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Concentration-time Profiles (concentration-time + profile)
Selected AbstractsDevelopment of capillary zone electrophoresis-electrospray ionization-mass spectrometry for the determination of lamotrigine in human plasmaELECTROPHORESIS, Issue 13 2004Jack Zheng Abstract A method of coupling capillary zone electrophoresis (CZE) with electrospray ionization-mass spectrometry (ESI-MS) detection has been developed for monitoring an antiepileptic drug, lamotrigine (LTG) in human plasma. The CZE-MS was developed in three stages: (i) CZE separation and ESI-MS detection of LTG and tyramine (TRM, internal standard) were simultaneously optimized by studying the influence of CZE background electrolyte (BGE) pH, BGE ionic strength, and nebulizer pressure of the MS sprayer; (ii) sheath liquid parameters, such as pH, ionic strength, organic modifier content, and flow rate of the sheath liquid, were systematically varied under optimum CZE-MS conditions developed in the first stage; (iii) MS sprayer chamber parameters (drying gas temperature and drying gas flow rate) were varied for the best MS detection of LTG. The developed assay was finally applied for the determination of LTG in plasma samples. The linear range of LTG in plasma sample assay was between 0.1,5.0 ,g/mL with a limit of detection as low as 0.05 ,g/mL and run time less than 6 min. Finally, the concentration-time profile of LTG in human plasma sample was found to correlate well when CZE-ESI-MS was compared to a more established method of high-performance liquid chromatography with ultraviolet detection. [source] Investigation of human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble/highly permeable drug (efavirenz)JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2007J. ZH. Abstract Human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble, highly permeable, micronized drug (efavirenz) was investigated. The tablets and capsule, prepared with samarium oxide and neutron activated to produce radioactive samarium-153, were evaluated for their in vivo disintegration and gastrointestinal (GI) transit in healthy subjects under fasted condition. Scintigraphic images were acquired to coincide with blood sampling times to assess the plasma concentration-time profile in relation to in vivo disintegration and GI transit. The mean gastric emptying times were approximately the same for all three formulations. Although in vivo dosage form disintegration was faster for Tablet A as compared to Tablet B and was similar between Tablet A and the capsule, Tablet A showed a slower rate and extent of drug absorption than Tablet B and the capsule. The results of this study eliminated the initial hypothesis that the difference in in vivo performance between the two tablet formulations is due to a different rate of in vivo disintegration and suggest that for this drug the in vivo dissolution rate of the drug from its disintegrated dosage form was a more important factor affecting the rate and extent of drug absorption. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2970,2977, 2007 [source] Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compoundsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2008Aberra Fura Abstract The oral pharmacokinetics (concentration-time profile) of four proprietary compounds in humans were predicted using the Cvss - MRT method. The first step was to demonstrate superposition of intravenous (i.v.) pharmacokinetic profiles of preclinical species following mathematical transformation of their respective concentration-time curves using the corresponding Cvss (where Cvss=dose/Vss; Vss is the volume of distribution at steady state) and mean residence time (MRT) values. The resultant profiles were then back-transformed to estimate human i.v. plasma concentration-time profiles using human Cvss and MRT values. Human Cvss and MRT values were estimated from projected human Vss and CL values. Projection of CL was based on scaled (in vitro) metabolic clearance, simple allometry with and without various correction factors and the unbound fraction corrected intercept method. Vss values were estimated by allometric scaling with and without correction for interspecies differences in plasma protein binding. The predicted human i.v. profiles, in combination with the estimated mean absorption rate constants and bioavailability, were then used to simulate the oral pharmacokinetics in human using one- or multi-compartment kinetic models. Overall, with this approach, key oral pharmacokinetic parameters such as AUC, Cmax, Cmin and oral plasma T½ were projected to be within two-fold of the actual values in humans. Copyright © 2008 John Wiley & Sons, Ltd. [source] Proposal for a standardised identification of the mono-exponential terminal phase for orally administered drugsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2008Christian Scheerans Abstract The area under the plasma concentration-time curve from time zero to infinity (AUC0,inf) is generally considered to be the most appropriate measure of total drug exposure for bioavailability/bioequivalence studies of orally administered drugs. However, the lack of a standardised method for identifying the mono-exponential terminal phase of the concentration-time curve causes variability for the estimated AUC0,inf. The present investigation introduces a simple method, called the two times tmax method (TTT method) to reliably identify the mono-exponential terminal phase in the case of oral administration. The new method was tested by Monte Carlo simulation in Excel and compared with the adjusted r squared algorithm (ARS algorithm) frequently used in pharmacokinetic software programs. Statistical diagnostics of three different scenarios, each with 10,000 hypothetical patients showed that the new method provided unbiased average AUC0,inf estimates for orally administered drugs with a monophasic concentration-time curve post maximum concentration. In addition, the TTT method generally provided more precise estimates for AUC0,inf compared with the ARS algorithm. It was concluded that the TTT method is a most reasonable tool to be used as a standardised method in pharmacokinetic analysis especially bioequivalence studies to reliably identify the mono-exponential terminal phase for orally administered drugs showing a monophasic concentration-time profile. Copyright © 2007 John Wiley & Sons, Ltd. [source] Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure modelJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2008P. R. TERRITO The anticonvulsant ameltolide (LY201116) is a novel potential therapy for the treatment of canine epilepsy. Eight dogs were administered five different oral doses of ameltolide and clinical scoring of the maximal electroshock (MES) induced seizures at 3 and 24 h postdosing were determined in two separate crossover design studies. Plasma ameltolide concentrations were determined at the time of seizures in all dogs and complete plasma concentration-time profiles were also determined in a separate study. A nonlinear mixed effects PK/PD model was fit to the resulting data. A one compartment open model with first order absorption was determined to best fit the ameltolide pharmacokinetics. An effect compartment with a cumulative logistic regression equation was used to establish the PK/PD relationship. The mean bioavailability normalized volume of distribution and the elimination half-life were estimated at 1.20 L/kg and 5.46 h, respectively. The fitted model estimated that from 2 to 15 h following a single 3 mg/kg oral ameltolide dose the mean probability of obtaining a 1 unit reduction in the seizure clinical score severity was greater than 0.80. The utilized PK/PD analysis combined with the canine MES model allowed for the rapid and efficient determination of the plasma ameltolide concentration-anticonvulsant relationship preclinically in dogs. [source] Clinical Pharmacokinetics of the PDT Photosensitizers Porfimer Sodium (Photofrin), 2-[1-Hexyloxyethyl]-2-Devinyl Pyropheophorbide-a (Photochlor) and 5-ALA-Induced Protoporphyrin IXLASERS IN SURGERY AND MEDICINE, Issue 5 2006David A. Bellnier PhD Abstract Background and Objectives Photodynamic therapy (PDT) uses a photosensitizer activated by light, in an oxygen-rich environment, to destroy malignant tumors. Clinical trials of PDT at Roswell Park Cancer Institute (RPCI) use the photosensitizers Photofrin, Photochlor, and 5-ALA-induced protoporphyrin IX (PpIX). In some studies the concentrations of photosensitizer in blood, and occasionally in tumor tissue, were obtained. Pharmacokinetic (PK) data from these individual studies were pooled and analyzed. This is the first published review to compare head-to-head the PK of Photofrin and Photochlor. Study Design/Materials and Methods Blood and tissue specimens were obtained from patients undergoing PDT at RPCI. Concentrations of Photofrin, Photochlor, and PpIX were measured using fluorescence analysis. A non-linear mixed effects modeling approach was used to analyze the PK data for Photochlor (up to 4 days post-infusion; two-compartment model) and a simpler multipatient-data-pooling approach was used to model PK data for both Photofrin and Photochlor (at least 150 days post-infusion; three-compartment models). Physiological parameters were standardized to correspond to a standard (70 kg; 1.818 m2 surface area) man to facilitate comparisons between Photofrin and Photochlor. Results Serum concentration-time profiles obtained for Photofrin and Photochlor showed long circulating half-lives, where both sensitizers could be found more than 3 months after intravenous infusion; however, estimated plasma clearances (standard man) were markedly smaller for Photofrin (25.8 ml/hour) than for Photochlor (84.2 ml/hour). Volumes of distribution of the central compartment (standard man) for both Photofrin and Photochlor were about the size (3.14 L, 4.29 L, respectively) of plasma volume, implying that both photosensitizers are almost 100% bound to serum components. Circulating levels of PpIX were generally quite low, falling below the level of instrument sensitivity within a few days after topical application of 5-ALA. Conclusion We have modeled the PK of Photochlor and Photofrin. PK parameter estimates may, in part, explain the relatively long skin photosensitivity attributed to Photofrin but not Photochlor. Due to the potential impact and limited experimental PK data in the PDT field further clinical studies of photosensitizer kinetics in tumor and normal tissues are warranted. Lasers Surg. Med. © 2006 Wiley-Liss, Inc. [source] An automated method for nonparametric kinetic analysis of clinical DCE-MRI data: Application to glioblastoma treated with bevacizumabMAGNETIC RESONANCE IN MEDICINE, Issue 5 2010Gregory Z. Ferl Abstract Here, we describe an automated nonparametric method for evaluating gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) kinetics, based on dynamic contrast-enhanced,MRI scans of glioblastoma patients taken before and after treatment with bevacizumab; no specific model or equation structure is assumed or used. Tumor and venous blood concentration-time profiles are smoothed, using a robust algorithm that removes artifacts due to patient motion, and then deconvolved, yielding an impulse response function. In addition to smoothing, robustness of the deconvolution operation is assured by excluding data that occur prior to the plasma peak; an exhaustive analysis was performed to demonstrate that exclusion of the prepeak plasma data does not significantly affect results. All analysis steps are executed by a single R script that requires blood and tumor curves as the sole input. Statistical moment analysis of the Impulse response function yields the area under the curve (AUC) and mean residence time (MRT). Comparison of deconvolution results to fitted Tofts model parameters suggests that and AUC of the Impulse response function closely approximate fractional clearance from plasma to tissue (Ktrans) and fractional interstitial volume (ve) . Intervisit variability is shown to be comparable when using the deconvolution method (11% [] and 13%[AUC]) compared to the Tofts model (14%[Ktrans] and 24%[ve]). AUC and both exhibit a statistically significant decrease (P < 0.005) 1 day after administration of bevacizumab. Magn Reson Med 63:1366,1375, 2010. © 2010 Wiley-Liss, Inc. [source] Variability and Impact on Design of Bioequivalence StudiesBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2010Achiel Van Peer Revisions of the regulatory guidance are based upon many questions over the past years and sometimes continuing scientific discussions on the use of the most suitable statistical analysis methods and study designs, particularly for drugs and drug products with high within-subject variability. Although high within-subject variability is usually associated with a coefficient of variation of 30% or more, new approaches are available in the literature to allow a gradual increase and a levelling off of the bioequivalence limits to some maximum wider values (e.g. 75,133%), dependent on the increase in the within-subject variability. The two-way, cross-over single dose study measuring parent drug is still the design of first choice. A partial replicate design with repeating the reference product and scaling the bioequivalence for the reference variability are proposed for drugs with high within-subject variability. In case of high variability, more regulatory authorities may accept a two-stage or group-sequential bioequivalence design using appropriately adjusted statistical analysis. This review also considers the mechanisms why drugs and drug products may exhibit large variability. The physiological complexity of the gastrointestinal tract and the interaction with the physicochemical properties of drug substances may contribute to the variation in plasma drug concentration-time profiles of drugs and drug products and to variability between and within subjects. A review of submitted bioequivalence studies at the Food and Drug Administration's Office of Generic Drugs over the period 2003,2005 indicated that extensive pre-systemic metabolism of the drug substance was the most important explanation for consistently high variability drugs, rather than a formulation factor. These scientific efforts are expected to further lead to revisions of earlier regulatory guidance in other regions as is the current situation in Europe. [source] Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compoundsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2008Aberra Fura Abstract The oral pharmacokinetics (concentration-time profile) of four proprietary compounds in humans were predicted using the Cvss - MRT method. The first step was to demonstrate superposition of intravenous (i.v.) pharmacokinetic profiles of preclinical species following mathematical transformation of their respective concentration-time curves using the corresponding Cvss (where Cvss=dose/Vss; Vss is the volume of distribution at steady state) and mean residence time (MRT) values. The resultant profiles were then back-transformed to estimate human i.v. plasma concentration-time profiles using human Cvss and MRT values. Human Cvss and MRT values were estimated from projected human Vss and CL values. Projection of CL was based on scaled (in vitro) metabolic clearance, simple allometry with and without various correction factors and the unbound fraction corrected intercept method. Vss values were estimated by allometric scaling with and without correction for interspecies differences in plasma protein binding. The predicted human i.v. profiles, in combination with the estimated mean absorption rate constants and bioavailability, were then used to simulate the oral pharmacokinetics in human using one- or multi-compartment kinetic models. Overall, with this approach, key oral pharmacokinetic parameters such as AUC, Cmax, Cmin and oral plasma T½ were projected to be within two-fold of the actual values in humans. Copyright © 2008 John Wiley & Sons, Ltd. [source] | ||||||||||