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Pharmacokinetic Modeling (pharmacokinetic + modeling)
Selected AbstractsPharmacokinetic and pharmacodynamic properties of metomidate in turbot (Scophthalmus maximus) and halibut (Hippoglossus hippoglossus)JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2003M. K. Hansen Metomidate was administered to halibut (Hippoglossus hippoglossus) and turbot (Scophthalmus maximus) intravenously at a dose of 3 mg/kg bodyweight, as a bath treatment at a dose of 9 mg/L water for 5 min to study the disposition of metomidate, and as bath treatment (9 mg/L) for 10 min to study the absorption and effect of metomidate on respiration and balance/motor control. Additionally, turbot were given metomidate orally at a dose of 7 mg/kg. The studies were performed in seawater at a temperature of 10.3 ± 0.4 °C (halibut) and 18.0 ± 0.3 °C (turbot). Pharmacokinetic modeling of the data showed that metomidate had shorter elimination half-life and higher plasma concentrations in turbot compared with halibut, both species displaying a rapid uptake, distribution and excretion. Following intravenous administration, the volumes of distribution at steady state (Vd(ss)) were 0.21 L/kg (halibut) and 0.44 L/kg (turbot). Plasma clearances (Cl) were 0.099 L/h·kg in halibut and 0.26 L/h·kg in turbot and the elimination half-lives (t½,z) were calculated to be 5.8 h and 2.2 h in halibut and turbot, respectively. Mean residence times (MRT) were 2.2 h in halibut and 1.7 h in turbot. Following oral administration, the t½,z was 3.5 h in turbot. The maximum plasma concentration (Cmax) was 7.8 mg/L in turbot 1 h after administration. The oral bioavailability (F) was calculated to 100% in turbot. Following 5 min bath the maximum plasma concentrations (Cmax), which were observed immediately after end of the bath, were 9.5 mg/L and 13.3 mg/L in halibut and turbot, respectively. Metomidate rapidly immobilized the fish, with respiratory depression, reduced heart rate, and loss of balance/motor control within 1 min (mean). Recovery was slow, with resumed balance/motor control after 26.4 min. Opercular respiration movements were resumed more rapidly with a recorded mean of 1.7 min. Oral administration was demonstrated to be a way of immobilizing fish, for example in large aquariums, without exposing them to unwanted stress. [source] Removing undersampling artifacts in DCE-MRI studies using independent components analysisMAGNETIC RESONANCE IN MEDICINE, Issue 4 2008A.L. Martel Abstract In breast MRI mammography both high temporal resolution and high spatial resolution have been shown to be important in improving specificity. Adaptive methods such as projection reconstruction time-resolved imaging of contrast kinetics (PR-TRICKS) allow images to be reconstructed at various temporal and spatial resolutions from the same data set. The main disadvantage is that the undersampling, which is necessary to produce high temporal resolution images, leads to the presence of streak artifacts in the images. We present a novel method of removing these artifacts using independent components analysis (ICA) and demonstrate that this results in a significant improvement in image quality for both simulation studies and for patient dynamic contrast-enhanced (DCE)-MRI images. We also investigate the effect of artifacts on two quantitative measures of contrast enhancement. Using simulation studies we demonstrate that streak artifacts lead to pronounced periodic oscillations in pixel concentration curves which, in turn, lead to increased errors and introduce bias into heuristic measurements. ICA filtering significantly reduces this bias and improves accuracy. Pharmacokinetic modeling was more robust and there was no evidence of bias due to the presence of streak artifacts. ICA filtering did not significantly reduce the errors in the estimated pharmacokinetic parameters; however, the chi-squared error was greatly reduced after ICA filtering. Magn Reson Med, 2008. © 2008 Wiley-Liss, Inc. [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] Pharmacokinetic mapping for lesion classification in dynamic breast MRIJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 6 2010Matthias C. Schabel PhD Abstract Purpose: To prospectively investigate whether a rapid dynamic MRI protocol, in conjunction with pharmacokinetic modeling, could provide diagnostically useful information for discriminating biopsy-proven benign lesions from malignancies. Materials and Methods: Patients referred to breast biopsy based on suspicious screening findings were eligible. After anatomic imaging, patients were scanned using a dynamic protocol with complete bilateral breast coverage. Maps of pharmacokinetic parameters representing transfer constant (Ktrans), efflux rate constant (kep), blood plasma volume fraction (vp), and extracellular extravascular volume fraction (ve) were averaged over lesions and used, with biopsy results, to generate receiver operating characteristic curves for linear classifiers using one, two, or three parameters. Results: Biopsy and imaging results were obtained from 93 lesions in 74 of 78 study patients. Classification based on Ktrans and kep gave the greatest accuracy, with an area under the receiver operating characteristic curve of 0.915, sensitivity of 91%, and specificity of 85%, compared with values of 88% and 68%, respectively, obtained in a recent study of clinical breast MRI in a similar patient population. Conclusion: Pharmacokinetic classification of breast lesions is practical on modern MRI hardware and provides significant accuracy for identification of malignancies. Sensitivity of a two-parameter linear classifier is comparable to that reported in a recent multicenter study of clinical breast MRI, while specificity is significantly higher. J. Magn. Reson. Imaging 2010;31:1371,1378. © 2010 Wiley-Liss, Inc. [source] Recent advances in pharmacokinetic modelingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2007Alaa M. Ahmad Abstract A major part of the science of pharmacokinetics is the modeling of the underlying processes that contribute to drug disposition. The purpose of pharmacokinetic models is to summarize the knowledge gained in preclinical and clinical studies at various stages in drug development and to rationally guide future studies with the use of adequately predictive models. This review highlights a variety of recent advances in mechanistic pharmacokinetic modeling. It is aimed at a broad audience, and hence, an attempt was made to maintain a balance between technical information and practical applications of pharmacokinetic modeling. It is hoped that drug researchers from all disciplines would be able to get a flavor of the function and capacity of pharmacokinetic modelers and their contribution to drug development. While this review is not intended to be a technical reference on modeling approaches, the roles of statistical applications and population methodologies are discussed where appropriate. Copyright © 2007 John Wiley & Sons, Ltd. [source] | ||||||||||