Using Front-end Kinetics to Optimize Target-controlled Drug Infusions

2003 ◽  
Vol 99 (5) ◽  
pp. 1078-1086 ◽  
Author(s):  
Michael J. Avram ◽  
Tom C. Krejcie
Keyword(s):  
Intravenous Administration ◽  
Pharmacokinetic Model ◽  
Sampling Site ◽  
Model Parameters ◽  
Drug Infusion ◽  
Concentration Data ◽  
Blood Concentrations ◽  
Compartment Models ◽  
Drug Concentrations ◽  
Recirculatory Model

Background The mode of drug administration, blood sampling schedule, and sampling site affect the pharmacokinetic model derived. The present study tested the hypothesis that three-compartment pharmacokinetic model parameters derived from arterial drug concentrations obtained after rapid intravenous administration can be used to design a target-controlled drug infusion (TCI) that deviates minimally from the target. Methods Arterial thiopental concentration data obtained from the moment of injection in a previous study of five dogs were used. Three three-compartment models were constructed, one based on early concentrations classically obtained at 1, 2, and 3 min; another using all concentrations obtained beginning with the thiopental recirculation peak; and the last with the initial distribution volume (VC) fixed to the sum of VC and the nondistributive volume of the recirculatory model from the earlier study. Using these models, TCIs were designed that would maintain 20 mug/ml thiopental concentrations in VC for 60 min if simulated with the models used in their design. Drug concentrations resulting from these TCIs were then simulated using recirculatory model kinetics, and prediction errors were evaluated. Results Models with VCs estimated from intermittent or frequent early blood concentrations overestimated not only VC but also the volume and clearance of the rapidly equilibrating tissues, and their TCIs significantly overshot the target. With VC fixed to recirculatory model parameters, drug distribution was described in a manner consistent with that of the recirculatory model, and the TCI deviated minimally from the target. A similar three-compartment model was derived from data obtained from a simulation of a 2-min infusion using recirculatory kinetic parameters. Conclusions Because three-compartment models based on drug concentration histories obtained after rapid intravenous administration do not characterize VC accurately, TCIs based on them produce concentrations exceeding the target. A model capable of producing TCIs deviating minimally from the target can be derived from data obtained during and after a brief drug infusion.

scholarly journals Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(–) Ketamine Concentrations

2018 ◽  
Vol 129 (2) ◽  
pp. 260-270 ◽  
Author(s):  
Thomas K. Henthorn ◽  
Michael J. Avram ◽  
Albert Dahan ◽  
Lars L. Gustafsson ◽  
Jan Persson ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Venous Blood ◽  
Population Pharmacokinetic ◽  
Drug Infusion ◽  
Population Pharmacokinetic Modeling ◽  
Front End ◽  
Drug Concentrations ◽  
Link Rate ◽  
Recirculatory Model ◽  
Venous Plasma

Abstract What We Already Know about This Topic What This Article Tells Us That Is New Background The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(–) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations. Methods S(+) or R(–) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses. Results A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(–) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(–) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min–1, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01. Conclusions Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.

Pharmacodynamic Effect of Morphine-6-glucuronide versus  Morphine on Hypoxic and Hypercapnic Breathing in Healthy Volunteers

2003 ◽  
Vol 99 (4) ◽  
pp. 788-798 ◽  
Author(s):  
Raymonda Romberg ◽  
Erik Olofsen ◽  
Elise Sarton ◽  
Luc Teppema ◽  
Albert Dahan
Keyword(s):  
Carbon Dioxide ◽  
Input Function ◽  
Time Profile ◽  
Population Pharmacokinetic ◽  
Model Parameters ◽  
Drug Infusion ◽  
Potency Ratio ◽  
Effect Site ◽  
Drug Concentrations ◽  
End Tidal

Background Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is generally associated with less respiratory depression than morphine. Because M6G will be on the market in the near future, the authors assessed the time profile and relative potency of M6G's effect versus morphine's effect on carbon dioxide-driven and hypoxic breathing. Methods In nine healthy female volunteers, the effects of 0.2 mg/kg intravenous M6G, 0.13 mg/kg intravenous morphine, and intravenous placebo were tested on ventilation at a fixed end-tidal pressure of carbon dioxide (Petco2) of 45 mmHg (Vi45) and on the acute hypoxic ventilatory response (AHR). All subjects participated in all three arms of the study. Respiratory studies were performed at 1-h intervals for 7 h after drug infusion. The data were analyzed using a population dose-driven approach, which uses a dose rate in function of time as input function driving the pharmacodynamics, and a population pharmacokinetic-pharmacodynamic (PK/PD) approach in which fixed pharmacokinetic parameter values from the literature were used as input function to the respiratory model. From the latter analysis, the authors obtained the blood effect-site equilibration half-life (t1/2ke0) and the effect-site concentration producing 25% depression of Vi45 and AHR (C25). Values reported are mean +/- SE. Results Placebo had no effect on Vi45 or AHR over time. Both analysis approaches yielded good descriptions of the data with comparable model parameters. M6G PK/PD model parameters for Vi45 were t1/2ke0 2.1 +/- 0.2 h and C25 528 +/- 88 nm and for AHR were t1/2ke0 1.0 +/- 0.1 h and C25 873 +/- 81 nm. Morphine PK/PD model parameters for Vi45 were t1/2ke0 3.8 +/- 0.9 h and C25 28 +/- 6 nm and for AHR were t1/2ke0 4.3 +/- 0.6 h and C25 16 +/- 2 nm. Conclusions Morphine is more potent in affecting hypoxic ventilatory control than M6G, with a potency ratio ranging from 1:19 for Vi45 to 1:50 for AHR. At drug concentrations causing 25% depression of Vi45, M6G caused only 15% depression of AHR, whereas morphine caused greater than 50% depression of AHR. Furthermore, the speed of onset/offset of M6G is faster than morphine by a factor of approximately 2. The authors discuss some of the possible mechanisms for the observed differences in opioid behavior.

scholarly journals A “Smart” Biosensor-Enabled Intravascular Catheter and Platform for Dynamic Delivery of Propofol to “Close the Loop” for Total Intravenous Anesthesia

2021 ◽  
Vol 186 (Supplement_1) ◽  
pp. 370-377
Author(s):  
Edward Chaum ◽  
Ernő Lindner
Keyword(s):  
Real Time ◽  
Drug Distribution ◽  
Population Based ◽  
Pharmacokinetic Data ◽  
Drug Infusion ◽  
Blood Concentrations ◽  
The Usa ◽  
The Difference ◽  
Automated Delivery

ABSTRACT Background Target-controlled infusion anesthesia is used worldwide to provide user-defined, stable, blood concentrations of propofol for sedation and anesthesia. The drug infusion is controlled by a microprocessor that uses population-based pharmacokinetic data and patient biometrics to estimate the required infusion rate to replace losses from the blood compartment due to drug distribution and metabolism. The objective of the research was to develop and validate a method to detect and quantify propofol levels in the blood, to improve the safety of propofol use, and to demonstrate a pathway for regulatory approval for its use in the USA. Methods We conceptualized and prototyped a novel “smart” biosensor-enabled intravenous catheter capable of quantifying propofol at physiologic levels in the blood, in real time. The clinical embodiment of the platform is comprised of a “smart” biosensor-enabled catheter prototype, a signal generation/detection readout display, and a driving electronics software. The biosensor was validated in vitro using a variety of electrochemical methods in both static and flow systems with biofluids, including blood. Results We present data demonstrating the experimental detection and quantification of propofol at sub-micromolar concentrations using this biosensor and method. Detection of the drug is rapid and stable with negligible biofouling due to the sensor coating. It shows a linear correlation with mass spectroscopy methods. An intuitive graphical user interface was developed to: (1) detect and quantify the propofol sensor signal, (2) determine the difference between targeted and actual propofol concentration, (3) communicate the variance in real time, and (4) use the output of the controller to drive drug delivery from an in-line syringe pump. The automated delivery and maintenance of propofol levels was demonstrated in a modeled benchtop “patient” applying the known pharmacokinetics of the drug using published algorithms. Conclusions We present a proof-of-concept and in vitro validation of accurate electrochemical quantification of propofol directly from the blood and the design and prototyping of a “smart,” indwelling, biosensor-enabled catheter and demonstrate feedback hardware and software architecture permitting accurate measurement of propofol in blood in real time. The controller platform is shown to permit autonomous, “closed-loop” delivery of the drug and maintenance of user-defined propofol levels in a dynamic flow model.

scholarly journals Comparative Drug Disposition, Urinary Pharmacokinetics, and Renal Effects of Multilamellar Liposomal Nystatin and Amphotericin B Deoxycholate in Rabbits

2003 ◽  
Vol 47 (12) ◽  
pp. 3917-3925 ◽  
Author(s):  
Andreas H. Groll ◽  
Diana Mickiene ◽  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Raul M. Alfaro ◽  
...  
Keyword(s):  
Total Dose ◽  
Amphotericin B ◽  
Drug Disposition ◽  
Fungal Infections ◽  
Standard Dose ◽  
Concentration Data ◽  
Drug Concentrations ◽  
Amphotericin B Deoxycholate ◽  
Dose Dependent Decrease ◽  
Dose Dependent

ABSTRACT The comparative drug dispositions, urinary pharmacokinetics, and effects on renal function of multilamellar liposomal nystatin (LNYS; Nyotran) and amphotericin B deoxycholate (DAMB; Fungizone) were studied in rabbits. Drug concentrations were determined by high-performance liquid chromatography as total concentrations of LNYS and DAMB. In comparison to a standard dose of 1 mg of DAMB/kg of body weight, therapeutic dosages of LNYS, i.e., 2, 4, and 6 mg/kg, resulted in escalating maximum concentrations (C max) (17 to 56μ g/ml for LNYS versus 3.36 μg/ml for DAMB; P< 0.001) and values for the area under the concentration-time curve from 0 to 24 h (AUC0-24) (17 to 77μ g · h/ml for LNYS versus 12μ g · h/ml for DAMB; P < 0.001) in plasma but a significantly faster total clearance from plasma (0.117 to 0.080 liter/h/kg for LNYS versus 0.055 liter/h/kg for DAMB; P = 0.013) and a ≤8-fold-smaller volume of distribution at steady state (P = 0.002). Urinary drug concentration data revealed a ≥10-fold-higher C max (16 to 10 μg/ml for LNYS versus 0.96μ g/ml for DAMB; P = 0.015) and a 4- to 7-fold-greater AUC0-24 (63 to 35μ g · h/ml for LNYS versus 8.9μ g · h/ml for DAMB; P = 0.015) following the administration of LNYS, with a dose-dependent decrease in the dose-normalized AUC0-24 in urine (P= 0.001) and a trend toward a dose-dependent decrease in renal clearance. Except for the kidneys, the mean concentrations of LNYS in liver, spleen, and lung 24 h after dosing were severalfold lower than those after administration of DAMB (P,<0.002 to <0.001). Less than 1% each of the total dose of LNYS was recovered from the kidneys, liver, spleen, and lungs; in contrast, a quarter of the total dose was recovered from the livers of DAMB-treated animals. LNYS had dose-dependent effects on glomerular filtration and distal, but not proximal, renal tubular function which did not exceed those of DAMB at the highest investigated dosage of 6 mg/kg. The results of this experimental study demonstrate fundamental differences in the dispositions of LNYS and DAMB. Based on its enhanced urinary exposure, LNYS may offer a therapeutic advantage in systemic fungal infections involving the upper and lower urinary tracts that require therapy with antifungal polyenes.

Buprenorphine blood concentrations: A biomarker for analgesia

2021 ◽  
Vol 17 (7) ◽  
pp. 15-20
Author(s):  
Michael Guarnieri, PhD, MPH
Keyword(s):  
Clinical Evidence ◽  
Acute Postoperative Pain ◽  
Blood Concentrations ◽  
Patient Reports ◽  
Drug Concentrations ◽  
Subjective Pain ◽  
Nonopioid Analgesics ◽  
Pain Reports ◽  
Quantitative Sensory Tests ◽  
Sensory Tests

Opioids, the frontline drugs for postsurgical analgesia, have been linked to diversion and abuse with lethal consequences. The search for safe analgesics with less harm potential has been decades long. However, clinical trials for safe opioid and nonopioid analgesics have relied on subjective pain reports, which are biased by placebo effects that increase the complexity of trials to develop new therapies to manage pain.Research in opioid naïve animals and humans demonstrates that blood concentrations of opioids that effectively saturate the morphine opioid receptor are tightly linked with patient reports and quantitative sensory tests for analgesia. Opioid drug concentrations can predict clinical responses.This report reviews preclinical and clinical evidence correlating buprenorphine pharmacokinetics with analgesia. More than 30 years of data confirm buprenorphine blood concentrations can be an objective biomarker of analgesia for moderate to severe acute postoperative pain.

scholarly journals Pharmacokinetic Model-Predicted Anticancer Drug Concentrations in Human Tumors

2004 ◽  
Vol 10 (23) ◽  
pp. 8048-8058 ◽  
Author(s):  
James M. Gallo ◽  
Paolo Vicini ◽  
Amy Orlansky ◽  
Shaolan Li ◽  
Feng Zhou ◽  
...  
Keyword(s):  
Anticancer Drug ◽  
Pharmacokinetic Model ◽  
Human Tumors ◽  
Drug Concentrations

scholarly journals Methadone, Buprenorphine, Oxycodone, Fentanyl, and Tramadol in Multiple Postmortem Matrices

2021 ◽  
Author(s):  
Stine Marie Havig ◽  
Vigdis Vindenes ◽  
Åse Marit Leere Øiestad ◽  
Sidsel Rogde ◽  
Cecilie Hasselø Thaulow
Keyword(s):  
Peripheral Blood ◽  
Vitreous Humor ◽  
Pericardial Fluid ◽  
Limited Information ◽  
Blood Concentrations ◽  
Bodily Fluids ◽  
Drug Concentrations ◽  
Quantitative Analyses ◽  
Alternative Matrices ◽  
Almost All

Abstract Peripheral blood concentrations are generally preferred for postmortem toxicological interpretation, but some autopsy cases may lack blood for sampling due to decomposition or large traumas etc. In such cases, other tissues or bodily fluids must be sampled; however, limited information exists on postmortem concentrations in matrices other than blood. Pericardial fluid, muscle, and vitreous humor have been suggested as alternatives to blood, but only a few studies have investigated the detection of opioids in these matrices. In this study, we aimed to investigate the detection of methadone, buprenorphine, oxycodone, fentanyl, and tramadol in postmortem samples of pericardial fluid, skeletal muscle, and vitreous humor, in addition to peripheral and cardiac blood; and if drug concentrations in these alternative matrices were comparable to those in peripheral blood, and thereby useful for interpretation. In most of the 54 included cases, only one opioid was detected. Methadone, oxycodone, fentanyl, and tramadol were detected in all of the alternative matrices in almost all cases, while buprenorphine was detected less often. For methadone, the concentrations in the alternative matrices, except for in vitreous humor, were relatively similar to those in peripheral blood. Larger variations in concentrations were found for buprenorphine, oxycodone, and tramadol. Quantitative analyses appeared useful for fentanyl, in all of the alternative matrices, but only four cases were included. Toxicological analyses of opioids in these alternative postmortem matrices can be useful for detection, but interpretation of quantitative results must be performed with caution.

scholarly journals Pharmacokinetics and Pharmacodynamics of Imipenem during Continuous Renal Replacement Therapy in Critically Ill Patients

2005 ◽  
Vol 49 (6) ◽  
pp. 2421-2428 ◽  
Author(s):  
Douglas N. Fish ◽  
Isaac Teitelbaum ◽  
Edward Abraham
Keyword(s):  
High Performance ◽  
Continuous Venovenous Hemofiltration ◽  
Systemic Clearance ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Drug Infusion ◽  
Dosing Interval ◽  
Adult Intensive Care Unit ◽  
Drug Concentrations ◽  
Elimination Half ◽  
Higher Doses

ABSTRACT The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n = 6 patients) or hemodiafiltration (CVVHDF; n = 6 patients). Patients (mean ± standard deviation age, 50.9 ± 15.9 years; weight, 98.5 ± 15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL S ) and elimination half-life (t 1/2) of imipenem were 145 ± 18 ml/min and 2.7 ± 1.3 h during CVVH versus 178 ± 18 ml/min and 2.6 ± 1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL S , respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 μg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC = 4 to 8 μg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.

scholarly journals The Influence of Sampling Site upon the Distribution Phase Kinetics of Thiopentone

1984 ◽  
Vol 12 (1) ◽  
pp. 5-8 ◽  
Author(s):  
Robin Barrett ◽  
G. G. Graham ◽  
T. A. Torda
Keyword(s):  
Plasma Concentration ◽  
Intravenous Administration ◽  
Femoral Artery ◽  
Time Course ◽  
Sampling Site ◽  
Acute Tolerance ◽  
Hplc Assay ◽  
Distribution Phase ◽  
Kinetics Of

In six sheep anaesthetised with ketamine blood was sampled from the jugular and femoral veins and the femoral artery at frequent intervals for 12 minutes following the intravenous administration of 5 or 10 mg/kg sodium thiopentone. Samples were also taken from cubital veins and radial arteries of five patients who received 5 mg/kg thiopentone. The plasma concentration of thiopentone was determined by an HPLC assay. The time course of plasma concentration of thiopentone showed considerable variation according to sampling site as well as variation between individuals. Such sampling site-dependent variation may result in the appearance of acute tolerance.

scholarly journals Model Reference Adaptive Scheme for Multi-drug Infusion for Blood Pressure Control

2011 ◽  
Vol 8 (3) ◽  
pp. 43-56 ◽  
Author(s):  
S. Enbiya ◽  
F. Mahieddine ◽  
A. Hossain
Keyword(s):  
Pressure Control ◽  
Model Parameters ◽  
Multivariable Model ◽  
Drug Infusion ◽  
Model Reference ◽  
Adaptive Scheme ◽  
Control Objective ◽  
Patient Model ◽  
The Mean ◽  
Model Reference Adaptive

Summary Using multiple interacting drugs to control both the mean arterial pressure (MAP) and cardiac output (CO) of patients with different sensitivity to drugs is a challenging task which this paper attempts to address. A multivariable model reference adaptive control (MRAC) algorithm is developed using a two-input, two-output patient model. The control objective is to maintain the homodynamic variables MAP and CO at the normal values by simultaneously administering two drugs; sodium nitroprusside (SNP) and dopamine (DPM). Computer simulations were carried out to investigate the performance of this controller. The results show that the proposed adaptive scheme is robust with respect to disturbances and variations in model parameters.

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