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Clinical Pharmacokinetics 41 Clin Pharmacokinet 2002; 41 (8): 581-602 CONCEPTS 0312-5963/02/0008-0581/$25.00/0 © Adis International Limited. All rights reserved. Pharmacokinetic Imaging A Noninvasive Method for Determining Drug Distribution and Action Alan J. Fischman,1,2 Nathaniel M. Alpert1 and Robert H. Rubin1,2 1 Division of Nuclear Medicine of the Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA 2 Division of Health Sciences and Technology, Center for Experimental Pharmacology and Therapeutics, Harvard-Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Contents Abstract . 581 1. Radionuclide Imaging Techniques . 583 1.1 Instrumentation . 583 1.2 Tracer Techniques . 584 1.3 Radiochemistry . 585 1.4 Advantages and Limitations of Positron Emission Tomography Measurements . 585 2. Types of Studies with Positron Emission Tomography . 586 2.1 Antimicrobial Agents . 587 2.1.1 Erythromycin . 588 2.1.2 Fluconazole . 588 2.1.3 Fluoroquinolones . 589 2.2 CNS Drugs . 590 3. Pharmacodynamics . 594 4. Magnetic Resonance Spectroscopy . 597 4.1 Antineoplastic Drugs . 597 4.2 Antimicrobial Agents . 598 4.3 CNS Drugs . 598 5. Conclusions . 599 Abstract Advances in positron emission tomography (PET), single photon emission computed tomography (SPECT) and magnetic resonance spectroscopy (MRS), and the ability to label a wide variety of compounds for in vivo use in humans, have created a new technology for making precise physiological and pharma- cological measurements. Due to the noninvasive nature of these approaches, re- petitive and/or continuous measurements have become possible. Thus far, these techniques have been primarily used for one-time assessments of individuals. However, experience suggests that a major use of this technology will be in the evaluation of new drug therapies. Already, these techniques have been used to measure precisely and noninvasively the pharmacokinetics of a variety of anti- microbial, antineoplastic and CNS agents. In the case of CNS drugs, imaging 582 Fischman et al. techniques (particularly PET) have been used to define the classes of neuro- receptors with which the drug interacts. The physiological, pharmacological and biochemical measurements that can be performed noninvasively using modern imaging techniques can greatly facilitate the evaluation of new therapies. These measurements are most likely to be useful during drug development in preclinical studies and in phase I/II human studies. Preclinically, new drugs can be precisely compared with standard therapies, or a series of analogues can be screened for further development on the basis of performance in animal models. In Phase I/II, imaging measurements can be combined with classical pharmacokinetic data to establish optimal administration schedules, evaluate the utility of interventions in specific clinical situations, and aid in the design of Phase III trials. In recent years, the techniques employed for rently performed with a much higher degree of so- drug discovery, design and evaluation have under- phistication. In contrast to the largely empirical gone many changes. Historically, the process of procedures of the past, modern drug development drug discovery involved screening of large num- is usually directed to specific molecular targets and bers of samples of natural products for biological is guided by principles of molecular structure and effects until a compound with the desired proper- dynamics, genomics and proteomics. Laborious ties was identified. After elucidation of the struc- one-by one synthesis and biological evaluation of ture of this potential drug, large numbers of ana- analogues has been supplemented by approaches logues were prepared by standard methods of based on combinatorial chemistry and high- organic chemistry and screened with in vitro and throughput screening methods. Applications of ge- in vivo assays until an agent or agents with optimal netic engineering to drug design (gene therapy) has pharmacology emerged. Lead compounds from fostered a transition from developing drugs for this discovery and design process were further treating symptoms to the design of agents that cor- evaluated to define their pharmacokinetic and rect or modulate pathophysiology of disease pro- pharmacodynamic profiles by studies of normal cesses. animals and animal models of the condition for Recent developments in techniques for non- which the drug was being developed. Tissue distri- invasive imaging of drug distribution and effect bution studies in large numbers of animals yielded have begun to have similar impact on drug evalu- precise pharmacokinetic data, and detailed physio- ation in humans. In numerous situations, imaging logical monitoring produced information about procedures such as positron emission tomography pharmacodynamics. Candidate drugs that contin- (PET), single photon emission computed tomogra- ued to show promise in the animal studies were phy (SPECT) and magnetic resonance spectros- further evaluated in Phase I to III studies in hu- copy (MRS) can provide tissue pharmacokinetic mans. Compared with the results of animal studies, information in humans that is comparable in detail data obtained from human clinical trials were less and quality to the results from invasive studies in extensive. In general, the quality of blood and animals. With PET, it has been possible to obtain plasma pharmacokinetic data obtained from hu- detailed quantitative information about drug phar- man subjects were comparable to those from ani- macokinetics and pharmacodynamics in a variety mal studies; however, information about tissue dis- of tissues, including the CNS. This review will tribution was considerably less precise and usually concentrate on recent applications of PET to phar- limited to body secretions and biopsy samples. macokinetic analysis. Although SPECT and MRS Similarly, pharmacodynamic evaluations were much are less generally applicable to pharmacokinetic less extensive. analysis, several important applications of these Drug discovery, design and evaluation are cur- approaches will also be discussed. Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (8) Pharmacokinetic Imaging 583 1. Radionuclide Imaging Techniques jections of the distribution of radioactivity in the object are obtained. By acquiring images in multi- 1.1 Instrumentation ple projections, three-dimensional distribution of radioactivity can be estimated. The instrumenta- Radionuclide imaging techniques have the goal tion for SPECT is similar to that used for planar of providing noninvasive measurements of the imaging; however, projections at all angles around three-dimensional distribution of radiolabelled an axis of the object are acquired. These data are [1] compounds in living organisms. In many as- then reconstructed using filtered back-projection pects, radionuclide imaging is similar to conven- or iterative algorithms (similar to x-ray computed tional serial section autoradiography. However, in- tomography) to produce transaxial, coronal and sa- stead of film, an array of scintillation detectors is gittal images of the distribution of radioactivity. used to record images. Imprecise quantification is the major disad- Three different procedures are currently used vantage of both planar and SPECT imaging. This for radionuclide imaging: planar imaging, SPECT and PET. The technical details of the three tech- deficiency is caused by loss of photons by tissue niques vary considerably, however, the general attenuation and by imprecise positioning of disin- principles are similar. tegrations due to scatter within the body. Further- γ With planar imaging, a large sodium iodide more, obtaining a - camera image requires absorp- scintillation detector optically coupled to an array tive collimation of photons emitted by the of photomultiplier tubes is placed close to the ob- radioactive object.[1] These collimators are made ject of interest and emitted photons are measured of lead and contain many parallel-aligned channels (figure 1).[1] By appropriate interconnections of that allow detection of only those photons that pass the photomultiplier tubes, two-dimensional pro- through the channels from the source to the crystal. Collimator Nal crystal X-position signal Y-position signal Computer PHA Position logic circuits Position Energy information Patient Image PM tubes Fig. 1. Basic components of a single photon imaging device (Anger camera) used for planar or single photon emission computed tomography (SPECT) imaging. PHA = pulse height analyser; PM = photomultiplier. Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (8) 584 Fischman et al. Photons that travel in other orientations are ab- process of annihilation, coincidence and detection sorbed by the collimator (figure 1) and do not con- defines a volume between the detectors from tribute to the image. This method of collimation which coincidence events originate (figure 2).[3] By imposes significant limits on both detection sensi- positioning rings of detectors around the object, tivity and image resolution. maps of the three-dimensional distribution of posi- The main problems inherent to single photon tron emitting isotope in an object can be recon- imaging are not important issues with PET. Many structed using filtered-back projection or iterative radionuclides with low atomic number and relative algorithms. The process of annihilation, coinci- proton excess decay by emission of positrons (posi- dence
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