Computer Simulation of the Effects of Alterations in Blood Flows and Body Composition on Thiopental Pharmacokinetics in Humans 

1997 ◽  
Vol 87 (4) ◽  
pp. 884-899 ◽  
Author(s):  
D. Russell Wada ◽  
Sven Bjorkman ◽  
William F. Ebling ◽  
Hideyoshi Harashima ◽  
Sandra R. Harapat ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Scientific Basis ◽  
Concentration Data ◽  
Blood Flows ◽  
Physiological Variables ◽  
Physiological Pharmacokinetic Model ◽  
Elimination Clearance

Background Understanding the influence of physiological variables on thiopental pharmacokinetics would enhance the scientific basis for the clinical usage of this anesthetic. Methods A physiological pharmacokinetic model for thiopental previously developed in rats was scaled to humans by substituting human values for tissue blood flows, tissue masses, and elimination clearance in place of respective rat values. The model was validated with published serum concentration data from 64 subjects. The model was simulated after intravenous thiopental administration, 250 mg, over 1 min, to predict arterial plasma concentrations under conditions of different cardiac outputs, degrees of obesity, gender, or age. Results The human pharmacokinetic model is characterized by a steady state volume of distribution of 2.2 l/kg, an elimination clearance of 0.22 l/min, and a terminal half-life of 9 h. Measured thiopental concentrations are predicted with an accuracy of 6 +/- 37% (SD). Greater peak arterial concentrations are predicted in subjects with a low versus a high cardiac output (3.1 and 9.4 l/min), and in subjects who are lean versus obese (56 and 135 kg). Acutely, obesity influences concentrations because it affects cardiac output. Prolonged changes are due to differences in fat mass. Changes with gender and age are relatively minor. Conclusions The physiological pharmacokinetic model developed in rats predicts thiopental pharmacokinetics in humans. Differences in basal cardiac output may explain much of the variability in early thiopental disposition between subjects.

Application of Physiologic Models to Predict the Influence of Changes in Body Composition and Blood Flows on the Pharmacokinetics of Fentanyl and Alfentanil in Patients 

1998 ◽  
Vol 88 (3) ◽  
pp. 657-667 ◽  
Author(s):  
Sven Bjorkman ◽  
Russell D. Wada ◽  
Donald Stanski
Keyword(s):  
Body Composition ◽  
Cardiac Output ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Studies ◽  
Concentration Data ◽  
Blood Flows ◽  
Wide Range ◽  
Regional Blood Flows ◽  
Physiologic Models

Background The influence of changes in the physiologic state of a patient on the disposition of fentanyl and alfentanil is poorly understood. The aims of this study were to determine whether physiologic pharmacokinetic models for fentanyl and alfentanil, based on data from rats, could predict plasma concentrations of these opioids in humans and to determine how changes in physiology would influence the predictions of their disposition. Methods The predictions of the models were tested against plasma concentration data from published pharmacokinetic studies. The influences of changes in body composition, cardiac output, and regional blood flows on the disposition of the opioids were simulated. Results The models could predict independently measured plasma concentrations of the opioids after short infusions in humans. Simulations then predicted that differences in body composition between men and women would have little influence on the pharmacokinetics of the opioids. Changes in cardiac output would affect drug redistribution, and consequently the early decay of the plasma concentrations, but not markedly influence rates of elimination. Further, the clearance of the opioids would decrease and their volumes of distribution increase with the age of the patient, but this would only marginally affect the early disposition of the drugs. Even large fluctuations in peripheral or hepatic blood flows would have modest effects on arterial plasma concentrations of the opioids, and sudden "postoperative" increases in peripheral blood flows would cause minor secondary plasma concentration peaks. Conclusions The ability of the physiologic models to predict plasma concentrations of fentanyl and alfentanil in humans was confirmed. When changes in physiologic condition were simulated, effects on the pharmacokinetics of the opioids with possible implications for dosing were obtained only if cardiac output was varied over a wide range.

Physiological pharmacokinetic model for ceftazidime disposition in the rat and its application to prediction of plasma concentrations in humans

1993 ◽  
Vol 1 (1) ◽  
pp. 3-11 ◽  
Author(s):  
Luis Granero ◽  
Jesús Chesa-Jiménez ◽  
Víctor Monserrat ◽  
Mercedes Almela ◽  
María-José Gimeno ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Physiological Pharmacokinetic Model

scholarly journals Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 566 ◽  
Author(s):  
Yoann Cazaubon ◽  
Yohann Talineau ◽  
Catherine Feliu ◽  
Céline Konecki ◽  
Jennifer Russello ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Concentration Data ◽  
Starting Dose ◽  
Dosing Regimens ◽  
Data Files

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2–3 g/day and should be slightly increased to reach the therapeutic index of 14–20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h−1 (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.

scholarly journals Aspects of Theophylline Clearance in Children

1997 ◽  
Vol 25 (5) ◽  
pp. 497-501 ◽  
Author(s):  
B. J. Anderson ◽  
N. H. G. Holford ◽  
G. A. Woollard
Keyword(s):  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Power Model ◽  
Theophylline Clearance ◽  
Concentration Data ◽  
Model Parameter ◽  
Age Related ◽  
Menten Constant

Michaelis-Menten pharmacokinetic parameters for theophylline were estimated in a three-month infant following an accidental overdose of intravenous aminophylline. Fitting of time-concentration data was performed using nonlinear regression with MKMODEL. A mixed order elimination model was superior to a first order model. Parameter estimates were standardized to a 70 kg human using an allometric power model. Parameter estimates (SE) were: maximum rate of metabolism (Vmax) 71(42) mg.h–1, Michaelis-Menten constant (Km) 32.3 (33.5) mg.l–1, volume of distribution (Vd) 46.9 (2.6) l. This Michaelis-Menten constant is lower than that reported for adults and consequently non-linear elimination will occur at lower plasma concentrations in infants than in adults. Theophylline clearance has traditionally been reported as directly proportional to body weight. This per kilogram model gives an erroneous impression that clearance is greatest in early childhood and then decreases with age until adult rates are reached in late adolescence. Age-related clearance values reported in the literature were reviewed using an allometric 3/4 power model. This size model demonstrates that clearance increases in infancy and reaches adult rates in the first one to two years of life.

scholarly journals Effects of Thiopental on Regional Blood Flows in the Rat

1996 ◽  
Vol 84 (3) ◽  
pp. 596-604 ◽  
Author(s):  
Russell D. Wada ◽  
Hideyoshi Harashima ◽  
William F. Ebling ◽  
Eileen W. Osaki ◽  
Donald R. Stanski
Keyword(s):  
Blood Flow ◽  
Cardiac Output ◽  
Plasma Concentrations ◽  
Brain Blood Flow ◽  
Blood Gas ◽  
Fat Tissue ◽  
Blood Flows ◽  
Hypnotic Effect ◽  
Regional Blood Flows ◽  
Arterial Plasma

Background The goal of this investigation was to characterize the effects of thiopental on cardia output and regional blood flows in the rat. Blood flows influence thiopental pharmacokinetics. Acquisition of these data may ultimately permit evaluation of the contribution of thiopental-induced alterations in regional blood flows to the disposition and hypnotic effect of this drug. Methods Chronically instrumented unrestrained Wistar rats (n=20) aged 3-4 months received either a dose of thiopental sufficient to induce a brief period of unconsciousness (20 mg.kg(-1)) or a larger dose achieving electroencephalographic burst suppression (45 mg.kg(-1)). Cardiac output and blood flows to 14 tissues were determined at 4 times in each rat for a period of 420 min using injections of radioactive microspheres (expressed as mean +/- SD). Mean arterial pressure, heart rate, and blood gas tensions were determined at all measurement times. Arterial plasma concentrations were sampled at postinfusion times. Results No important changes in systemic cardiovascular measurements were detected after the smaller dose of thiopental. One minute after the larger dose, cardiac output decreased from baseline (123 +/- 14 to 84 +/- ml.min (-1), P< 0.01), flow to muscle and fat decreased, and muscle and fat resistance increased. At 5 min, compared to baseline, no difference in cardiac output was detected (123 +/- vs. 119 +/- ml.min (-1)), intestinal flows increased and intestinal resistances decreased. Cardiac output was again depressed at 30, 90, and 180 min. Brain blood flow decreased 25 +/- 19 % (P< 0.01) from baseline for the duration of the study. Conclusions Thiopental acutely decreases cardiac output, and blood flows to muscle and fat tissue. The temporary return of cardiac output to baseline may be related to intestinal vasodilation. These blood flow alterations may influence the pharmacokinetics of thiopental.

Does vasopressin-induced vasoconstriction persist during prolonged infusion in dogs?

1987 ◽  
Vol 252 (4) ◽  
pp. R668-R673
Author(s):  
J. F. Liard
Keyword(s):  
Heart Rate ◽  
Cardiac Output ◽  
Arginine Vasopressin ◽  
Total Peripheral Resistance ◽  
Plasma Concentrations ◽  
Peripheral Resistance ◽  
Plasma Osmolality ◽  
Blood Flows ◽  
Specific Antagonist ◽  
Vascular Beds

I have examined the systemic and regional hemodynamic effects of an intravenous arginine vasopressin (AVP) infusion at a rate of 220 pg X kg-1 X min-1 maintained for 48 h in 12 conscious dogs. Plasma AVP concentration increased from 2.8 +/- 1.1 to 8.2 +/- 1.4 pg/ml, and plasma osmolality fell from 294.8 +/- 1.4 to 287.1 +/- 1.5 mosmol/kg. Mean arterial pressure increased slightly but significantly despite a reduction in blood volume. Contrary to what we previously observed with 1-h AVP infusion at the same rate, cardiac output and heart rate did not decrease, and total peripheral resistance did not increase. Most vascular beds sensitive to the acute vasoconstrictor effects of AVP, such as those of the skeletal muscle, fat, colon, and skin, did not show any significant reduction in blood flow after 48 h. Only in the pancreas and in the thyroid gland was there a significant flow decrease, which was similar in magnitude to that measured after 1 h of infusion. It therefore appears that vasoconstriction induced by modest increases in plasma concentrations of AVP is not maintained during prolonged administration in most vascular beds. However, injection of a specific antagonist of the pressor action of AVP [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-(O-methyl)tyrosine]arginine vasopressin, 10 micrograms/kg, induced a significant increase in cardiac output and heart rate, as well as a fall in total peripheral resistance and significant increases in myocardial, fat, and skin blood flows after 48 h of AVP infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Pharmacokinetics of Vancomycin in Elderly Patients Aged over 80 Years

2016 ◽  
Vol 60 (8) ◽  
pp. 4563-4567 ◽  
Author(s):  
Laurent Bourguignon ◽  
Yoann Cazaubon ◽  
Guillaume Debeurme ◽  
Constance Loue ◽  
Michel Ducher ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
External Validation ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Very Elderly ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Severe Infections ◽  
People First

ABSTRACTSince the 1950s, vancomycin has remained a reference treatment for severe infections caused by Gram-positive bacteria, including methicillin-resistantStaphylococcus aureus. Vancomycin is a nephrotoxic and ototoxic drug mainly eliminated through the kidneys. It has a large interindividual pharmacokinetic variability, which justifies monitoring its plasma concentrations in patients. This is especially important in patients aged over 80 years, who frequently have renal impairment. However, the pharmacokinetics of vancomycin in this population is very poorly described in the literature. The objective of this work was to propose a model able to predict the pharmacokinetics of vancomycin in very elderly people. First, a population pharmacokinetic model was carried out using the algorithm NPAG (nonparametric adaptive grid) on a database of 70 hospitalized patients aged over 80 years and treated with vancomycin. An external validation then was performed on 41 patients, and the predictive capabilities of the model were assessed. The model had two compartments and six parameters. Body weight and creatinine clearance significantly influenced vancomycin volume of distribution and body clearance, respectively. The means (± standard deviations) of vancomycin volume of distribution and clearance were 36.3 ± 15.2 liter and 2.0 ± 0.9 liter/h, respectively. In the validation group, the bias and precision were −0.75 mg/liter and 8.76 mg/liter for population predictions and −0.39 mg/liter and 2.68 mg/liter for individual predictions. In conclusion, a pharmacokinetic model of vancomycin in a very elderly population has been created and validated for predicting plasma concentrations of vancomycin.

Mixed-effects Modeling of the Influence of Alfentanil on Propofol Pharmacokinetics

2004 ◽  
Vol 100 (4) ◽  
pp. 795-805 ◽  
Author(s):  
Martijn J. Mertens ◽  
Erik Olofsen ◽  
Anton G. L. Burm ◽  
James G. Bovill ◽  
Jaap Vuyk
Keyword(s):  
Heart Rate ◽  
Cardiac Output ◽  
Venous Blood ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Mixed Effects ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Elimination Clearance ◽  
End Tidal

Background The influence of alfentanil on the pharmacokinetics of propofol is poorly understood. Therefore, the authors studied the effect of a pseudo-steady state concentration of alfentanil on the pharmacokinetics of propofol. Methods The pharmacokinetics of propofol were studied on two occasions in eight male volunteers in a randomized crossover manner with a 3-week interval. While volunteers breathed 30% O2 in air, 1 mg/kg intravenous propofol was given in 1 min, followed by 3 mg.kg(-1).h(-1) for 59 min (sessions A and B). During session B, a target-controlled infusion of alfentanil (target concentration, 80 ng/ml) was given from 10 min before the start until 6 h after termination of the propofol infusion. Blood pressure, cardiac output, electrocardiogram, respiratory rate, oxygen saturation, and end-tidal carbon dioxide were monitored. Venous blood samples for determination of the blood propofol and plasma alfentanil concentration were collected until 6 h after termination of the propofol infusion. Nonlinear mixed-effects population pharmacokinetic models examining the influence of alfentanil and hemodynamic parameters on propofol pharmacokinetics were constructed. Results A two-compartment model, including a lag time accounting for the venous blood sampling, adequately described the concentration-time curves of propofol. Alfentanil decreased the elimination clearance of propofol from 2.1 l/min to 1.9 l/min, the distribution clearance from 2.7 l/min to 2.0 l/min, and the peripheral volume of distribution from 179 l to 141 l. Scaling the pharmacokinetic parameters to cardiac output, heart rate, and plasma alfentanil concentration significantly improved the model. Conclusions Alfentanil alters the pharmacokinetics of propofol. Cardiac output and heart rate have an important influence on the pharmacokinetics of propofol.

Enzyme autoinduction by mitotane supported by population pharmacokinetic modeling in a large cohort of adrenocortical carcinoma patients

2018 ◽  
Vol 179 (5) ◽  
pp. 287-297 ◽  
Author(s):  
U Arshad ◽  
M Taubert ◽  
M Kurlbaum ◽  
S Frechen ◽  
S Herterich ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Pharmacokinetic Model ◽  
Structural Model ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Volume Of Distribution ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Population Pharmacokinetic Modeling

ObjectiveMitotane is used for the treatment of adrenocortical carcinoma. High oral daily doses of typically 1–6 g are required to attain therapeutic concentrations. The drug has a narrow therapeutic index and patient management is difficult because of a high volume of distribution, very long elimination half-life and drug interaction through induction of metabolizing enzymes. The present evaluation aimed at the development of a population pharmacokinetic model of mitotane to facilitate therapeutic drug monitoring (TDM).MethodsAppropriate dosing information, plasma concentrations (1137 data points) and covariates were available from TDM of 76 adrenocortical carcinoma patients treated with mitotane. Using nonlinear mixed-effects modeling, a simple structural model was first developed, with subsequent introduction of metabolic autoinduction. Covariate data were analyzed to improve overall model predictability. Simulations were performed to assess the attainment of therapeutic concentrations with clinical dosing schedules.ResultsA one-compartment pharmacokinetic model with first order absorption was found suitable to describe the data, with an estimated central volume of distribution of 6086 L related to a high interindividual variability of 81.5%. Increase in clearance of mitotane during treatment could be modeled by a linear enzyme autoinduction process. BMI was found to have an influence upon disposition kinetics of mitotane. Model simulations favor a high-dose regimen to rapidly attain therapeutic concentrations, with the first TDM suggested on day 16 of treatment to avoid systemic toxicity.ConclusionThe proposed model describes mitotane pharmacokinetics and can be used to facilitate therapy by predicting plasma concentrations.

Human Pharmacokinetics and Pharmacodynamics of MF 701 Dermatan Sulfate Administered by Continuous Intravenous Infusion

1990 ◽  
Vol 64 (02) ◽  
pp. 256-259 ◽  
Author(s):  
Giancarlo Agnelli ◽  
Benilde Cosmi ◽  
Cinzia Renga ◽  
Fiorella Federici ◽  
Giuseppe G Necil ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Dermatan Sulfate ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Human Pharmacokinetics ◽  
Bolus Administration ◽  
Thrombin Inhibition ◽  
Chromogenic Assay ◽  
Single Compartment ◽  
Human Thrombin

SummaryThe pharmacokinetics and haemostatic effects of MF 701 dermatan sulfate (DS) administered by i. v. infusion were studied in 11 healthy volunteers. Each subject received 0.6 mg kg-1 h-1 MF 701 for 10 h. DS plasma concentrations were measured by a chromogenic assay based on the catalysis of thrombin inhibition by HCII. DS plasma levels followed a single compartment pharmacokinetic model, with a half-life of 1.28 ± 0.46 h, a plasma clearance of 2.75 ± 0.46 1/h and a volume of distribution of 4.92 ± 1.36 1 (means ± SD). Steady-state was reached 3 to 6 h after infusion started. The maximal DS plasma concentration was 16.4 ± 5.7 μg/ml. Maximal APTT prolongation over pre-infusion values was 42 ± 7%; TCT performed with bovine and human thrombin was prolonged by 16 ± 7% and 83 ± 35% respectively. No anti-IIa or anti-Xa activities were detected by chromogenic tests. The treatment was well tolerated. The pharmacokinetics of MF 701 infusion are consistent with those previously described after i. v. bolus administration. The infusion of MF 701 allows fast achievement and steady maintenance of elevated DS plasma concentrations.

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