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Kinds of F Terms modified by F Selected AbstractsDensity gradients in Galactic planetary nebulaeMONTHLY NOTICES OF THE ROYAL ASTRONOMICAL SOCIETY, Issue 1 2007J. P. Phillips ABSTRACT Certain hydrodynamic models of planetary nebulae (PNe) suggest that their shells possess appreciable radial density gradients. However, the observational evidence for such gradients is far from clear. On the one hand, Taylor et al. claim to find evidence for radio spectral indices 0.6 < , < 1.8, a trend which is taken to imply a variation ne,r,2 in most of their sample of PNe. On the other hand, Siódmiak & Tylenda find no evidence for any such variations in density; shell inhomogeneities, where they occur, are primarily attributable to ,blobs or condensations'. It will be suggested that both of these analyses are unreliable, and should be treated with a considerable degree of caution. A new analysis within the log(F(5 GHz)/F(1.4 GHz)),log(TB(5 GHz)) plane will be used to show that at least 10,20 per cent of PNe are associated with strong density gradients. We shall also show that the ratio F(5 GHz)/F(1.4 GHz) varies with nebular radius; an evolution that can be interpreted in terms of varying shell masses, and declining electron densities. [source] Analysis and selection criteria of BSIM4 flicker noise simulation modelsINTERNATIONAL JOURNAL OF CIRCUIT THEORY AND APPLICATIONS, Issue 7 2008T. Noulis Abstract CMOS transistors' noise performance is mainly dominated by flicker (1/f) noise. BSIM4.X MOSFET simulation model develops two distinct models, SPICE-Flicker and BSIM-Flicker, to calculate flicker noise. In this paper, these two models are analytically examined and compared to noise measurements, using an NMOS and a PMOS device fabricated in 0.6µm process by Austria Mikro Systeme (AMS). MOSFET 1/f noise measurements and the respective simulations were obtained under various bias conditions, as to study which flicker noise model is the optimum in each operating region. Measurement temperature was constant at 295,K. Comparisons suggest that in an NMOS transistor operating in the triode or saturation region, BSIM-Flicker model is accurate and therefore preferable. In a PMOS transistor, the most suitable model to describe its 1/f noise performance in the linear regime is also BSIM-Flicker, whereas SPICE-Flicker is more preferable in saturation. In NMOS transistors, the selected model provides a great accurate description of flicker noise, contrary to PMOS transistors, where simulation models appear to be quite unreliable and need further improvement. Copyright © 2007 John Wiley & Sons, Ltd. [source] Low-frequency noise conversion modeling in RF devices under forced nonlinear operationINTERNATIONAL JOURNAL OF RF AND MICROWAVE COMPUTER-AIDED ENGINEERING, Issue 1 2006Gabriele Conte Abstract The article addresses the frequency conversion of low-frequency noise deriving from trap-assisted generation-recombination (GR) noise in RF devices under forced, nonlinear operation through a physics-based noise model. The superposition of the stationary (small-signal) GR spectra originating from noninteracting trap levels with properly distributed energies is shown, in simple yet significant device case studies, to yield a 1/f or 1/f -like behaviour over a prescribed frequency range. The same trap distribution is also exploited for large-signal, cyclostationary noise simulation in forced periodic conditions. In this case, low-frequency 1/f -like noise is shown to be upconverted from the baseband to all noise sidebands. Circuit-level compact modeling strategies for noise-frequency conversion based on the modulation of small-signal low-frequency noise are also investigated and compared to the fundamental approach. © 2005 Wiley Periodicals, Inc. Int J RF and Microwave CAE, 2006. [source] Many electron theory of 1/f -noise in hopping conductivityPHYSICA STATUS SOLIDI (C) - CURRENT TOPICS IN SOLID STATE PHYSICS, Issue 3 2008Alexander L. Burin The cover picture of this issue of physica status solidi (c) has been taken from the article [1]. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Concomitant contact allergy to the resins, reactive diluents and hardener of a bisphenol A/F-based epoxy resin in subway construction workersCONTACT DERMATITIS, Issue 3 2006Chia-Yu Chu An outbreak of suspected contact dermatitis among subway construction workers was suspected to be due to a new bisphenol A/F-based epoxy resin system (ERS). The construction workers used ERSs during the insertion of iron bars into concrete walls. The objective of the study was to determine the components (if any) of the ERS responsible for the contact allergy. Patch testing was performed on 20 of the 22 construction workers who had had contact with the ERS, and to the various subcomponents of component A on 5 of the 7 who reacted to this component. 9 patients (9/22, 40.9%) had clinical symptoms and signs of suspected contact dermatitis at presentation. 7 of these 9, but none of the 11 asymptomatic individuals, were positive to component A, while all were negative to component B. Of the 5 cases receiving further patch testing, all reacted to m -xylylene diamine, 4 to 1,6-hexanediol diglycidyl ether, 3 to epoxy resins of the bisphenol F-type and trimethylolpropane triglycidyl ether 0.25% petrolatum, and only 1 to epoxy resins of the bisphenol A-type. Contact allergy to ERSs may involve hardeners and diluents as well as resins, and patch testing for reaction to all components should be performed. [source] Subcrestal placement of two-part implantsCLINICAL ORAL IMPLANTS RESEARCH, Issue 3 2009Maria Welander Abstract Objective: The aim of the present experiment was to study the healing around two-part implants that were placed in a subcrestal position. Material and methods: Five mongrel dogs, about 2 years old, were included. The mandibular premolars and the first, second and third maxillary premolars were extracted. Three months later two test and two control implants (OsseoSpeedÔ, 3.5 mm × 8 mm) were placed in one side of the mandible. The implants were placed in such a way that the implant margin was located 2 mm apical to the bone crest. In the test implants, the surface modification extended to the implant margin and, thus, included the shoulder part of the implant. Regular abutments with a turned surface (ZebraÔ) were connected to the control implants, while experimental abutments with a modified surface (TiOblastÔ) were connected to the test implants. A plaque control program that included cleaning of implants and teeth every second day was initiated. Four months later the dogs were euthanized and biopsies were obtained and prepared for histological analysis. Results: The marginal bone level at the test implants was identified in a more coronal position than that at the control implants. In 40% of the test implants, the bone-to-implant contact extended coronal of the abutment/fixture (A/F) border, i.e. in contact with the abutment part of the implant. The connective tissue portion of the peri-implant mucosa that was facing the test abutments contained a higher density of collagen and a smaller proportion of fibroblasts than that at the control sites. Conclusion: It is suggested that osseointegration may occur coronal to the A/F interface of two-part implants. Such a result, however, appears to depend on the surface characteristics of the implant components. [source] Molecular epidemiology of HIV-1 in Santa Catarina State confirms increases of subtype C in Southern BrazilJOURNAL OF MEDICAL VIROLOGY, Issue 10 2007Dayse Locateli Abstract Recent studies have demonstrated an increased prevalence of human immunodeficiency virus type 1 (HIV-1) subtype C in southern Brazil. Although Santa Catarina State (SC) is located in this area and presents one of the country's highest incidences of HIV/AIDS, knowledge on the molecular epidemiology of HIV-1 in such State is lacking. The aim of this study was to investigate the HIV-1 molecular diversity and epidemiological profile of HIV-1-infected patients from SC. DNA samples were PCR amplified and HIV-1 subtypes were determined using both env and gag genes by direct sequencing. Phylogenetic analyses revealed that 48% were subtype C and 23% were subtype B. Possible recombinant forms were observed for both B/C (23%) and B/F (6%) subtypes. Our results, for the first time, identifies HIV-1 subtype C as a major clade circulating in SC and contributes to the understanding of HIV epidemics in the country by confirming the epidemic spread of the HIV-1 subtype C in southern Brazil. J. Med. Virol. 79:1455,1463, 2007. © Wiley-Liss, Inc. [source] Effects of extra-fine inhaled beclomethasone/formoterol on both large and small airways in asthmaALLERGY, Issue 7 2010N. Scichilone To cite this article: Scichilone N, Battaglia S, Sorino C, Paglino G, Martino L, Paternò A, Santagata R, Spatafora M, Nicolini G, Bellia V. Effects of extra-fine inhaled beclomethasone/formoterol on both large and small airways in asthma. Allergy 2010; 65: 897,902. Abstract Background:, Airway inflammation in asthma involves both large and small airways, and the combination of inhaled corticosteroids (ICS) and long acting beta-2 agonists (LABA) is the mainstay of therapy. Available inhaled combinations differ in terms of drug delivery to the lung and the ability to reach small airways. Aim:, To evaluate whether treatment with an extra-fine inhaled combination provides additional effects vs a nonextra-fine combination on airway function. Methods:, After a 1- to 4-week run-in period, patients with asthma were randomized to a double blind, double dummy, 12-week treatment with either extra-fine beclomethasone/formoterol (BDP/F) 400/24 ,g daily or fluticasone propionate/salmeterol (FP/S) 500/100 ,g daily. Methacholine (Mch) bronchoprovocation challenge and single breath nitrogen (sbN2) test were performed. Results:, Thirty patients with asthma (15 men), mean age 43, mean forced expiratory volume in the first second (FEV1) 71.4% of predicted, were included. A significant increase (P < 0.01) versus baseline was observed in predose FEV1 in both BDP/F and FP/S groups (0.37 ± 0.13 l and 0.36 ± 0.12 l, respectively). PD20FEV1 Mch improved significantly from 90.42 (±30.08) ,g to 432.41 (±122.71) ,g in the BDP/F group (P = 0.01) but not in the FP/S group. A trend toward improvement vs baseline was observed for BDP/F in closing capacity (CC), whereas no differences were recorded in other sbN2 test parameters. Conclusion:, The findings of this pilot study suggest that an extra-fine inhaled combination for the treatment of asthma has beneficial effects on both large and small airways function as expressed by Mch and sbN2 tests. [source] Rufinamide: Clinical pharmacokinetics and concentration,response relationships in patients with epilepsyEPILEPSIA, Issue 7 2008Emilio Perucca Summary Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6,10 h. The apparent volume of distribution (Vd/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of ,13.7% in female children comedicated with vigabatrin to a maximum of ,46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from placebo-controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady-state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration-related. [source] Impact of pharmacokinetics and pharmacogenetics on the efficacy of pranlukast in Japanese asthmaticsRESPIROLOGY, Issue 6 2009Koichiro ASANO ABSTRACT Background and objective: Wide inter-individual variability in therapeutic effects limits the efficacy of leukotriene (LT) receptor antagonists in the treatment of asthma. We have reported that genetic variability in the expression of LTC4 synthase is associated with responsiveness to pranlukast in Japanese asthmatic patients. However, the effects of pharmacokinetic variability are less well known. This was an analysis of the pharmacokinetics of pranlukast in a population of adult asthmatics, and its effect on clinical responses. Other factors that may be related to the therapeutic effects of pranlukast, including LTC4 synthase gene polymorphisms, were also investigated. Methods: The population pharmacokinetics of pranlukast was analysed in a one-compartment model, using data collected in 50 Japanese adults with moderate to severe asthma, who were treated with pranlukast, 225 mg bd for 4 days. In 32 of these patients, in whom the clinical response to pranlukast (increase in FEV1 after 4 weeks of treatment) was measured in a previous study, a combined pharmacokinetic and pharmacogenetic analysis was performed. Results: Using the population pharmacokinetic model, the estimated the mean oral clearance (CL/F) of pranlukast was 16.4 L/h, and the inter-individual variability was 30.1%. Univariate and multivariate analyses showed that LTC4 synthase polymorphisms, but not the CL/F of the drug, predicted an improvement in pulmonary function with pranlukast treatment (P < 0.05). Conclusions: There was marked inter-individual variability in the pharmacokinetics of pranlukast among adult asthmatics, but this had little impact on the clinical effectiveness of the drug. [source] Simulation of sirolimus exposures and population variability immediately post renal transplantation: importance of the patient's CYP3A5 genotype in tailoring treatmentBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2-3 2010John C. Lukas Abstract The rapid achievement of efficacious exposure to sirolimus (SRL) after renal transplantation is crucial. However, there is high unpredictability in the dose to exposure relationship. Part of the variation is related to patients originating from subpopulations of fast or slow metabolizers via the CYP3A5*1/*3 genotype. The probability of achieving therapeutic SRL blood concentrations for each subpopulation under two equal-intensity increasing-frequency protocols after the start of treatment was explored with Monte Carlo simulation. The population pharmacokinetic model and inter-patient variability distributions of Djebli et al. (DRH2006) were sampled. They developed a base and final model with a genotype covariate for CL/F in patients receiving calcineurin inhibitor (CNI)-free therapy with SRL, mycophenolate mofetil and corticosteroids. Fast metabolizers (expressers) had a CL/F of 28.3,l/h whilst slow metabolizers (non-expressers) had a CL/F of 14.1,l/h. Here, in simulation, a standard 10,mg QD SRL was contrasted with a higher frequency of 5,mg BID SRL as related to the proportion of next dosed patients being within the 15,30,ng/ml trough levels on day 7 after transplantation. Near 0% of expressers on either regimen reached or exceeded the 30,ng/ml trough on day 7. Expressers showed protocol dependence for the chance of being within the 15,30,ng/ml range with the 5,mg BID protocol doubling those chances. Non-expressers appeared less protocol dependent for the probability of being above or below the 15,30,ng/ml range. The ability to determine the genotype early on may help to rationalize the initial titration of individual patients receiving CNI-free renal transplantation treatment with SRL. Copyright © 2010 John Wiley & Sons, Ltd. [source] Quercetin pharmacokinetics in humansBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2008Young J. Moon Abstract The purpose of this study was to examine the pharmacokinetics of quercetin aglycone as well as its conjugated metabolites and to develop a population pharmacokinetic model for quercetin that incorporates enterohepatic recirculation. The stability of quercetin in different matrices at various temperatures and pH, and the quercetin content of six capsules of the herbal preparation Quercetin-500 Plus® were determined by HPLC. Subjects received quercetin 500,mg three times daily and blood and urine samples were obtained. The concentration of quercetin aglycone and conjugated metabolites were assayed using a liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined using noncompartmental analysis with WinNonlin. A population compartment model incorporating input from the gallbladder was developed to account for the enterohepatic recirculation observed with quercetin. The oral clearance (CL/F) was high (3.5,×,104l/h) with an average terminal half-life of 3.5,h for quercetin. The plasma concentration versus time curves exhibited re-entry peaks. A one-compartment model that included enterohepatic recirculation best described the plasma data. This represents the first comprehensive evaluation of the pharmacokinetics and enterohepatic recirculation of quercetin in humans. Population pharmacokinetic models adapted for enterohepatic recirculation allowed an assessment of the magnitude and frequency of the enterohepatic recirculation process. Copyright © 2008 John Wiley & Sons, Ltd. [source] Comparison of the pharmacokinetics of moxidectin and ivermectin after oral administration to beagle dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2007Sayer I. Al-Azzam Abstract This study compares plasma disposition kinetics of ivermectin and moxidectin after oral administration to beagle dogs experimentally infected with the filarial parasite, Brugia pahangi. Sixteen dogs were selected and randomly allocated into two groups of eight dogs each. Animals in each group received either ivermectin or moxidectin by oral route at a dose of 250 µg/kg. Blood samples were collected from 0.5 h up to 56 days post-treatment and the plasma was analysed by high performance liquid chromatography (HPLC). The obtained data were analysed by compartmental and non-compartmental pharmacokinetic techniques. Peak plasma concentrations (Cmax) of 234.0 ± 64.3 ng/ml (mean ± SD) were obtained for moxidectin and 132.6 ± 43.0 ng/ml for ivermectin. The terminal elimination half-life was significantly (p<0.01) longer in the moxidectin treated group (621.3 ± 149.3 h) than for ivermectin treated group (80.3 ± 29.8 h). A significantly (p< 0.01) larger Vss/F was obtained for moxidectin (19.21 ± 3.61 l/kg) compared with ivermectin (5.35 ± 1.29 l/kg). The mean estimates of CL/F of moxidectin and ivermectin were 0.0220 ± 0.00381 and 0.0498 ± 0.0179 l/h/kg, respectively. The comparative plasma disposition kinetics of ivermectin and moxidectin in dogs is reported for the first time. Copyright © 2007 John Wiley & Sons, Ltd. [source] Pharmacokinetics and allometric scaling of levormeloxifene, a selective oestrogen receptor modulatorBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2003O. Østerberg Abstract The pharmacokinetics of a new selective oestrogen receptor modulator levormeloxifene was investigated in mice, rats, cynomolgus monkeys and humans by compartmental pharmacokinetics. Levormeloxifene was administered as an oral solution in all studies. Allometric scaling was used to predict human pharmacokinetic parameters and the performance of the approach was evaluated. Mean values of clearance confounded by F(CL/F) were 0.073, 0.29, 3.18 and 2.4 l/h in mice, rats, monkeys and humans, respectively. Values of distribution volume at steady state confounded by F(Vss/F) were 0.073 and 7.5 l in mice and rats. In monkeys, values of the central volume F(Vc/F) and volume at steady state F(Vss/F) were 28.9 and 57.9 l, respectively. In humans, values of Vc/F and Vss/F were 106 and 587 l, respectively. Predicted CL/F and Vss/F showed a linear relationship when plotted vs BW on a log,log scale; for CL/F, r was 0.95,0.98 and for Vss/F, r was 0.99. Using allometric scaling the predicted human Vss/F deviated 3-fold from the experimentally determined values. Observed values of CL/F deviated 21,25 fold from the predicted, the latter depending on the scaling method. Confidence intervals for the predicted parameters showed major lack of precision for all the allometric scaling methods. Copyright © 2003 John Wiley & Sons, Ltd. [source] Pharmacokinetics of andolast after administration of single escalating doses by inhalation in mild asthmatic patientsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2001S. Persiani Abstract The pharmacokinetics of andolast, a new tetrazolyl-benzamido derivative with antiallergic, antiinflammatory, mucosal protective and antisecretive activities, have been investigated in patients suffering from mild asthma (FEV1,70% of predicted) in whom obstruction was reversible (FEV1 increase,15% of initial) after the administration of 0.2 mg of salbutamol by inhalation. Twelve out-patients (seven males and five females) were enrolled in the present study and were treated with a single dose of andolast of 2, 4 and 8 mg by inhalation using the MIAT Monohaler® device according to a randomised crossover design. Plasma samples were collected before drug administration and up to 540 min after dosing. Andolast plasma concentrations were determined using a validated LC-MS/MS method with a limit of quantitation of 0.2 ng ml,1. Pharmacokinetic analysis was carried out using standard non-compartmental methods. In addition, andolast safety and tolerability were evaluated by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence of adverse events throughout the study period. Andolast was absorbed after inhalation and was available to the systemic circulation. The mean peak plasma concentrations were 6.3, 10.9 and 30.5 ng ml,1 at the three doses, respectively, and occurred at 30, 52.5 and 30 min (median tmax). The mean AUCt values were 1852, 2889 and 7677 ng min ml,1. The apparent plasma clearance (CL/F) and volume of distribution (Vz/F) were, respectively, 1168 ml min,1 and 430 l at the dose of 2 mg, 1143 ml min,1 and 468 l at the dose of 4 mg, and 1141 ml min,1 and 486 l at the dose of 8 mg. The apparent elimination half-life averaged 4.5, 5.0 and 4.6 h at the three doses, respectively. Even though the small number of subjects participating in the present study reduced the power of the statistical test, there was no statistically significant evidence of non-proportionality for all the andolast pharmacokinetic parameters calculated at the three doses. Thus, the data obtained as a whole suggest that andolast pharmacokinetics are dose-independent in the dose range investigated. Finally, the safety and tolerabilty of the drug administered to mild asthmatic patients was good up to the maximum investigated dose of 8 mg. Copyright © 2001 John Wiley & Sons, Ltd. [source] Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Hee-Doo Yoo WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The interindividual variability of the pharmacokinetic parameters of cilostazol is relatively large. , Cilostazol undergoes extensive hepatic metabolism via the P450 enzymes, primarily CYP3A and, to a lesser extent, CYP2C19. , Indeed, <1% of the administered dose of cilostazol is excreted unchanged in the urine. WHAT THIS STUDY ADDS , A population pharmacokinetic analysis of cilostazol was conducted to evaluate the impact of CYP3A, CYP2C19 and ABCB1 polymorphisms on cilostazol disposition in vivo. , Genetic polymorphisms of CYP3A5 and CYP2C19 explain the substantial interindividual variability in the pharmacokinetics of cilostazol. , ABCB1 genotypes do not to appear to be associated with the disposition of cilostazol. AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h,1. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h,1. Absorption rate constant was estimated at 0.24 h,1 and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol. [source] Population pharmacokinetic analysis of varenicline in adult smokersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2009Patanjali Ravva WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in young adult and elderly smokers and subjects with impaired renal function. , Varenicline pharmacokinetics is linear over the recommended dose range. , Varenicline total clearance is linearly related to its renal clearance. , Both are progressively reduced as renal function declines, which results in a progressive increase in varenicline systemic exposure and prolonged half-life. WHAT THIS STUDY ADDS? , This work provides an integrated model-based analysis of varenicline pharmacokinetics across multiple studies in the target patient population. , The model describes the impact of patient-specific covariates, such as renal function, and provides a rationale for dose adjustment. , The resulting model also provides a means to predict individual-specific drug exposures to clinical responses in subsequent analyses. AIMS To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers. METHODS Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration,time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling. RESULTS A two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h,1 (10.2, 10.6); V2/F, 337 l (309, 364); V3/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h,1 (1.39, 3.79); Ka, 1.69 h,1 (1.27, 2.00); and Alag, 0.43 h (0.37, 0.46). Random interindividual variances were estimated for Ka[70% coefficient of variation (CV)], CL/F (25% CV), and V2/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h,1 for a typical subject with normal renal function (CLcr = 100 ml min,1) to 4.4 l h,1 for a typical subject with severe renal impairment (CLcr = 20 ml min,1), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics. CONCLUSIONS Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day,1, which is half the recommended dose, is indicated for subjects with severe renal impairment. [source] Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2009Zheng Jiao WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? , Sirolimus is an immunosuppressive agent used for the prophylaxis of renal allograft rejection. , Several conventional pharmacokinetic and population pharmacokinetic studies have been conducted to assess the pharmacokinetic characteristics of sirolimus in White or African-American recipients. WHAT THIS STUDY ADDS? , The population pharmacokinetics of sirolimus in Chinese adult renal transplant recipients was characterized for the first time. , New drug,drug interactions between herbal medicines and sirolimus were identified as the covariates on sirolimus clearance. AIMS This study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients. METHODS Data were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C0) from 112 patients were used to develop a population pharmacokinetic model using the nonmem program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporin C0 as well as other commonly used co-medications were explored. RESULTS The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h,1 (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C0. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from nonmem. CONCLUSIONS These results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients. [source] Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2008Jung-Ryul Kim WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Almost all reported studies have investigated the pharmacokinetics of aripiprazole in healthy volunteers. , The pharmacokinetics of dehydroaripiprazole have not been identified in a combined model with aripiprazole. WHAT THIS STUDY ADDS , The data on aripiprazole and dehydroaripiprazole in psychiatric patients were modelled jointly using a population approach. , The apparent clearance of aripiprazole in cytochrome P450 (CYP) 2D6 intermediate metabolizers (IM) was approximately 60% of that in CYP2D6 extensive metabolizers (EM) having two functional alleles, but the exposure to dehydroaripiprazole in CYP2D6 IM was similar to that in EM. AIMS The aims of this study were to develop a combined population pharmacokinetic model for both aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients and to identify to what extent the genetic polymorphisms of cytochrome P450 (CYP) enzymes contribute to the variability in pharmacokinetics (PK). METHODS A population pharmacokinetic analysis was performed using NONMEM software based on 141 plasma concentrations at steady state from 80 patients receiving multiple oral doses of aripiprazole (10,30 mg day,1). RESULTS A one-compartment model with first-order kinetics for aripiprazole and dehydroaripiprazole each was developed to describe simultaneously the concentration data. The absorption rate constant was fixed to 1.06 h,1. The typical value of apparent distribution volume of aripiprazole was estimated to be 192 l. Covariate analysis showed that CYP2D6 genetic polymorphisms significantly influenced the apparent clearance of aripiprazole (CL/F), reducing the interindividual variability on CL/F from 37.8% CV (coefficient of variation) to 30.5%. The CL/F in the CYP2D6 IMs was approximately 60% of that in CYP2D6 EMs having two functional alleles. Based on the CYP2D6 genotype, the metabolic ratios were calculated at 0.20,0.34. However, the plasma concentration : dose ratios of dehydroaripiprazole were not different across the CYP2D6 genotype. CONCLUSIONS This population pharmacokinetic model provided an adequate fit to the data for both aripiprazole and dehydroaripiprazole in psychiatric patients. The usefulness of CYP genotyping as an aid to select the starting dose should be further investigated. [source] Population pharmacokinetics of oral diclofenac for acute pain in childrenBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2008Joseph F. Standing WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range. , Diclofenac is frequently used ,off-label' in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5,2.5 mg kg,1). There is currently no licensed oral paediatric formulation of diclofenac. WHAT THIS STUDY ADDS , Using a new diclofenac oral suspension, a dose of 1 mg kg,1 in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses. AIMS To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml,1) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children. METHODS Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg,1 dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults. RESULTS A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and VD/F were 53.98 l h,1 70 kg,1 and 4.84 l 70 kg,1 respectively. Allometric size models appeared to predict adequately changes in CL and VD with age. Of the simulated doses investigated, 1 mg kg,1 gave paediatric AUC(0,12 h) to adult 50 mg AUC(0,12 h) ratios of 1.00, 1.08 and 1.18 for ages 1,3, 4,6 and 7,12 years respectively. CONCLUSIONS This study has shown 1 mg kg,1 diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses. [source] Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2008Furong Qiu What is already known about this subject ,,Danshen extract is widely used for the treatment and prevention of coronary heart disease and other diseases of senility in Asia. ,,Danshen extract and theophylline may be prescribed together to treat patients with asthma. ,,In human, theophylline with low therapeutic index is mainly metabolized by CYP1A2. ,,In vitro findings have shown that human CYP1A2 is inhibited by the ethyl acetate extract of danshen and danshen pharmaceutical product. ,,There may be drug interactions between danshen extract and theophylline (CYP1A2 substrate). What this study adds ,,This study concerned drug interactions between danshen extract and theophylline in Chinese volunteers. ,,Long-term oral intake of danshen extract does not change the basic pharmacokinetic parameters of theophylline. ,,Dose adjustment of theophylline thus may not be necessary in patients receiving concomitant therapy with danshen extract. Aims To examine the potential effect of danshen extract on the pharmacokinetics of theophylline. Methods In a sequential cross-over study with two phases, 12 volunteers took 100 mg theophylline on day 1 and day 15. From day 2 to day 15, volunteers received danshen extract tablets three times daily, four tablets each time for 14 days. On day 15, they received four danshen extract tablets with 100 mg theophylline. Plasma concentrations of theophylline were measured on days 1 and 15 periodically for 24 h. Results The 90% confidence interval of Cmax, t1/2 and CL/F of theophylline with 14-day danshen extract tablets vs. without comedication were (101.42, 121.36) (84.57, 106.72) and (88.82, 105.72), respectively. The time to peak plasma theophylline concentration was unchanged by danshen (P > 0.05). The pharmacokinetics parameter of theophylline was unaffected by danshen extract. Conclusions Danshen extract does not influence the metabolism of theophylline in healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with danshen extract tablets. [source] Desloratadine dose selection in children aged 6 months to 2 years: comparison of population pharmacokinetics between children and adultsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2007Samir K. Gupta What is already known about this subject ,,According to recent literature, the pathophysiologies of allergic rhinitis and chronic idiopathic urticaria are thought to be similar in adults and children. In addition, the response to antihistamine treatment is similar in adults and children, suggesting a similar concentration-response relationship. ,,However, an appropriate dose selection and the pharmacokinetics of desloratadine in children of ,6 months,,2 years old have never been addressed in the literature. What this study adds ,,This study demonstrated that desloratadine syrup offers a safe treatment option for allergic conditions in young children. ,,A suitable dose for children aged ,6 months,<1 year is 1.0 mg, while the corresponding predicted dose for children aged ,1 year,,2 years is 1.25 mg. These paediatric doses yielded similar systemic desloratadine exposures (AUC) to those seen with a typical adult dose of 5.0 mg. Aims The aim of this study was to identify the dose of desloratadine in children aged ,6 months,,2 years that would yield a single-dose target exposure (AUC) comparable with that in adults taking 5 mg desloratadine as syrup. Methods In a phase 1, single-dose, open-label, pharmacokinetic study in 58 children aged ,6 months,<1 year and ,1 year,,2 years were randomly assigned to desloratadine syrup 0.625 mg (1.25 ml) and 1.25 mg (2.5 ml), respectively. Because the volume of blood that could be collected from individual subjects was limited, a population pharmacokinetic approach was used to estimate the pharmacokinetics of desloratadine. Safety was assessed based on results of screening and postdose physical examinations, laboratory safety tests, vital signs, and adverse events. Results The apparent clearance (CL/F) of desloratadine, population estimate (%CV), in children aged ,6 months,<1 year was 27.8 l h,1 (35) and corresponding values in children ,1 year,,2 years was 35.5 l h,1 (51), compared with 137 l h,1 (58) for adults. The CL/F ratios (children to adults) indicated that doses of 1 mg for ,6 months,<1 year and 1.25 mg for ,1 year,,2 years would result in similar systemic exposure to that observed in adults receiving the recommended 5 mg dose. Desloratadine was well tolerated with no safety issues. Conclusions Doses of 1.0 and 1.25 mg in children aged ,6 months,,2 years should result in an exposure to desloratadine similar to that of adults receiving doses of 5 mg. [source] Age-related differences in the pharmacokinetics of stavudine in 272 children from birth to 16 years: a population analysisBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2007V. Jullien Aims To develop a population pharmacokinetic model for stavudine in children and to investigate the consistency of the currently recommended dose based on adult target concentrations. Methods The pharmacokinetics of stavudine were investigated using a population approach. Individual estimates of CL/F were used to calculate the stavudine dose required to achieve the area under the concentration-time curve reported in adults given recommended doses. Results Stavudine pharmacokinetics were well described by a one-compartment model with zero-order absorption. Typical population estimates (% interindividual variability) of the apparent distribution volume (V/F) and plasma clearance (CL/F) were 40.9 l (32%) and 16.5 l h,1 (38%), respectively. Stavudine V/F and CL/F were similarly related to age. Mean calculated doses (0.61 mg kg,1 for children less than 2 weeks, 1.23 mg kg,1 for children more than 2 weeks with bodyweight less than 30 kg, and 31.5 mg for children with a bodyweight between 30 and 60 kg) were in agreement with the current paediatric doses (0.5 mg kg,1, 1 mg kg,1, and 30 mg, respectively). Conclusions Our findings support the current recommended paediatric dosage regimens for stavudine, as they result in the same exposure to the drug as in adults. [source] Population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy chlorproguanil/dapsoneBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006Julie A. Simpson Aims To determine the population pharmacokinetics of chlorproguanil, dapsone and the active metabolite of chlorproguanil, chlorcycloguanil; and to estimate the duration of parasitocidal activity for chlorpoguanil/dapsone against Plasmodium falciparum isolates of varying sensitivity. Methods Rich and sparse pharmacokinetic data were collected prospectively from: healthy volunteers (n = 48) and adults (n = 65) and children (n = 68) suffering from P. falciparum malaria. All subjects received 2.0 mg kg,1 of chlorproguanil and 2.5 mg kg,1 of dapsone. Results The population pharmacokinetic parameter estimates for chlorproguanil were ka = 00.09 h,1 (intersubject variability was 44%), CL/F = 51.53 l h,1 (57%), CLD/F = 54.67 l h,1, V1/F = 234.40 l (50%) and V2/F = 1612.75 l; for dapsone were ka = 00.93 h,1, CL/F = 1.99 l h,1 (72%) and V/F = 76.96 l (48%); and for chlorcycloguanil were CLm/Fm = 3.72 l h,1 kg,1 (67%) and Vm/Fm = 12.76 l kg,1 (64%). For dapsone, CL/F and V/F were both significantly positively correlated with body weight. For a 10-kg child, the mean duration of parasitocidal activity for chlorproguanil/dapsone against the three most susceptible P. falciparum strains was 4.5 days [5th and 95th percentiles 2.4, 7.3] for W282; 5.9 days (3.6, 9.7) for ItG2F6; and 6.1 days (3.7, 10.1) for K39. For an isolate with the ile-164-leu mutation, V1/S, activity ranged from 0.8 days (0.0, 3.3) for a 10-kg child to 1.8 days (0.0, 4.0) for a 60-kg adult. Conclusions Plasmodium falciparum malaria has no effect on the pharmacokinetic parameters for chlorproguanil, dapsone or chlorcycloguanil. Chlorproguanil/dapsone will probably prove to be ineffective against parasite strains with the mutation ile-164-leu, were these to become prevalent in Africa. [source] Stereoselective pharmacokinetics of clausenamide enantiomers and their major metabolites after single intravenous and oral administration to ratsCHIRALITY, Issue 8 2003Chuan Jiang Zhu Abstract The pharmacokinetics of clausenamide (CLA) enantiomers and their metabolites were investigated in Wistar rat. After intravenous and oral administration at a dose of 80 and 160 mg/kg each enantiomer, plasma concentrations of (,)- or (+)-CLA and its major metabolites were simultaneously determined by reverse-phase HPLC with UV detection. Notably, stereoselective differences in pharmacokinetics were found. The mean plasma levels of (+)-CLA were higher at almost all time points than those of (,)-CLA. (+)-CLA also exhibited greater tmax, Cmax, t1/2,, AUC0,12h, and AUC0,, and smaller CL (or CL/F) and Vd (or Vd/F), than its antipode. The (+)/(,) isomer ratios for t1/2,, tmax, AUC0,12 h, and AUC0,,, which ranged from 1.26 to 2.08. The ratio for CL (or CL/F) was about 0.5, and there were significant differences in these values between CLA enantiomers (P < 0.05), implying that the absorption, distribution, and elimination of (,)-CLA were more rapid than those of (+)-CLA. Similar findings for (,)-7-OH-CLA, the major metabolite of (,)-CLA, and (+)-4-OH-CLA, the major metabolite of (+)-CLA, can be also seen in rat plasma. The contributing factors for the differences in stereoselective pharmacokinetics of CLA enantiomers appeared to be involved in their different plasma protein binding, first-pass metabolism and interaction with CYP enzymes, especially with their metabolizing enzyme CYP 3A isoforms. Chirality 15:668,673, 2003. © 2003 Wiley-Liss, Inc. [source] Population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy chlorproguanil/dapsoneBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006Julie A. Simpson Aims To determine the population pharmacokinetics of chlorproguanil, dapsone and the active metabolite of chlorproguanil, chlorcycloguanil; and to estimate the duration of parasitocidal activity for chlorpoguanil/dapsone against Plasmodium falciparum isolates of varying sensitivity. Methods Rich and sparse pharmacokinetic data were collected prospectively from: healthy volunteers (n = 48) and adults (n = 65) and children (n = 68) suffering from P. falciparum malaria. All subjects received 2.0 mg kg,1 of chlorproguanil and 2.5 mg kg,1 of dapsone. Results The population pharmacokinetic parameter estimates for chlorproguanil were ka = 00.09 h,1 (intersubject variability was 44%), CL/F = 51.53 l h,1 (57%), CLD/F = 54.67 l h,1, V1/F = 234.40 l (50%) and V2/F = 1612.75 l; for dapsone were ka = 00.93 h,1, CL/F = 1.99 l h,1 (72%) and V/F = 76.96 l (48%); and for chlorcycloguanil were CLm/Fm = 3.72 l h,1 kg,1 (67%) and Vm/Fm = 12.76 l kg,1 (64%). For dapsone, CL/F and V/F were both significantly positively correlated with body weight. For a 10-kg child, the mean duration of parasitocidal activity for chlorproguanil/dapsone against the three most susceptible P. falciparum strains was 4.5 days [5th and 95th percentiles 2.4, 7.3] for W282; 5.9 days (3.6, 9.7) for ItG2F6; and 6.1 days (3.7, 10.1) for K39. For an isolate with the ile-164-leu mutation, V1/S, activity ranged from 0.8 days (0.0, 3.3) for a 10-kg child to 1.8 days (0.0, 4.0) for a 60-kg adult. Conclusions Plasmodium falciparum malaria has no effect on the pharmacokinetic parameters for chlorproguanil, dapsone or chlorcycloguanil. Chlorproguanil/dapsone will probably prove to be ineffective against parasite strains with the mutation ile-164-leu, were these to become prevalent in Africa. [source] Pharmacokinetic interaction between efavirenz and dual protease inhibitors in healthy volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 2 2008Qing Ma Abstract The combination of efavirenz with HIV-1 protease inhibitors (PI) results in complex interactions secondary to mixed induction and inhibition of oxidative metabolism. ACTG A5043 was a prospective, open-label, controlled, two-period, multiple-dose study with 55 healthy volunteers. The objective of the present study was to evaluate the potential pharmacokinetic interaction between efavirenz and dual PIs. The subjects received a daily dose of 600,mg efavirenz for 10 days with amprenavir 600,mg twice daily added at day 11 and were randomized to receive nelfinavir, indinavir, ritonavir, saquinavir, or no second PI on days 15,21. Intensive pharmacokinetic studies were conducted on day 14 and 21. Efavirenz plasma concentrations were fit to candidate models using weighted non-linear regression. The disposition of efavirenz was described by a linear two-compartment model with first order absorption following a fitted lag time. Apparent clearance (CLt/F), volume of distribution at steady state (Vss/F), inter-compartmental clearance, and the central and peripheral volume of distribution were estimated. The mean CLt/F and Vss/F of efavirenz were 0.126,l/h/kg and 4.412,l/kg, respectively. Both AUC and CLt/F of efavirenz remained unchanged after 7 days of dual PI dosing. The mean Vss/F of efavirenz increased an average of 89% across arms, ranging from 52% (nelfinavir) to 115% (indinavir) relative to efavirenz with amprenavir alone. Increases were also observed in Vp/F after the addition of nelfinavir, indinavir, ritonavir and saquinavir by 85%, 170%, 162% and 111%, respectively. In conclusion, concomitant administration of dual PIs is unlikely to have any clinically significant effect on the pharmacokinetics of CYP2B6 substrates in general or oral efavirenz specifically. Copyright © 2007 John Wiley & Sons, Ltd. [source] The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007Joachim Stangier Aims The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. Methods Dabigatran etexilate or placebo was administered orally at single doses of 10,400 mg (n = 40) or at multiple doses of 50,400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. Results Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8,10 h and 14,17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430,2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min,1 (range 1480,2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration,time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. Conclusions These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted. [source] OATP1B1 388A>G polymorphism and pharmacokinetics of pitavastatin in Chinese healthy volunteersJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2010J. Wen PhD Summary Purpose:, To investigate the contribution of the most frequent single nucleotide polymorphism (SNPs) of the organic anion transporting polypeptide 1B1 (OATP1B1) 388A>G to the pharmacokinetics of pitavastatin in Chinese healthy volunteers. Methods:, Eighteen healthy volunteers participated in this study. Group 1 consisted of nine subjects who were of 388AA wild-type OATP1B1 genotype. Group 2 consisted of seven subjects with the 388GA genotype and two 388GG homozygotes. Two milligram of pitavastatin was administered orally to the volunteers. The plasma concentration of pitavastatin was measured for up to 48 h by liquid chromatography,mass spectrometry (LC,MS). Results:, The pharmacokinetic parameters of pitavastatin were significantly different between the two genotyped groups. The concentration (Cmax) value was higher in the 388GA + 388GG group than that in the 388AA group (39·22 ± 8·45 vs. 22·90 ± 4·03 ng/mL, P = 0·006). The area under the curve to the last measurable concentration (AUC0,48) and area under the curve extrapolated to infinity (AUC0,,) of pitavastatin were lower in the 388AA group than in the 388GA + 388GG group (100·42 ± 21·19 vs. 182·19 ± 86·46 ng h/mL, P = 0·024; 108·12 ± 24·94 vs. 199·64 ± 98·70ng h/mL, P = 0·026) respectively. The oral clearance (Cl/F) was lower in the 388GA + 388GG group than that in the 388AA group (12·46 ± 4·79 vs. 19·21 ± 3·74/h, P = 0·012). The elimination of half-life (t1/2) and peak concentration times (Tmax) values showed no difference between these groups. Conclusions:, The OATP 388A>G polymorphism causes significant alterations in the pharmacokinetics of pitavastatin in healthy Chinese volunteers and this may well be clinically significant. [source] Validation of an LC,MS Method for the Detection and Quantification of BZP and TFMPP and their Hydroxylated Metabolites in Human Plasma and its Application to the Pharmacokinetic Study of TFMPP in Humans,JOURNAL OF FORENSIC SCIENCES, Issue 5 2010Ushtana Antia M.Sc. Abstract:, An LC,MS method was developed for benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP), constituents of "party pills" or "legal herbal highs," and their metabolites in human blood plasma. Compounds were resolved using a mixture of ammonium formate (pH 4.5, 0.01 M) and acetonitrile (flow rate of 1.0 mL/min) with a C18 column. Calibration curves were linear from 1 to 50 ng/mL (R2 > 0.99); the lower limit of quantification (LLOQ) was 5 ng/mL; the accuracy was >90%; the intra- and interday relative standard deviations (R.S.D) were <5% and <10%, respectively. Human plasma concentrations of TFMPP were measured in blood samples taken from healthy adults (n = 6) over 24 h following a 60-mg oral dose of TFMPP: these peaked at 24.10 ng/mL (±1.8 ng/mL) (Cmax) after 90 min (Tmax). Plasma concentrations of 1-(3-trifluoromethyl-4-hydroxyphenyl) piperazine peaked at 20.2 ng/mL (±4.6 ng/mL) after 90 min. TFMPP had two disposition phases (t½ = 2.04 h (±0.19 h) and 5.95 h (±1.63 h). Apparent clearance (Cl/F) was 384 L/h (±45 L/h). [source] | |||||||||||||||||||||||||||||||||||||||||||||||||