Prediction of Concentration–Time Profile and its Inter-Individual Variability following the Dermal Drug Absorption

2012 ◽  
Vol 101 (7) ◽  
pp. 2584-2595 ◽  
Author(s):  
Sebastian Polak ◽  
Cyrus Ghobadi ◽  
Himanshu Mishra ◽  
Malidi Ahamadi ◽  
Nikunjkumar Patel ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Time Profile ◽  
Individual Variability ◽  
Concentration Time ◽  
Dermal Drug Absorption

scholarly journals A General Fitting Function to Estimate Apparent Reaction Orders of Kinetic Profiles

2019 ◽  
Author(s):  
Robert Pollice
Keyword(s):  
Chemical Reactions ◽  
Catalyst Deactivation ◽  
Rapid Development ◽  
Product Inhibition ◽  
Time Profile ◽  
Time Data ◽  
Concentration Time ◽  
Wide Range ◽  
Reaction Orders

The rapid development of analytical methods in recent decades has resulted in a wide range of readily available and accurate reaction-monitoring techniques, which allow for easy determination of high-quality concentration-time data of chemical reactions. However, while the acquisition of kinetic data has become routine in the development of new chemical reactions and the study of their mechanisms, not all the information contained therein is utilized because of a lack of suitable analysis tools which unnecessarily complicates mechanistic studies. Herein, we report on a general method to analyze a single concentration-time profile of chemical reactions and extract information regarding the reaction order with respect to substrates, the presence of multiple kinetic regimes, and the presence of kinetic complexities, such as catalyst deactivation, product inhibition, and substrate decomposition.<br>

scholarly journals Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs

2020 ◽  
Author(s):  
Armin Sadighi ◽  
Lorenzo Leggio ◽  
Fatemeh Akhlaghi
Keyword(s):  
Pbpk Model ◽  
Organ Damage ◽  
Time Profile ◽  
Sensitivity Analyses ◽  
Pbpk Modeling ◽  
Time Curve ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

Abstract Aims A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions. Methods A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted. Results Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss). Conclusions The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies.

scholarly journals Pharmacokinetics of Telavancin at Fixed Doses in Normal-Body-Weight and Obese (Classes I, II, and III) Adult Subjects

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Kristen L. Bunnell ◽  
Manjunath P. Pai ◽  
Monica Sikka ◽  
Susan C. Bleasdale ◽  
Eric Wenzler ◽  
...  
Keyword(s):  
Body Weight ◽  
Time Profile ◽  
Primary Objective ◽  
Fixed Dose ◽  
Target Area ◽  
Obese Patients ◽  
Time Curve ◽  
Content Type ◽  
Time Zero ◽  
Concentration Time

ABSTRACT A recommended total-body-weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obese classes I, II, and III. Healthy adult subjects ( n = 32) received a single, weight-stratified, fixed dose of 500 mg ( n = 4), 750 mg ( n = 8), or 1,000 mg ( n = 20) of telavancin. Noncompartmental PK analyses revealed that subjects with a body mass index (BMI) of ≥40 kg/m 2 had a higher volume of distribution (16.24 ± 2.7 liters) than subjects with a BMI of <30 kg/m 2 (11.71 ± 2.6 liters). The observed area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) ranged from 338.1 to 867.3 mg · h/liter, with the lowest exposures being in subjects who received 500 mg. AUC 0–∞ values were similar among obese subjects who received 1,000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1,000 mg had similar target attainment probabilities for efficacy as doses of 10 mg/kg of body weight based on ABW and TBW, respectively. However, the probability of achieving a target area under the concentration-time curve from time zero to 24 h of ≥763 mg · h/liter in association with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750-mg dose. These results suggest that a fixed dose of 750 mg is a safe and effective alternative to telavancin doses based on TBW or ABW for the treatment of obese patients with normal renal function and Staphylococcus aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02753855.)

scholarly journals Large Inter-individual Variation in Postprandial Lipemia Following a Mixed Meal in over 1000 Twins and Singletons from the UK and US: The PREDICT I Study (OR19-06-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Sarah Berry ◽  
Ana Valdes ◽  
Richard Davies ◽  
Haya Al Khatib ◽  
Linda Delahanty ◽  
...  
Keyword(s):  
Standardized Test ◽  
Postprandial Lipemia ◽  
Area Under The Curve ◽  
Individual Variability ◽  
Mixed Meal ◽  
Multiple Factors ◽  
Funding Sources ◽  
Concentration Time ◽  
The Uk ◽  
Time Point

Abstract Objectives Postprandial lipemia is an important risk factor for cardiovascular disease, independent of fasting levels, and is influenced by multiple factors including; environmental, genetic, metabolic, metagenomic and the meal-context. Postprandial lipemic responses may therefore differ between individuals, however previously this has only been studied in limited numbers. The PREDICT I study is the largest study to date to measure inter-individual variability in postprandial lipemic responses using a standardized test meal model. Methods A multi-center postprandial study of 1000 individuals from the UK (unrelated, identical and non-identical twins) and 100 unrelated individuals from US, assessed postprandial (hourly 0–6h) lipemic responses to sequential mixed-nutrient dietary challenges (50g fat and 85g carbohydrate at 0h; 22g fat and 71g carbohydrate at 4h) in a clinical setting. Inter-individual variability in postprandial triacylglycerol (TG) responses was measured for incremental area under the curve (iAUC), Cmax, Tmax and increase above fasting at 5h (mean peak concentration time-point). Results Analysis showed high inter-individual variability in postprandial lipemic responses (Figures 1–3) in the tightly controlled clinic setting (interim analysis of n = 537); IQR (median) was; iAUC (0-6h) 2.34 (2.38) mmol/L.h; Cmax 1.32 (2.02) mmol/L; Tmax 30.0 (300) min; and increase above fasting at 5h 0.92 (0.95). TG variation was higher in the non-fasting versus the fasting state; fasting TG concentration IQR (median); 0.57 (0.91) mmol/L. Conclusions The large variation in the magnitude and pattern of lipemic responses to identical meals in healthy people demonstrates the limitations of using the group mean and the importance of individualized dietary approaches. Ongoing exploration in PREDICT I of the determinants of postprandial lipemic responses considering environmental, genetic, metagenomic and microbiome variables will significantly advance our ability to predict an individual's postprandial response. Funding Sources NIHR, Wellcome Trust, Zoe Global Ltd. Supporting Tables, Images and/or Graphs

scholarly journals Pharmacodynamics of Isavuconazole in a DynamicIn VitroModel of Invasive Pulmonary Aspergillosis

2015 ◽  
Vol 60 (1) ◽  
pp. 278-287 ◽  
Author(s):  
Helen Box ◽  
Joanne Livermore ◽  
Adam Johnson ◽  
Laura McEntee ◽  
Timothy W. Felton ◽  
...  
Keyword(s):  
Invasive Pulmonary Aspergillosis ◽  
Pathogenic Fungi ◽  
Time Profile ◽  
Wild Type ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Target Values ◽  
Maximal Suppression

ABSTRACTIsavuconazonium sulfate is a novel triazole prodrug that has been recently approved for the treatment of invasive aspergillosis by the FDA. The active moiety (isavuconazole) has a broad spectrum of activity against many pathogenic fungi. This study utilized a dynamicin vitromodel of the human alveolus to describe the pharmacodynamics of isavuconazole against two wild-type and two previously defined azole-resistant isolates ofAspergillus fumigatus. A human-like concentration-time profile for isavuconazole was generated. MICs were determined using CLSI and EUCAST methodologies. Galactomannan was used as a measure of fungal burden. Target values for the area under the concentration-time curve (AUC)/MIC were calculated using a population pharmacokinetics-pharmacodynamics (PK-PD) mathematical model. Isolates with higher MICs required higher AUCs in order to achieve maximal suppression of galactomannan. The AUC/MIC targets necessary to achieve 90% probability of galactomannan suppression of <1 were 11.40 and 11.20 for EUCAST and CLSI, respectively.

scholarly journals Concentration-time profile for perhexiline and hydroxyperhexiline in patients at steady state

2003 ◽  
Vol 57 (3) ◽  
pp. 263-269 ◽  
Author(s):  
Terry E. Jones ◽  
Raymond G. Morris ◽  
John D. Horowitz
Keyword(s):  
Steady State ◽  
Time Profile ◽  
Concentration Time

Azides. Part V. A kinetic study of the formation of N-(p-toluenesulphonyl)-1H-azepine by thermolysis of p-toluenesulphonylazide in benzene under nitrogen pressure

1985 ◽  
Vol 63 (4) ◽  
pp. 887-890 ◽  
Author(s):  
Nagaraj R. Ayyangar ◽  
Ramesh B. Bambal ◽  
Dattatraya D. Nikalje ◽  
Kumar V. Srinivasan
Keyword(s):  
Kinetic Study ◽  
Rate Constants ◽  
Nitrogen Pressure ◽  
Time Profile ◽  
First Order ◽  
First Order Kinetics ◽  
Concentration Time

The course of thermolysis of p-toluenesulphonylazide (A) in benzene at 160 °C and 40.1 atm of nitrogen pressure was followed by analysis of the reactants and products in the reaction mixture by hplc. The rate measurements indicate that the reaction follows first-order kinetics with respect to the formation of N-(p-toluenesulphonyl)-1H-azepine (B) and p-toluencsulphonamide (D). The concentration–time profile is consistent with the formation of p-toluenesulphonylanilide (C) from the azepine (B). The rate constants indicate that the azepine (B) decomposes to the anilide (C) at the same rate at which it is formed.

The application of resonance enhanced multiphoton ionization to the detection of hydrogen atoms during the oscillatory combustion of hydrogen

1991 ◽  
Vol 434 (1891) ◽  
pp. 399-412 ◽  
Keyword(s):  
Numerical Analysis ◽  
Flow Reactor ◽  
Multiphoton Ionization ◽  
Laser Wavelength ◽  
Time Profile ◽  
Experimental Result ◽  
Oh Radicals ◽  
Hydrogen Atoms ◽  
Experimental Conditions ◽  
Concentration Time

The relative concentrations of hydrogen atoms were measured during the oscillatory ignition of hydrogen in a well stirred flow reactor. Comparisons were made with the experimental concentration—time profiles of the hydroxyl radical obtained previously under similar experimental conditions. The predicted concentration profiles obtained from numerical analysis of a thermokinetic model were also compared with the experimental results. Experiments were performed in a 600 cm 3 Pyrex glass, jet-stirred reactor with the reactants, 2H 2 + O 2 , at a total pressure of 16 Torr ( ca . 2132.8 Pa) and at a vessel temperature of 753 K. The mean residence time was 1.2 s. Oscillatory ignition was established at a period of 3 s in which high radical concentrations were attained and in which the temperature rise was almost adiabatic. The concentration-time profile of hydrogen atoms was obtained by a resonance enhanced multiphoton ionization (rempi) which was induced by a laser pulse at energies in the vicinity of 364 nm, with ion collection at a stainless steel probe inserted into the reactor. Supplementary studies were made to characterize the signals and to identify effects of the probe within the reaction volume. A measurement of the relative concentrations of hydrogen atoms was obtained from an integration of the area of the rempi spectrum determined over the laser wavelength range 363.8-364.6 nm. The spectrum was measured at successive times in the oscillatory cycle by imposing a variable delay on the laser firing signal. The results show that, during oscillatory ignition, the maximum concentration of hydrogen atoms was reached and a sharp decay was already well advanced before that of the hydroxyl radicals was attained. The numerical analysis was in very good quantitative accord with this experimental result. The phase difference of the cyclic variation in the H atoms relative to that of OH radicals is a key feature of the kinetic mechanisms which control the oscillatory oxidation of hydrogen.

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