Regional Tissue Concentrations Research Articles

Predicting Regional Respiratory Tissue and Systemic Concentrations of Orally Inhaled Drugs through a Novel PBPK Model.

Oral inhalation (OI) of drugs is the route of choice to treat respiratory diseases or for recreational drug use (e.g., cannabis). After OI, the drug is deposited in and systemically absorbed from various regions of the respiratory tract. Measuring regional respiratory tissue drug concentrations at the site of action is important for evaluating the efficacy and safety of orally inhaled drugs (OIDs). Because such a measurement is routinely not possible in humans, the only alternative is to predict these concentrations, for example by physiologically based pharmacokinetic (PBPK) modeling. Therefore, we developed an OI-PBPK model to integrate the interplay between regional respiratory drug deposition and systemic absorption to predict regional respiratory tissue and systemic drug concentrations. We validated our OI-PBPK model by comparing the simulated and observed plasma concentration-time profiles of two OIDs, morphine and nicotine. Furthermore, we performed sensitivity analyses to quantitatively demonstrate the impact of key parameters on the extent and pattern of regional respiratory drug deposition, absorption, and the resulting regional respiratory tissue and systemic plasma concentrations. Our OI-PBPK model can be applied to predict regional respiratory tissue and systemic drug concentrations to optimize OID formulations, delivery systems, and dosing regimens. Furthermore, our model could be used to establish the bioequivalence of generic OIDs for which systemic plasma concentrations are not measurable or are not a good surrogate of the respiratory tissue drug concentrations. SIGNIFICANCE STATEMENT: Our OI-PBPK model is the first comprehensive model to predict regional respiratory deposition, as well as systemic and regional tissue concentrations of OIDs, especially at the drug's site of action, which is difficult to measure in humans. This model will help optimize OID formulations, delivery systems, dosing regimens, and bioequivalence assessment of generic OID. Furthermore, this model can be linked with organs-on-chips, pharmacodynamic and quantitative systems pharmacology models to predict and evaluate the safety and efficacy of OID.

Quantitative accuracy in total-body imaging using the uEXPLORER PET/CT scanner

Absolute quantification of regional tissue concentration of radioactivity in positron emission tomography (PET) is a critical parameter-of-interest across various clinical and research applications and is affected by a complex interplay of factors including scanner calibration, data corrections, and image reconstruction. The emergence of long axial field-of-view (FOV) PET systems widens the dynamic range accessible to PET and creates new opportunities in reducing scan time and radiation dose, delayed or low radioactivity imaging, as well as kinetic modeling of the entire human. However, these imaging regimes impose challenging conditions for accurate quantification due to constraints from image reconstruction, low count conditions, as well as large and rapidly changing radioactivity distribution across a large axial FOV. We comprehensively evaluated the quantitative accuracy of the uEXPLORER total-body scanner in conditions that encompass existing and potential imaging applications (such as dynamic imaging and ultralow-dose imaging) using a set of total-body specific phantom and human measurements. Through these evaluations we demonstrated a relative count rate accuracy of ±3%–4% using the NEMA NU 2-2018 protocol, an axial uniformity spread of ±3% across the central 90% axial FOV, and a 3% activity bias spread from 17 to 474 MBq 18F-FDG in a 210 cm long cylindrical phantom. Region-of-interest quantification spread of 1% was found by simultaneously scanning three NEMA NU 2 image quality phantoms, as well as relatively stable volume-of-interest quantification across 0.2%–100% of total counts through re-sampled datasets. In addition, an activity bias spread of −2% to +1% post-bolus injections in human subjects was found. Larger bias changes during the bolus injection phase in humans indicated the difficulty in providing accurate PET data corrections for complex activity distributions across a large dynamic range. Our results overall indicated that the quantitative performance achieved with the uEXPLORER scanner was uniform across the axial FOV and provided the accuracy necessary to support a wide range of imaging applications.

Linking left hemispheric tissue preservation to fMRI language task activation in chronic stroke patients

The preservation of near-typical function in distributed brain networks is associated with less severe deficits in chronic stroke patients. However, it remains unclear how task-evoked responses in networks that support complex cognitive functions such as semantic processing relate to the post-stroke brain anatomy. Here, we used recently developed methods for the analysis of multimodal MRI data to investigate the relationship between regional tissue concentration and functional MRI activation evoked during auditory semantic decisions in a sample of 43 chronic left hemispheric stroke patients and 43 age, handedness, and sex-matched controls. Our analyses revealed that closer-to-normal levels of tissue concentration in left temporo-parietal cortex and the underlying white matter correlated with the level of task-evoked activation in distributed regions associated with the semantic network. This association was not attributable to the effects of left hemispheric lesion or brain volumes, and similar results were obtained when using explicit lesion data. Left temporo-parietal tissue concentration and the associated task-evoked activations predicted patient performance on the in-scanner task, and also predicted patient performance on out-of-scanner naming and verbal fluency tasks. Exploratory analyses using the average HCP-842 tractography dataset revealed the presence of fronto-temporal, fronto-parietal, and temporo-parietal semantic network connections in the locations where tissue concentration was found to correlate with task-evoked activation in the semantic network. In summary, our results link the preservation of left posterior temporo-parietal structures with the preservation of task-evoked semantic network function in chronic left hemispheric stroke patients. Speculatively, this relationship may reflect the status of posterior temporo-parietal areas as cortical and white matter convergence zones that support coordinated processing in the distributed semantic network. Damage to these regions may contribute to atypical task-evoked responses during semantic processing in chronic stroke patients.

Intraarterial drug delivery for glioblastoma mutiforme: Will the phoenix rise again?

Intraarterial (IA) drug delivery is a physiologically appealing strategy as drugs are widely distributed throughout the tumor capillary network and high regional tissue concentrations can be achieved with low total doses. IA treatment of glioblastoma multiforme (GBM) has been attempted since the 1950s but success has been elusive. Although IA treatments have been embraced for the treatment of retinoblastoma and advanced liver cancers, this has not been the case for GBM. The development of IA drug delivery for the treatment of brain cancer over the last several decades reveals a number of critical oversights. For example, very few studies took into consideration the underlying hydrodynamic factors. Therapeutic failures were often blamed on an inability to penetrate the blood brain barrier or on the streaming of drugs. Similarly, there were few methods to investigate the ultra-fast pharmacokinetics of IA drugs. Despite past failures, clinical interest in IA drugs for the treatment of GBM persists. The advent of modern imaging methods along with a better understanding of hydrodynamics factors, better appreciation of the complex morphology of GBM, improved drug selection and formulations, and development of methods to minimize treatment-related neurological injury, promise to considerably advance the application of IA drugs for GBM treatment. There are several clinical trials with IA treatments in the National Trial Registry that are actively recruiting patients. This review of IA drug delivery for GBM treatment is therefore timely and is intended to assess how this method of drug delivery could be better applied to future treatments.

Radiolabelling and in vivo evaluation of [11C]GSK215083 as potential PET radioligand for the 5-HT6 receptor in the porcine brain

The 5-hydroxytryptamine-6 (5-HT6) receptor is one of 14 distinct mammalian 5-HT (serotonin) receptors expressed in the central nervous system through which 5-HT is involved in regulating a number of diverse biological processes 1. Binding studies with [125I]SB258585, have localised 5-HT6 receptors almost exclusively in the CNS 2. In these reports, SB258585 showed a high level of binding in rat, and pig striatal tissues and low in the cerebellum. In man SB258585 binding pattern is similar to rat and pig, being strongest in caudate, putamen, moderates in cerebral cortex and low in the cerebellum 3. Despite its good in vitro profile, the development of SB285585 as an in vivo imaging tool was hampered due to its poor brain penetration properties and to date no successful 5-HT6 ligand has been reported for use in PET. We present here the radiolabelling and preclinical evaluation of [11C]GSK215083 a novel tool to probe the 5-HT6 receptors in vivo. [11C]GSK215083,[11C-N-methyl]3-[(3-fluorophenyl)sulfonyl]-8-(4-methyl-1-piperazi nyl) quinoline, was prepared by N-methylation of the corresponding desmethyl precursor with [11C]MeOTf in methanol:acetonitrile in presence of 2,2,6,6-tetramethylpiperidine, followed by HPLC purification. In a pilot study [11C]GSK215083 was evaluated in anesthetized Yorlshire pigs (40 kg). [11C]GSK215083 readily enters the brain reaching peak regional tissue concentrations at approximately 20 min post injection followed by a slow washout from brain regions known to be rich in 5-HT6 receptors with highest uptake and retention observed in striatum. The observed rank order of regional brain concentrations was striatum>cortical regions>cerebellum, consistent with reported 5-HT6 receptor densities and localisation determined by tissue section autoradiograpgy in animals and man. Upon injection of [11C]GSK215083, striatum to cerebellum and cortex to cerebellum ratios of 2 to1 and 1.5 to 1, respectively were reached at 60 min post injection. Co-administration of [11C]GSK215083 with escalating dose of authentic GSK215083 (0.005, 0.05 and 0.5 mg/kg) have located a saturable and dose dependent signal in the striatum and cortical regions. Treatment of pigs with the 5-HT6 binding drug, clozapine (6.25 mg/kg), significantly reduced the specific binding in striatum as compared to cerebellum. No significant effect on [11C]GSK215083 signal in striatum was observed following treatment with ketanserine (0.3 mg/kg), a selective 5-HT2a receptor antagonist, in contrast the same treatment reduced >90% specific binding in frontal cortex. Radio-HPLC analysis revealed that [11C]GSK215083 is rapidly metabolised in arterial plasma, representing approximately 60% of the total radioactivity 30 min post injection. [11C]GSK215083 shows properties suitable for studies probing 5HT6 receptor in man with PET (See Figure 1).

Monitoring of cerebral perfusion pressure during intracranial hypertension: a sufficient parameter of adequate cerebral perfusion and oxygenation?

A cerebral perfusion pressure (CPP) oriented treatment is a widely accepted standard for patients with intracranial hypertension. In an animal model of controlled intracranial hypertension we investigated whether CPP is a reliable parameter of sufficient cerebral perfusion and oxygenation. Using near-infrared reflexion spectroscopy the effect of decreasing CPP due to increasing intracranial pressure (ICP) on cerebral tissue oxygenation was studied. Ten rabbits were subjected to artificially elevated ICP using the cisterna-magna infusion technique. Regional cerebral O(2) saturation of hemoglobin (tiSO(2)), regional tissue concentration of hemoglobin (tiHb), and CPP were recorded continuously. CPP was investigated with respect to tiSO(2). Electrocortical activity was simultaneously recorded by two-channel EEG to determine the onset of ischemia. Reduced CPP due to increased ICP led to a continuous decrease in tiSO(2.) There was progressive suppression of EEG frequency and amplitude with decreasing CPP in all animals. Onset of EEG-silence due to elevated ICP was observed in a wide range of CPP-values between 9 and 42 mmHg. At the same time tiSO(2) varied merely between 0 and 5%. Regarding the EEG effects due to increased ICP (EEG silence), CPP values showed a wide interindividual variability, in contrast to tiSO(2). In our animal model the sole calculation of CPP did not reflect adequate cerebral perfusion.

Cortical Activation in Profoundly Deaf Patients during Cochlear Implant Stimulation Demonstrated by H215O PET

Cochlear implants (CIs) are used to provide sensations of sound to profoundly deaf patients. The performance of the CI is assessed mainly by the subjective reports of patients. The aim of this study was to look for objective cortical responses to the stimulation of the CI. Two postlingually and two prelingually deaf patients were investigated by positron emission tomography (PET) using 15O-labeled water (H2(15)O) to determine the regional cerebral blood flow (rCBF). Instead of quantifying rCBF in absolute terms, it was estimated by referring the regional tissue concentration of H2(15)O to the mean whole brain concentration. CI stimulation encoded from white noise and sequential words led to an increased rCBF in the primary and secondary (Wernicke) auditory cortex. Relative elevations of up to 33% were observed bilaterally, although they were higher contralateral to the CI. These results were obtained not only in the postlingually deaf patients but also in two patients who had never been able to hear. Thus, it could be demonstrated that PET measurements of cerebral H2(15)O distribution yield objective responses of the central auditory system during electrical stimulation by CIs in profoundly deaf patients.

Where have we got to with neuroreceptor mapping of the human brain?

In the past two decades, tritiated radioligand receptor binding, a tool commonly used to investigate the site of action of drugs in laboratory animals, has provided a vast body of information on neuropharmacology and neurobiology. Several neurological and psychiatric diseases have been related to neurotransmitter and receptor disorders. In order to study ligand interactions with receptors in vivo in humans, new tracers capable of carrying a gamma-emitting radionuclide to the receptor have been designed. Emission computerized tomography (ECT) techniques such as positron (PET) or single photon emission tomography (SPET) allow monitoring of the time-course of regional tissue concentration of these radiolabelled ligands. PET and SPET each have their inherent advantages and drawbacks. The cyclotron-based technology of PET is a demanding and expensive technique that, to date, is still mainly reserved for research purposes. It is hoped that once the scientific basis of a physiopathological study is established using PET, diagnostic information might be provided by the more readily available SPET technology. The purpose of this article is to review the current state of receptor-binding gamma-emitting radioligands and to present the clinical potential of these new kinds of radiopharmaceuticals in clinical investigation.

Positron Emission Tomography in the Investigation of Central Nervous System Disorders

Positron emission tomography is a noninvasive tomographic technique for measuring regional tissue concentrations of labeled radionuclides in man. Detection of two photons emitted from the annihilation of a positron and an electron is used to reconstruct the distribution of a positron-emitting isotope within an organ. PET provides the capacity to measure quantitatively the local tissue distribution of a variety of radionuclides that are attached to compounds that distribute according to function. Commonly measured functions include local cerebral metabolism using 18F-fluorodeoxyglucose or 11C-deoxyglucose, cerebral blood flow, cerebral oxygen utilization, and cerebral blood volume. Clinical applications of PET are multiple, involving normal and disease states. By demonstrating the metabolic alterations, PET adds another dimension to our understanding of the brain, which up until recently has been based on the structural changes seen on CT and MRI.

Positron emission tomography in the study of human tumors

To increase our understanding of cancer and improve cancer treatment on a rational basis we need to identify both qualitative and quantitative differences between normal and neoplastic tissue. The multimodality approach to cancer treatment includes radiotherapy, chemotherapy, hyperthermia, and immunotherapy. Most of the data on which we base our therapeutic strategies have been derived from in vitro studies or animal tumor models. More information is required on the physiology of in vivo human tumors and their response to therapy. Positron emission tomography allows the regional tissue concentration of a positron emitting radionuclide to be measured in absolute units. If valid tracer models can be formulated that accurately describe the fate of an administered "biological" tracer then the physiological process under investigation can be measured quantitatively. The sequential inhalation of C15O2, 15O2, and 11CO allows regional tissue blood flow, oxygen utilization and blood volume to be measured in absolute units. Tissue perfusion, a measure of nutrient (eg, oxygen) supply, drug delivery, or a means of heat dissipation, is of immense importance to oncologists. The oxygen-15 technique has been used not only to study regional blood flow and oxygen utilization in both tumor and normal tissue but also their response to therapeutic intervention. In those studies were tracer models are thought to be less than complete (eg, due to insufficient biological data) then only a semiquantitative or qualitative assessment of the pathophysiological state may be possible. In this respect, tumor function has been characterized by the rate of uptake of 18F-2-deoxyglucose. This technique has provided a means of tumor grading and differentiating between radiation-induced tissue necrosis and tumor recurrence. Metabolic imaging with labeled amino acids appears particularly useful in the delineation of tumor extent. Blood brain barrier integrity and the pharmacokinetics of cytotoxic drugs have also been studied quantitatively. In the future, receptor studies are likely to play an increasing role. In this review dealing with the positron emission tomography oncologic work to date, emphasis has been placed on the physiological information obtainable and how it may further our understanding of cancer and its treatment.