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Pharmacokinetic Models (pharmacokinetic + models)
Selected AbstractsDeep percutaneous penetration into muscles and jointsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2006Christine M. Lee Abstract The transdermal absorption of drugs and its subsequent deep tissue delivery is a complex process, with many factors influencing the penetration mechanisms. Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used in the treatment of joint and muscle diseases. However, the dangers associated with oral medications highlight the need for alternative methods of targeting and retaining drugs; one such means is through topical delivery. The drug's lipophilicity, permeability, and fraction unbound found in the viable skin are some physiochemical factors influencing the delivery mechanism after transdermal absorption. These and other variables play a role in determining whether the drug reaches the deep tissues via direct penetration or from systemic redistribution. Pharmacokinetic models have been developed to help elucidate the penetration routes and efficacy for various drugs. While there are still uncertainties regarding the deep tissue penetration kinetics, improvements to current research methodologies may bring about a greater understanding of percutaneous absorption into the deep muscle and joints. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 95: 1405,1413, 2006 [source] Two-stage kinetic analysis of fragrance evaporation and absorption from skinINTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 5 2003P. Saiyasombati Synopsis Human in vivo fragrance evaporation data from a previously published study are reanalysed in terms of compartmental pharmacokinetic models in which the microscopic rate constants are functions of the physicochemical properties of the fragrance components. According to the proposed analysis, which is restricted to low doses, absorption and evaporation of each component are first-order processes occurring from either the skin (one-compartment model) or the skin and a more rapidly depleted vehicle layer (two-compartment models). Evaporation rates of ingredients from a 12-component mixture containing a musk fixative followed single exponential decays that were well described by the one-compartment model. An otherwise identical mixture without fixative yielded evaporation rates that could be characterized as biexponential decays associated with loss from two compartments. This result shows that ingredient interactions qualitatively and quantitatively change evaporation rate profiles of fragrance components; however, an attempt to account for these interactions explicitly by means of activity coefficients inserted as multipliers for the microscopic rate constants was unsuccessful. Re-examination of this approach in the context of a diffusion/evaporation model is suggested. The developed models have potential utility for dermal risk assessment and for prediction of aroma evolution following topical application of complex fragrances. Résumé Des données d'une étude publiée précédemment sur l'évaporation de parfum de humaine in vivo sont réanalysées en utilisant des modèles pharmacocinétiques compartimentés dont les constants microscopiques de taux sont des functions des propriétés physio-chimiques des composants de parfum. Selon l'analyse proposée, qui est limitée aux petites doses, l'absorption et l'évaporation de chaque composant sont des processus de premier ordre se produisant l'un de la peau (modèle d'un compartiment), ou l'autre de la peau et d'une couche de véhicule plus rapidement épuisée (modèles de deux compartiments). Les taux d'évaporation d'ingrédients d'un mélange de 12 composants contenant un fixatif de musc suivi par des décompositions exponentielles uniques qui ont été bien décrites par le modèle d'un compartiment. Un mélange sans fixatif mais identique pour le reste a rapporté des taux d'évaporation qui pourraient être caractérisés commes des décompositions bi-exponentielles avec une perte de deux compartiments. Ce résultat montre que les interactions d'ingrédient changent qualitativement et quantitativement les profils de taux d'évaporation des composants de parfum. Cependant, une tentative d'expliquer précisement ces interactions au moyen des coefficients d'activité insérés comme multiplicateurs pour les constants microscopiques de taux n'a pas été réussie. Le réexamen de cette approche dans le contexte d'un modèle de diffusion/evaporation est suggéré. Les modèles développés ont une utilité potentielle dans l'évaluation des risques cutané et pour la prévision de l'évolution d'arome suivant l'application topique des parfums complexes. [source] Predictive ability of propofol effect,site concentrations during fast and slow infusion ratesACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2010P. O. SEPÚLVEDA Background: The performance of propofol effect,site pharmacokinetic models during target-controlled infusion (TCI) might be affected by propofol administration rate. This study compares the predictive ability of three effect,site pharmacokinetic models during fast and slow infusion rates, utilizing the cerebral state index (CSI) as a monitor of consciousness. Methods: Sixteen healthy volunteers, 21,45 years of age, were randomly assigned to receive either a bolus dose of propofol 1.8 mg/kg at a rate of 1200 ml/h or an infusion of 12 mg/kg/h until 3,5 min after loss of consciousness (LOC). After spontaneous recovery of the CSI, the bolus was administered to patients who had first received the infusion and vice versa. The study was completed after spontaneous recovery of CSI following the second dose scheme. LOC was assessed and recorded when it occurred. Adequacies of model predictions during both administration schemes were assessed by comparing the effect,site concentrations estimated at the time of LOC during the bolus dose and during the infusion scheme. Results: LOC occurred 0.97 ± 0.29 min after the bolus dose and 6.77 ± 3.82 min after beginning the infusion scheme (P<0.05). The Ce estimated with Schnider (ke0=0.45/min), Marsh (ke0=1.21/min) and Marsh (ke0=0.26/min) at LOC were 4.40 ± 1.45, 3.55 ± 0.64 and 1.28 ± 0.44 ,g/ml during the bolus dose and 2.81 ± 0.61, 2.50 ± 0.39 and 1.72 ± 0.41 ,g/ml, during the infusion scheme (P<0.05). The CSI values observed at LOC were 70 ± 4 during the bolus dose and 71 ± 2 during the infusion scheme (NS). Conclusion: Speed of infusion, within the ranges allowed by TCI pumps, significantly affects the accuracy of Ce predictions. The CSI monitor was shown to be a useful tool to predict LOC in both rapid and slow infusion schemes. [source] Using Biomonitoring Equivalents to interpret human biomonitoring data in a public health risk contextJOURNAL OF APPLIED TOXICOLOGY, Issue 4 2009Sean M. Hays Abstract Increasingly sensitive analytical tools allow measurement of trace concentrations of chemicals in human biological media in persons from the general population. Such data are being generated by biomonitoring programs conducted by the US Centers for Disease Control and other researchers. However, few screening tools are available for interpretation of such data in a health risk assessment context. This review describes the concept and implementation of Biomonitoring Equivalents (BEs), estimates of the concentration of a chemical or metabolite in a biological medium that is consistent with an existing exposure guidance value such as a tolerable daily intake or reference dose. The BE approach integrates available pharmacokinetic data to convert an existing exposure guidance value into an equivalent concentration in a biological medium. Key concepts regarding the derivation and communication of BE values resulting from an expert workshop held in 2007 are summarized. BE derivations for four case study chemicals (toluene, 2,4-dichlorophenoxyacetic acid, cadmium and acrylamide) are presented, and the interpretation of biomonitoring data for these chemicals is presented using the BE values. These case studies demonstrate that a range of pharmacokinetic data and approaches can be used to derive BE values; fully developed physiologically based pharmacokinetic models, while useful, are not required. The resulting screening level evaluation can be used to classify these compounds into relative categories of low, medium and high priority for risk assessment follow-up. Future challenges related to the derivation and use of BE values as tools in risk management are discussed. Copyright © 2008 John Wiley & Sons, Ltd. [source] Evaluation of physiologically based pharmacokinetic models for use in risk assessment,JOURNAL OF APPLIED TOXICOLOGY, Issue 3 2007Weihsueh A. Chiu Abstract Physiologically based pharmacokinetic (PBPK) models are sophisticated dosimetry models that offer great flexibility in modeling exposure scenarios for which there are limited data. This is particularly of relevance to assessing human exposure to environmental toxicants, which often requires a number of extrapolations across species, route, or dose levels. The continued development of PBPK models ensures that regulatory agencies will increasingly experience the need to evaluate available models for their application in risk assessment. To date, there are few published criteria or well-defined standards for evaluating these models. Herein, important considerations for evaluating such models are described. The evaluation of PBPK models intended for risk assessment applications should include a consideration of: model purpose, model structure, mathematical representation, parameter estimation, computer implementation, predictive capacity and statistical analyses. Model purpose and structure require qualitative checks on the biological plausibility of a model. Mathematical representation, parameter estimation, computer implementation involve an assessment of the coding of the model, as well as the selection and justification of the physical, physicochemical and biochemical parameters chosen to represent a biological organism. Finally, the predictive capacity and sensitivity, variability and uncertainty of the model are analysed so that the applicability of a model for risk assessment can be determined. Published in 2007 by John Wiley & Sons, Ltd. [source] A comparison of Ktrans measurements obtained with conventional and first pass pharmacokinetic models in human gliomasJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 5 2004Hamied A. Haroon MSc Abstract Purpose To compare in a group of patients with cerebral gliomas the estimates of Ktrans between a conventionally established pharmacokinetic model and a recently developed first pass method. Materials and Methods Glioma patients (23) were studied using T1 -weighted dynamic contrast-enhanced magnetic resonance imaging (MRI), and two alternative pharmacokinetic models were used for analysis to derive the volume transfer constant Ktrans. These were a modified version of the established model (yielding KTK) and a recently published method based on first pass leakage profile (FP) of contrast bolus (yielding Kfp). Results We found a strong correlation between intra-tumoral median KTK and Kfp (rho = 0.650, P < 0.01), but the values from the conventional model were consistently and significantly higher (mean of inter-tumoral Kfp and KTK medians were 0.018 minute,1 and 0.284 minute,1, respectively, P < 0.001). The spatial distribution of KTK and Kfp showed poor correlation in the presence of large vascular structures and good correlation elsewhere. Conclusion KTK and Kfp produce similar biologic information within voxels not dominated by vascular tissue. The FP method avoids erroneous overestimation of Ktrans in areas of significant intravascular contrast. Findings are in keeping with the predictions of previous mathematical simulations. J. Magn. Reson. Imaging 2004;19:527,536. © 2004 Wiley-Liss, Inc. [source] Individualized population pharmacokinetic model with limited sampling for cyclosporine monitoring after liver transplantation in clinical practiceALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2007P. LANGERS Summary Background, We recently developed and validated limited sampling models (LSMs) for cyclosporine monitoring after orthotopic liver transplantation based on individualized population pharmacokinetic models with Bayesian modelling. Aim, To evaluate LSM in practice, and to seek optimal balance between benefit and discomfort. Methods, In 30 stable patients, more than 6 months after orthotopic liver transplantation, previously switched from trough- to 2 h post-dose (C2)-monitoring, we switched to 3-monthly LSM 0,1,2,3 h-monitoring. During 18 months we evaluated dose, creatinine clearance, calculated area under the curve, intra-patient pharmacokinetic variability and ability to assess systemic exposure by several previously validated LSMs. Results, Within patients, there was variability of cyclosporine-area under the curve with the same dose (CV of 15%). Compared to C2-monitoring, there was no significant difference in dose (P = 0.237), creatinine clearance (P = 0.071) and number of rejections. Some models showed excellent correlation and precision with LSM 0,1,2,3 h comparing area under the curves (0,2 h: r2 = 0.88; 0,1,3 h: r2 = 0.91; 0,2,3 h: r2 = 0.92, all P < 0.001) with no difference in advised dose. Conclusions, The limited sampling model, with only trough- and 2-h sampling, yields excellent accuracy and assesses systemic exposure much better than C2 with less bias and greater precision. Considering the calculated intra-patient variability, more precision is redundant, so LSM 0,2 h seems the optimal way of cyclosporine-monitoring. [source] The time course of drug effectsPHARMACEUTICAL STATISTICS: THE JOURNAL OF APPLIED STATISTICS IN THE PHARMACEUTICAL INDUSTRY, Issue 3 2009Hesham S. Al-Sallami Abstract This review aims to introduce the concepts and principles underpinning the time course of drug effects. Models describing the time course of drug concentrations (pharmacokinetic models) and the ensuing concentration-effect (pharmacodynamics models) as well as the linked time-effect (pharmacokinetic-pharmacodynamic models) are introduced. Different types of drug time-effects models are discussed with examples which aim to explain the time course of onset, duration, and maximal effect that occurs from any given dosing schedule. These drug effects are also described in relation to disease progression models. Copyright © 2009 John Wiley & Sons, Ltd. [source] Hepatopancreatic and muscular distribution of oxytetracycline antibiotics in farmed pacific white shrimp (Penaeus vannamei): a physiological-based pharmacokinetic model approachAQUACULTURE RESEARCH, Issue 1 2009Damrongsak Faroongsarng Abstract Oxytetracycline (OTC) pharmacokinetic models previously used to investigate Penaeus vannamei have not addressed the specific problems related to drug distribution/disposition in particular tissues. This study aimed to provide an insight into OTC kinetics in the hepatopancreas and muscle based on a physiological model approach. Adult male P. vannamei at the C-D0 inter-moulting stage were randomly assigned to intra-sinus and oral administrations. In the intra-sinus group, shrimps were dosed via the ventral sinus at an OTC level of 10.0 ,g g,1 body weight, while in the oral one, they were force fed at a dose level of 50.2 ,g g,1. The medicated animals were sampled at various time intervals until 170 h after dosing. Haemolymph, muscle and hepatopancreas samples were taken and OTC levels were determined using the validated HPLC method. A model focused on the hepatopancreas and muscle was developed. Oxytetracycline pharmacokinetic profiles in particular tissues were fitted into the model with an R2 of between 0.6568 and 0.9904. Oxytetracycline muscular distributions were essentially identical for both groups and the drug did not accumulate in muscle. The distributions in the hepatopancreas for both groups were extensive, whereas that for oral administration was approximately 2.3 times greater than that for the intra-sinus one. It was demonstrated that hepatopancreatic OTC may undergo significant first-pass elimination with non-linear kinetics. [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] 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] Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and convulsionsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2008Simon N. Muchohi WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Midazolam (MDZ), a water-soluble benzodiazepine, can be administered via several routes, including intravenously (IV), intramuscularly (IM) and buccal routes to terminate convulsions. It may be a suitable alternative to diazepam to stop convulsions in children with severe malaria, especially at peripheral healthcare facilities. The pharmacokinetics of MDZ have not been described in African children, in whom factors such as the aetiology and nutritional status may influence the pharmacokinetics. WHAT THIS STUDY ADDS , Administration of MDZ (IV, IM, or buccal) at the currently recommended dose (0.3 mg kg,1) resulted in rapid achievement of median maximum plasma concentrations of MDZ within the range 64,616 ng ml,1, with few clinically significant cardio-respiratory effects. A single dose of MDZ rapidly terminated (within 10 min) seizures in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration, respectively. Although IM and buccal MDZ may be the preferred treatment for children in the pre-hospital settings the efficacy appears to be poorer. AIM To investigate the pharmacokinetics and clinical efficacy of intravenous (IV), intramuscular (IM) and buccal midazolam (MDZ) in children with severe falciparum malaria and convulsions. METHODS Thirty-three children with severe malaria and convulsions lasting ,5 min were given a single dose of MDZ (0.3 mg kg,1) IV (n = 13), IM (n = 12) or via the buccal route (n = 8). Blood samples were collected over 6 h post-dose for determination of plasma MDZ and 1,-hydroxymidazolam concentrations. Plasma concentration,time data were fitted using pharmacokinetic models. RESULTS Median (range) MDZ Cmax of 481 (258,616), 253 (96,696) and 186 (64,394) ng ml,1 were attained within a median (range) tmax of 10 (5,15), 15 (5,60) and 10 (5,40) min, following IV, IM and buccal administration, respectively. Mean (95% confidence interval) of the pharmacokinetic parameters were: AUC(0,,) 596 (327, 865), 608 (353, 864) and 518 (294, 741) ng ml,1 h; Vd 0.85 l kg,1; clearance 14.4 ml min,1 kg,1, elimination half-life 1.22 (0.65, 1.8) h, respectively. A single dose of MDZ terminated convulsions in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration. Four children (one in the IV, one in the IM and two in the buccal groups) had respiratory depression. CONCLUSIONS Administration of MDZ at the currently recommended dose resulted in rapid achievement of therapeutic MDZ concentrations. Although IM and buccal administration of MDZ may be more practical in peripheral healthcare facilities, the efficacy appears to be poorer at the dose used, and a different dosage regimen might improve the efficacy. [source] | |||||||||||||