasis being placed on the results obtained fromin vitrostudies and animal models regarding the new pharmacokinetically enhanced formulation. Theoretical considerations concerning the efficacy of this formulation provided by the application of pharmacokinetic/pharmacodynamic analysis to the scarce pharmacokinetic data available are also included. The broad pharmacokinetic variability of both amoxicillin and clavulanic acid, particularly when administered together and at high doses of amoxicillin, is highlighted and the interest in considering this aspect to improve predictions based on pharmacokinetic/pharmacodynamic analyses for the new formulations is indicated. Methodological recommendations such as the Monte Carlo simulation are proposed in order to obtain more realistic predictions in clinical practice.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Patients with acute psychosis often exhibit agitation, which can be distressing and hazardous to others as well as to the patient. In such psychiatric emergencies, intramuscular antipsychotic agents can be easier to administer than oral formulations, and they have the added advantage of more rapid absorption and a faster onset of action. However, intramuscular formulations of conventional antipsychotics, which have been the standard treatment, are associated with acute dystonia and other movement disorder-related adverse events. Ziprasidone is the first atypical antipsychotic to be clinically available in both intramuscular and oral formulations in the US. The intramuscular formulation of ziprasidone, ziprasidone mesylate, uses sulfobutylether β-cyclodextrin to solubilise the drug by complexation. The pharmacokinetics of intramuscular ziprasidone include rapid attainment of therapeutic drug level (time to reach peak serum concentration [tmax] ≤60 minutes postdose), a mean terminal elimination half-life ranging from 2 to 5 hours, bioavailability of approximately 100%, exposure to drug that increases in a dose-related manner and little drug accumulation even after 3 days of repeated intramuscular administration.The metabolism and elimination of intramuscular ziprasidone have not been extensively evaluated. The principal difference between any oral versus intramuscular formulations of a drug is in first-pass metabolism. Oral ziprasidone is eliminated mainly via the hepatic route and <1% is eliminated in urine and <4% in faeces as unchanged drug. That would not be expected to change with the intramuscular route of administration. Low concentrations of ziprasidone are seen 12–18 hours after the last intramuscular injection. The rapid clearance of ziprasidone from plasma after an intramuscular administration results in little to no persistence of plasma drug level when switching from intramuscular to oral drug administration. No clinically significant age-, sex- or race-related effects on the pharmacokinetics of intramuscular or oral ziprasidone have been noted, and the tolerability and cardiovascular safety profiles of intramuscular ziprasidone have been well characterised in clinical trials.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Cyclophosphamide is an extensively used anticancer and immunosuppressive agent. It is a prodrug undergoing a complicated process of metabolic activation and inactivation. Technical difficulties in the accurate determination of the cyclophosphamide metabolites have long hampered the assessment of the clinical pharmacology of this drug. As these techniques are becoming increasingly available, adequate description of the pharmacokinetics of cyclophosphamide and its metabolites has become possible.There is incomplete understanding on the role of cyclophosphamide metabolites in the efficacy and toxicity of cyclophosphamide therapy. However, relationships between toxicity (cardiotoxicity, veno-occlusive disease) and exposure to cyclophosphamide and its metabolites have been established. Variations in the balance between metabolic activation and inactivation of cyclophosphamide owing to autoinduction, dose escalation, drug-drug interactions and individual differences have been reported, suggesting possibilities for optimisation of cyclophosphamide therapy.Knowledge of the pharmacokinetics of cyclophosphamide, and possibly monitoring the pharmacokinetics of cyclophosphamide in individuals, may be useful for improving its therapeutic index.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

BackgroundThe objective of the five clinical studies presented in this article was to investigate the single-dose pharmacokinetics of gefitinib (IRESSA®, ZD1839), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in healthy volunteers and patients with advanced cancer.MethodsStudies 1 and 3–5 recruited healthy male volunteers aged 18–65 years; study 2 recruited male or female patients aged ≥18 years with any solid malignant tumour expressing EGFR and refractory to standard therapy. Gefitinib administration was as follows: study 1 (bioavailability in healthy volunteers; n = 12) – intravenous infusion of 50 or 100mg followed by a single oral dose of 250mg; study 2 (bioavailability in cancer patients; n = 19) − intravenous infusion of 50mg followed by a single oral dose of 250mg; study 3 (intrasubject variability; n = 24) – two single oral doses of 250mg; study 4 (dose-proportionality; n = 15) – three single oral doses of 50–500mg; study 5 (effect of food; n = 26) – two single doses of 250mg under either fed or fasted conditions. In all studies, venous blood samples for determination of gefitinib plasma concentrations were collected at predetermined intervals. Plasma concentrations of gefitinib were measured using liquid-liquid extraction after basification followed by high-performance liquid chromatography with tandem mass spectrometric detection. Appropriate pharmacokinetic parameters were determined by noncompartmental methods.ResultsStudy 1: Oral bioavailability of a gefitinib 250mg dose was 57% in healthy volunteers. Absorption was moderately slow, with geometric mean (gmean) peak plasma concentration (Cmax) of 85 ng/mL (range 43.5–110 ng/mL) reached 5 hours following an oral dose of 250mg. Study 2: Oral bioavailability of a gefitinib 250mg dose was 59% in patients. Absorption was again moderately slow, with gmean Cmaxof 159 ng/mL (range 48.7–324 ng/mL) typically reached 3 hours (range 1–8 hours) following an oral dose of 250mg. Study 3: Area under the plasma concentration-time curve from time zero to infinity (AUC∞) and Cmaxwere variable – up to 15-fold between subjects and 2-fold within an individual. Study 4: AUC∞and Cmaxincreased with dose across the range of 50–500mg, and increased dose-proportionally up to 250mg. Study 5: Small, clinically insignificant increases in AUC∞and Cmaxwere seen in the presence of food (32% and 37%, respectively).ConclusionsThe gefitinib 250mg tablet is orally bioavailable in both healthy volunteers and cancer patients; bioavailability is independent of dose and unaffected by food to any clinically significant extent. Gefitinib undergoes rapid plasma clearance and has an extensive volume of distribution, resulting in a pharmacokinetic profile supportive of a once-daily dosage regimen.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Background and objectiveThe metabolic activity of cytochrome P450 (CYP) 2C19 is genetically determined, and the pharmacokinetics of omeprazole, a substrate for CYP2C19, are dependent on the CYP2C19 genotype. However, a discrepancy between the CYP2C19 genotype and omeprazole pharmacokinetics was reported in patients with liver disease or advanced cancer. The objective of the present study was to evaluate the effect of aging on the relationship between the CYP2C19 genotype and its phenotype.MethodsTwenty-eight elderly and 23 young Japanese volunteers were enrolled after being genotyped. Each subject received a single intravenous dose of omeprazole (10mg and 20mg for the elderly and the young groups, respectively) and blood samples were obtained up to 6 hours after dose administration to determine  the  plasma  concentrations  of  omeprazole  and  its  metabolites, 5-hydroxyomeprazole and omeprazole sulfone. Pharmacokinetic parameters were obtained by noncompartmental analysis. Linear regression models were used to examine the joint effects of covariates such as genotype, age, etc., on the pharmacokinetic parameters, and the pharmacokinetic parameters showing statistical significance were compared by ANOVA.ResultsThere were significant differences between genotypes in the area under the plasma concentration-time curve of the young group and the elderly group. The number of mutation alleles and age were significant covariates for systemic clearance (CL), but age was the only significant covariate for volume of distribution at steady state (Vss). There were significant age- and genotype-related differences  and  a  significant  age × genotype  interaction  in  CL  (20.6 ± 11.0/12.7 ± 4.0/3.2 ± 1.0 and 5.4 ± 4.0/3.7 ± 1.4/2.1 ± 0.7 L/h for homozygous extensive metabolisers [EMs]/heterozygous EMs/poor metabolisers [PMs] of the young and the elderly groups, respectively). In Vss, a significant difference was found  between  the  young  and  the  elderly  groups  (219 ± 115 and 107 ± 44.5 mL/kg, respectively), but not between three genotypes (178 ± 142, 173 ± 79 and 110 ± 51 mL/kg for homozygous EMs, heterozygous EMs and PMs, respectively).ConclusionThe elderly EMs showed wide variance in thein vivoCYP2C19 activity and were phenotypically closer to the elderly PMs than the young EMs were to the young PMs. Some of the elderly homozygous EMs, as well as heterozygous EMs, have a metabolic activity similar to PMs, and the CYP2C19 genotype may therefore not be as useful as phenotyping in the elderly.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

ObjectiveTo evaluate the pharmacokinetics of α- and β-diastereomers of arteether in healthy male volunteers.Participants and methodsThe study was a single-centre clinical pharmacokinetic trial in healthy male subjects. A group comprising 13 subjects aged 25–50 years received a single intramuscular 150mg individual dose of the arteether formulation containing α- and β-isomers in a 30 : 70 ratio. Serial blood samples collected over a period of 0–192 hours were analysed by high-performance liquid chromatography-electrospray ionisation/tandem mass spectrometry and the plasma concentrations were subjected to compartmental and noncompartmental analyses. Pharmacodynamic parameters such as area under the inhibitory curve, ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC), maximum plasma concentration to MIC (Cmax/MIC) and time that plasma concentration exceeds the MIC (T>MIC) were calculatedin vitroin four strains ofPlasmodium falciparumto evaluate thein vivoeffectiveness of the proposed dosage regimen.ResultsThere were no adverse effects observed during the study. The extent of metabolism of arteether to dihydroartemisinin (DHA) was low (~5%) so as to be therapeutically nonsignificant. The pharmacokinetic profiles of the arteether diastereomers were different, and the maximum plasma concentrations of α- and β-isomers were reached at 4.77 ± 1.21 hours and 6.96 ± 1.62 hours, respectively, after which they showed biphasic decline with apparent terminal elimination half-lives of 13.24 ± 1.08 hours and 30.17 ± 2.44 hours, respectively. The plasma and renal clearances, as well as whole blood to plasma partition ratios of the isomers, were comparable, while the apparent volume of distribution during terminal phase of the β-isomer was approximately 3-fold higher than that of the α-isomer.In vitroerythrocyte culture experiments with four strains ofP. falciparumshowed similar MICs for both isomers of arteether. The highest observed MIC of 8 μg/L was selected for estimating the pharmacokinetic and pharmacodynamic parameters, which showed excellent correlation with published data on the clinical efficacy of arteether.ConclusionThe pharmacokinetics of arteether isomers demonstrated stereoselectivity, which was reflected mainly in the volume of distribution and the terminal elimination half-life. The α- and β-isomers of arteether appeared to compliment each other pharmacokinetically, with the α-isomer providing comparatively rapid and higher plasma concentrations resulting in immediate reduction in percentage parasitaemia, while the β-isomer, with its longer terminal elimination half-life, mean residence time and sustained plasma concentrations, maintained the activity for longer periods. The extent of metabolic conversion of arteether to DHA was minimal, so as to have any therapeutic or toxic significance.

ISSN:0312-5963    

出版商:ADIS    

年代:2005

数据来源: ADIS