Pharmacokinetics and Pharmacodynamics in Space

The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic regimens

Pharmacokinetic Analysis of Gd-DTPA Enhancement in dynamic three-dimensional MRI of breast lesions

The purpose of this study was to demonstrate that dynamic MRI covering both breasts can provide sensitivity for tumor detection as well as specificity and sensitivity for differentiation of tumor malignancy. Three-dimensional gradient echo scans were used covering both breasts. Before Gd-DTPA bolus injection, two scans were obtained with different flip angles, and after injection, a dynamic series followed. Thirty-two patients were scanned according to this protocol. From these scans, in addition to enhancement, the value of T1 before injection was obtained. This was used to estimate the concentration of Gd-DTPA as well as the pharmacokinetic parameters governing its time course. Signal enhancement in three-dimensional dynamic scanning was shown to be a sensitive basis for detection of tumors. In our series, all but two mam-mographically suspicious lesions did enhance, and in three cases, additional enhancing lesions were found, two of which were in the contralateral breast. The parameter most suited for classification of breast lesions into benign or malignant was shown to be the pharmacokinetically defined permeability k31, which, for that test, gave a sensitivity of 92% and a specificity of 70%. Our three-dimensional dynamic MRI data are sensitive for detection of mammographically occult breast tumors and specific for classification of these as benign or malignant

Methodological considerations in quantification of oncological FDG PET studies

Contains fulltext : 87741.pdf (publisher's version ) (Closed access) Contains fulltext : 87741-1.pdf (postprint version ) (Open Access)PURPOSE: This review aims to provide insight into the factors that influence quantification of glucose metabolism by FDG PET images in oncology as well as their influence on repeated measures studies (i.e. treatment response assessment), offering improved understanding both for clinical practice and research. METHODS: Structural PubMed searches have been performed for the many factors affecting quantification of glucose metabolism by FDG PET. Review articles and references lists have been used to supplement the search findings. RESULTS: Biological factors such as fasting blood glucose level, FDG uptake period, FDG distribution and clearance, patient motion (breathing) and patient discomfort (stress) all influence quantification. Acquisition parameters should be adjusted to maximize the signal to noise ratio without exposing the patient to a higher than strictly necessary radiation dose. This is especially challenging in pharmacokinetic analysis, where the temporal resolution is of significant importance. The literature is reviewed on the influence of attenuation correction on parameters for glucose metabolism, the effect of motion, metal artefacts and contrast agents on quantification of CT attenuation-corrected images. Reconstruction settings (analytical versus iterative reconstruction, post-reconstruction filtering and image matrix size) all potentially influence quantification due to artefacts, noise levels and lesion size dependency. Many region of interest definitions are available, but increased complexity does not necessarily result in improved performance. Different methods for the quantification of the tissue of interest can introduce systematic and random inaccuracy. CONCLUSIONS: This review provides an up-to-date overview of the many factors that influence quantification of glucose metabolism by FDG PET.01 juli 201

Impact of image-based motion correction on dopamine D3/D2 receptor occupancy-comparison of groupwise and frame-by-frame registration approaches

© 2015, Jiao et al.Background: Image registration algorithms are frequently used to align the reconstructed brain PET frames to remove subject head motion. However, in occupancy studies, this is a challenging task where competitive binding of a drug can further reduce the available signal for registration. The purpose of this study is to evaluate two kinds of algorithms—a conventional frame-by-frame (FBF) registration and a recently introduced groupwise image registration (GIR), for motion correction of a dopamine D3/D2 receptor occupancy study. Methods: The FBF method co-registers all the PET frames to a common reference based on normalised mutual information as the spatial similarity. The GIR method incorporates a pharmacokinetic model and conducts motion correction by maximising a likelihood function iteratively on tracer kinetics and subject motion. Data from eight healthy volunteers scanned with [11C]-(+)-PHNO pre- and post-administration of a range of doses of the D3 antagonist GSK618334 were used to compare the motion correction performance. Results: The groupwise registration achieved improved motion correction results, both by visual inspection of the dynamic PET data and by the reduction of the variability in the outcome measures, and required no additional steps to exclude unsuccessfully realigned PET data for occupancy modelling as compared to frame-by-frame registration. Furthermore, for the groupwise method, the resultant binding potential estimates had reduced variation and bias for individual scans and improved half maximal effective concentration (EC50) estimates were obtained for the study as a whole. Conclusions: These results indicate that the groupwise registration approach can provide improved motion correction of dynamic brain PET data as compared to frame-by-frame registration approaches for receptor occupancy studies

Respiratory motion correction in dynamic MRI using robust data decomposition registration - Application to DCE-MRI.

Motion correction in Dynamic Contrast Enhanced (DCE-) MRI is challenging because rapid intensity changes can compromise common (intensity based) registration algorithms. In this study we introduce a novel registration technique based on robust principal component analysis (RPCA) to decompose a given time-series into a low rank and a sparse component. This allows robust separation of motion components that can be registered, from intensity variations that are left unchanged. This Robust Data Decomposition Registration (RDDR) is demonstrated on both simulated and a wide range of clinical data. Robustness to different types of motion and breathing choices during acquisition is demonstrated for a variety of imaged organs including liver, small bowel and prostate. The analysis of clinically relevant regions of interest showed both a decrease of error (15-62% reduction following registration) in tissue time-intensity curves and improved areas under the curve (AUC60) at early enhancement

Improved hepatic arterial fraction estimation using cardiac output correction of arterial input functions for liver DCE MRI

Liver dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling could be useful in the assessment of diffuse liver disease and focal liver lesions, but is compromised by errors in arterial input function (AIF) sampling. In this study, we apply cardiac output correction to arterial input functions (AIFs) for liver dynamic contrast enhanced (DCE) MRI and investigate the effect on dual-input single compartment hepatic perfusion parameter estimation and reproducibility. Thirteen healthy volunteers (28.7±1.94 years, seven males) underwent liver DCE MRI and cardiac output measurement using aortic root phase contrast MRI (PCMRI), with reproducibility (n=9) measured at seven days. Cardiac output AIF correction was undertaken by constraining the first pass AIF enhancement curve using the indicator-dilution principle. Hepatic perfusion parameters with and without cardiac output AIF correction were compared and seven-day reproducibility assessed. Differences between cardiac output corrected and uncorrected liver DCE MRI portal venous (PV) perfusion (p=0.066), total liver blood flow (TLBF)(p=0.101), hepatic arterial (HA) fraction (p=0.895), mean transit time (MTT)(p=0.646), distribution volume (DV)(p=0.890) were not significantly different. Seven-day corrected HA fraction reproducibility was improved (mean difference 0.3%, Bland-Altman 95% Limits-of-Agreement (BA95%LoA) ±27.9%, Coefficient of Variation (CoV) 61.4% vs 9.3%, ±35.5%, 81.7% respectively without correction). Seven-day uncorrected PV perfusion was also improved (mean difference 9.3 ml/min/100g, BA95%LoA ±506.1 ml/min/100g, CoV 64.1% vs 0.9 ml/min/100g, ±562.8 ml/min/100g, 65.1% respectively with correction) as was uncorrected TLBF(mean difference 43.8 ml/min/100g, BA95%LoA ±586.7 ml/min/100g, CoV 58.3% vs 13.3 ml/min/100g, ±661.5 ml/min/100g, 60.9% respectively with correction). Reproducibility of uncorrected MTT was similar (uncorrected mean difference 2.4s, BA95%LoA ±26.7s, CoV 60.8% uncorrected vs 3.7s, ±27.8s, 62.0% respectively with correction), as was and DV (uncorrected mean difference 14.1%, BA95%LoA ±48.2%, CoV 24.7% vs 10.3%, ±46.0%, 23.9% respectively with correction). Cardiac output AIF correction does not significantly affect the estimation of hepatic perfusion parameters but demonstrates improvements in normal volunteer seven-day HA fraction reproducibility, but deterioration in PV perfusion and TLBF reproducibility. Improved HA fraction reproducibility maybe important as arterialisation of liver perfusion is increased in chronic liver disease and within malignant liver lesions

Estimation of contrast agent bolus arrival delays for improved reproducibility of liver DCE MRI

Delays between contrast agent (CA) arrival at the site of vascular input function (VIF) sampling and the tissue of interest affect dynamic contrast enhanced (DCE) MRI pharmacokinetic modelling. We investigate effects of altering VIF CA bolus arrival delays on liver DCE MRI perfusion parameters, propose an alternative approach to estimating delays and evaluate reproducibility. Thirteen healthy volunteers (28.7  ±  1.9 years, seven males) underwent liver DCE MRI using dual-input single compartment modelling, with reproducibility (n  =  9) measured at 7 days. Effects of VIF CA bolus arrival delays were assessed for arterial and portal venous input functions. Delays were pre-estimated using linear regression, with restricted free modelling around the pre-estimated delay. Perfusion parameters and 7 days reproducibility were compared using this method, freely modelled delays and no delays using one-way ANOVA. Reproducibility was assessed using Bland–Altman analysis of agreement. Maximum percent change relative to parameters obtained using zero delays, were  −31% for portal venous (PV) perfusion, +43% for total liver blood flow (TLBF), +3247% for hepatic arterial (HA) fraction, +150% for mean transit time and  −10% for distribution volume. Differences were demonstrated between the 3 methods for PV perfusion (p  =  0.0085) and HA fraction (p  <  0.0001), but not other parameters. Improved mean differences and Bland–Altman 95% Limits-of-Agreement for reproducibility of PV perfusion (9.3 ml/min/100 g, ±506.1 ml/min/100 g) and TLBF (43.8 ml/min/100 g, ±586.7 ml/min/100 g) were demonstrated using pre-estimated delays with constrained free modelling. CA bolus arrival delays cause profound differences in liver DCE MRI quantification. Pre-estimation of delays with constrained free modelling improved 7 days reproducibility of perfusion parameters in volunteers

Quantitative Magnetic Resonance Imaging of Tissue Microvasculature and Microstructure in Selected Clinical Applications

This thesis is based on four papers and aims to establish perfusion and diffusion measurements with magnetic resonance imaging (MRI) in selected clinical applications. While structural imaging provides invaluable geometric and anatomical information, new disease relevant information can be obtained from measures of physiological processes inferred from advanced modelling. This study is motivated by clinical questions pertaining to diagnosis and treatment effects in particular patient groups where inflammatory processes are involved in the disease. Paper 1 investigates acquisition parameters in dynamic contrast enhanced (DCE)-MRI of the temporomandibular joint (TMJ) with possible involvement of juvenile idiopathic arthritis. High level elastic motion correction should be applied to DCE data from the TMJ, and the DCE data should be acquired with a sample rate of at least 4 s. Paper 2 investigates choices of arterial input functions (AIFs) in dynamic susceptibility contrast (DSC)-MRI in brain metastases. AIF shapes differed across patients. Relative cerebral blood volume estimates differentiated better between perfusion in white matter and grey matter when scan-specific AIFs were used than when patient-specific AIFs and population-based AIFs were used. Paper 3 investigates DSC-MRI perfusion parameters in relation to outcome after stereotactic radiosurgery (SRS) in brain metastases. Low perfusion prior to SRS may be related to unfavourable outcome. Paper 4 applies free water (FW) corrected diffusion MRI to characterise glioma. Fractional anisotropy maps of the tumour region were significantly impacted by FW correction. The estimated FW maps may also contribute to a better description of the tumour. Although there are challenges related to post-processing of MRI data, it was shown that the advanced MRI methods applied can add to a more accurate description of the TMJ and of brain lesions.Doktorgradsavhandlin