scholarly journals Prediction of Repeat-Dose Occupancy from Single-Dose Data: Characterisation of the Relationship between Plasma Pharmacokinetics and Brain Target Occupancy

2010 ◽  
Vol 31 (3) ◽  
pp. 944-952 ◽  
Author(s):  
Sergio Abanades ◽  
Jasper van der Aart ◽  
Julien AR Barletta ◽  
Carmine Marzano ◽  
Graham E Searle ◽  
...  
Keyword(s):  
Single Dose ◽  
Drug Development ◽  
Time Course ◽  
Adaptive Design ◽  
Model Parameters ◽  
Repeat Dose ◽  
Dose Selection ◽  
Direct Model ◽  
Brain Target ◽  
The Relationship

Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [11C]DASB ([11C] N, N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC50=2.62±0.93 ng/mL) was significantly better ( P<0.05) than that from the direct model (OC50=2.29±1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD.

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET

2014 ◽  
Vol 28 (3) ◽  
pp. 244-253 ◽  
Author(s):  
Khanum Ridler ◽  
Roger N Gunn ◽  
Graham E Searle ◽  
Julien Barletta ◽  
Jan Passchier ◽  
...  
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Human Brain ◽  
Dose Range ◽  
Receptor Occupancy ◽  
Repeat Dose ◽  
Dose Selection ◽  
Dose Administration ◽  
Single Dose Administration

GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [11C]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration–occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration–occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50 ~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.

scholarly journals A Bayesian Adaptive Design in Cancer Phase I Trials Using Dose Combinations with Ordinal Toxicity Grades

Stats ◽  
2020 ◽  
Vol 3 (3) ◽  
pp. 221-238
Author(s):  
Márcio A. Diniz ◽  
Sungjin Kim ◽  
Mourad Tighiouart
Keyword(s):  
Adaptive Design ◽  
Parametric Models ◽  
Model Parameters ◽  
Operating Characteristics ◽  
Bayesian Adaptive Design ◽  
Continual Reassessment ◽  
Proportional Odds Assumption ◽  
Dose Combination ◽  
The One ◽  
The Relationship

We propose a Bayesian adaptive design for early phase drug combination cancer trials incorporating ordinal grade of toxicities. Parametric models are used to describe the relationship between the dose combinations and the probabilities of the ordinal toxicities under the proportional odds assumption. Trial design proceeds by treating cohorts of two patients simultaneously receiving different dose combinations. Specifically, at each stage of the trial, we seek the dose of one agent by minimizing the Bayes risk with respect to a loss function given the current dose of the other agent. We consider two types of loss functions corresponding to the Continual Reassessment Method (CRM) and Escalation with Overdose Control (EWOC). At the end of the trial, we estimate the MTD curve as a function of Bayes estimates of the model parameters. We evaluate design operating characteristics in terms of safety of the trial and percent of dose recommendation at dose combination neighborhoods around the true MTD by comparing this design to the one that uses a binary indicator of DLT. The methodology is further adapted to the case of a pre-specified discrete set of dose combinations.

scholarly journals Neural network-based modeling of the number of microbubbles generated with four circulation factors in cardiopulmonary bypass

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Satoshi Miyamoto ◽  
Zu Soh ◽  
Shigeyuki Okahara ◽  
Akira Furui ◽  
Taiichi Takasaki ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Flow Rate ◽  
Neurological Complications ◽  
Estimation Accuracy ◽  
Model Parameters ◽  
Perfusion Flow ◽  
Postsurgical Complication ◽  
Tenfold Cross Validation ◽  
Suction Flow ◽  
The Relationship

AbstractThe need for the estimation of the number of microbubbles (MBs) in cardiopulmonary bypass surgery has been recognized among surgeons to avoid postoperative neurological complications. MBs that exceed the diameter of human capillaries may cause endothelial disruption as well as microvascular obstructions that block posterior capillary blood flow. In this paper, we analyzed the relationship between the number of microbubbles generated and four circulation factors, i.e., intraoperative suction flow rate, venous reservoir level, continuous blood viscosity and perfusion flow rate in cardiopulmonary bypass, and proposed a neural-networked model to estimate the number of microbubbles with the factors. Model parameters were determined in a machine-learning manner using experimental data with bovine blood as the perfusate. The estimation accuracy of the model, assessed by tenfold cross-validation, demonstrated that the number of MBs can be estimated with a determinant coefficient R2 = 0.9328 (p < 0.001). A significant increase in the residual error was found when each of four factors was excluded from the contributory variables. The study demonstrated the importance of four circulation factors in the prediction of the number of MBs and its capacity to eliminate potential postsurgical complication risks.

scholarly journals Progress in Drug Development–Pediatric Dose Selection: Workshop Summary

2021 ◽  
Vol 61 (S1) ◽  
Author(s):  
Jian Wang ◽  
John N. den Anker ◽  
Gilbert J. Burckart
Keyword(s):  
Drug Development ◽  
Dose Selection ◽  
Pediatric Dose ◽  
Workshop Summary

scholarly journals Influence of Selected Model Parameters on the Electromagnetic Levitation Melting Efficiency

2021 ◽  
Vol 11 (9) ◽  
pp. 3827
Author(s):  
Blazej Nycz ◽  
Lukasz Malinski ◽  
Roman Przylucki
Keyword(s):  
Electromagnetic Levitation ◽  
Optimization Methods ◽  
Calculation Model ◽  
Model Parameters ◽  
Starting Point ◽  
Low Efficiency ◽  
The Relationship ◽  
Reactive Metals ◽  
Electromagnetic Levitation Melting ◽  
Metal Melting

The article presents the results of multivariate calculations for the levitation metal melting system. The research had two main goals. The first goal of the multivariate calculations was to find the relationship between the basic electrical and geometric parameters of the selected calculation model and the maximum electromagnetic buoyancy force and the maximum power dissipated in the charge. The second goal was to find quasi-optimal conditions for levitation. The choice of the model with the highest melting efficiency is very important because electromagnetic levitation is essentially a low-efficiency process. Despite the low efficiency of this method, it is worth dealing with it because is one of the few methods that allow melting and obtaining alloys of refractory reactive metals. The research was limited to the analysis of the electromagnetic field modeled three-dimensionally. From among of 245 variants considered in the article, the most promising one was selected characterized by the highest efficiency. This variant will be a starting point for further work with the use of optimization methods.

scholarly journals The Transformative Potential of Ruins: A Tool for a Nonlinear Design Perspective in Adaptive Reuse

2021 ◽  
Vol 13 (10) ◽  
pp. 5660
Author(s):  
Elena Guidetti ◽  
Matteo Robiglio
Keyword(s):  
Adaptive Design ◽  
Future Research ◽  
Existing Buildings ◽  
Quantitative And Qualitative Research ◽  
Transformative Potential ◽  
Nonlinear Design ◽  
Mental Construct ◽  
Design Perspective ◽  
Novel Concept ◽  
The Relationship

In recent years, the heritage preservation debate has seen a growing interest in emerging theories in which the concept of potential plays an essential role. Starting from the assumption that memory is an evolving mental construct, the present paper introduces the concept of “transformative potential” in existing buildings. This novel concept regards the inevitability of loss and the self-destructive potential as part of the transformation of each building. The “transformative potential” is defined here as the relationship between spatial settings and material consistency. This research hypothesizes five “transformative potential” types by analyzing five best-practices adapted ruins in the last 15 years. The analysis integrates quantitative and qualitative research methods: morphological analysis (dimensional variations, critical redrawing, configuration patterns) and decay stages evaluation (shearing layers analysis, adaptation approaches). The goal is to test the “transformative potential” effectiveness in outlining patterns between specific stages of decay and adaptive design projects. Adaptation projects may actualize this potential in a specific time through incremental and decremental phases, outlining a nonlinear relationship between decay and memory. The study provides insights for future research on adapting existing buildings in a particular decay stage.

Use of ionic currents to identify and estimate parameters in models of channel blockade

1990 ◽  
Vol 259 (2) ◽  
pp. H626-H634
Author(s):  
C. F. Starmer ◽  
V. V. Nesterenko ◽  
F. R. Gilliam ◽  
A. O. Grant
Keyword(s):  
Time Course ◽  
Experimental Studies ◽  
Ionic Currents ◽  
Blocking Agent ◽  
Model Parameters ◽  
Protein Conformations ◽  
Channel Blockade ◽  
Channel Blocking ◽  
Individual Contributions ◽  
Modulated Receptor

Models of ion channel blockade are frequently validated with observations of ionic currents resulting from electrical or chemical stimulation. Model parameters for some models (modulated receptor hypothesis) cannot be uniquely determined from ionic currents. The time course of ionic currents reflects the activation (fraction of available channels that conduct in the presence of excitation) and availability of channels (the ability of the protein to make a transition to a conducting conformation and where this conformation is not complexed with a drug). In the presence of a channel blocking agent, the voltage dependence of availability appears modified and has been interpreted as evidence that drug-complexed channels exhibit modified transition rates between channel protein conformations. Because blockade and availability both modify ionic currents, their individual contributions to macroscopic conductance cannot be resolved from ionic currents except when constant affinity binding to a bindable site is assumed. Experimental studies of nimodipine block of calcium channels and lidocaine block of sodium channels illustrate these concepts.

Computer Simulation of the Responses of Human Motoneurons to Composite 1A EPSPS: Effects of Background Firing Rate

1997 ◽  
Vol 77 (1) ◽  
pp. 405-420 ◽  
Author(s):  
Kelvin E. Jones ◽  
Parveen Bawa
Keyword(s):  
Computer Simulation ◽  
Firing Rate ◽  
Time Course ◽  
Current Model ◽  
Response Probability ◽  
Muscle Spindles ◽  
Excitatory Postsynaptic Potential ◽  
Biophysical Properties ◽  
Rhythmic Firing ◽  
The Relationship

Jones, Kelvin E. and Parveen Bawa. Computer simulation of the responses of human motoneurons to composite 1A EPSPS: effects of background firing rate. J. Neurophysiol. 77: 405–420, 1997. Two compartmental models of spinal alpha motoneurons were constructed to explore the relationship between background firing rate and response to an excitatory input. The results of these simulations were compared with previous results obtained from human motoneurons and discussed in relation to the current model for repetitively firing human motoneurons. The morphologies and cable parameters of the models were based on two type-identified cat motoneurons previously reported in the literature. Each model included five voltage-dependent channels that were modeled using Hodgkin-Huxley formalism. These included fast Na+ and K+ channels in the initial segment and fast Na+ and K+ channels as well as a slow K+ channel in the soma compartment. The density and rate factors for the slow K+ channel were varied until the models could reproduce single spike AHP parameters for type-identified motoneurons in the cat. Excitatory synaptic conductances were distributed along the equivalent dendrites with the same density described for la synapses from muscle spindles to type-identified cat motoneurons. Simultaneous activation of all synapses on the dendrite resulted in a large compound excitatory postsynaptic potential (EPSP). Brief depolarizing pulses injected into a compartment of the equivalent dendrite resulted in pulse potentials (PPs), which resembled the compound EPSPs. The effects of compound EPSPs and PPs on firing probability of the two motoneuron models were examined during rhythmic firing. Peristimulus time histograms, constructed between the stimulus and the spikes of the model motoneuron, showed excitatory peaks whose integrated time course approximated the time course of the underlying EPSP or PP as has been shown in cat motoneurons. The excitatory peaks were quantified in terms of response probability, and the relationship between background firing rate and response probability was explored. As in real human motoneurons, the models exhibited an inverse relationship between response probability and background firing rate. The biophysical properties responsible for the relationship between response probability and firing rate included the shapes of the membrane voltage trajectories between spikes and nonlinear changes in PP amplitude during the interspike interval at different firing rates. The results from these simulations suggest that the relationship between response probability and background firing rate is an intrinsic feature of motoneurons. The similarity of the results from the models, which were based on the properties of cat motoneurons, and those from human motoneurons suggests that the biophysical properties governing rhythmic firing in human motoneurons are similar to those of the cat.

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