Abstract
The last few years have witnessed enormous changes and upheavals in the pharmaceutical industry, with the buying of wholesalers and healthcare distribution networks, almagamations, takeovers, and the loss of tens of thousands of jobs on both sides of the Atlantic. The reason is that it is becoming increasingly difficult to find, develop, and launch new drugs. Once on the market the returns on this research investment are being eroded with a shorter usable patent life, increased government restrictions on prescribing, parallel importation and emphasis towards cheaper generics. There is now a growing gap between the amount spent in drug research and sales growth (Figure 1). Indeed, it has been estimated by Lehman Brothers of London that only 4% of all drugs that are now being developed will reach a break-even sales target of more than $175. Over the last 10 years when money was available there has been a large investment in research with the hope that this would produce more effective medications. Unfortunately it has not been the case, and although it is too early to provide reasons for this failure there is the suggestion that too much effort has been invested in the use of receptor screening and biotechnology without investigating the functional consequences of these interactions in validated animal models. There is therefore a great need to streamline the discovery process to get into man as quickly as possible and find methods that can allow us to extrapolate the findings from animal studies to clinical trials. This brief review describes this process of drug development and how PET may be used advantageously.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR., Mylecharane EJ, Saxene PR, Humphrey M. VII International union of pharmacological classification of receptors for 5-hydroxytryptamine (Serotonin). Pharm Rev 1994;46:157–203
Fowler CJ. Validity of human brain autopsy samples for characterising neurotransmitter function. TIPs 1988;9:232–234
Duncan GE, Little KY, Kirkman JA, Koplas RS, Stump WE, Breese GR. Autoradiographic characterisation of [3H] imipramine and [3H] citalopram binding in rat and human brain: Species differences and relationships to serotonin innervation patterns. Brain Res 1992;591:181–197
Duncan GE, Little KY, Koplas RS, Kirkman JA, Breese GR, Stump WE. β-adrenergic receptor distribution in the human and rat hippocampal formation: marked species differences. Brain Res 1991;561:84–92
Kohler C, Chan-Palay V. Cholecystokinin-octapeptide (CCK-8) receptors in the hippocampal region: a comparative in vitro autoradiographic study in the rat, monkey and the post mortem brain. Neurosci Lett 1988;90:51–56
Palacios JM, Probst A, Cortes R. β-1-adrenoreceptors in the mammalian brain: similar pharmacology but different distribution in rodents and primates. Brain Res 1987;419:65–75
Porsolt RD. Animal model of depression. Biomedicine 1978;30:139–140
Edvinson L. Experimental headache models in animals and humans. TIPs 1995; 16: 5–9
Boxenbaum H. Interspecies scaling, allometry, physiological time, and the ground plan of pharmacokinetics. J Pharmacokinet 1982;10(2):201–227
Campbell DB. Can allometric interspecies scaling be used to predict human kinetics? Drug Inf J 1994;28:235–245
Doudet DJ, Miyake H, Finn RT, McLellan CA, Aigner TG, Wan RQ, Adams HR, Cohen RM. 6-18F-L-dopa imaging of the dopamine neostriatal system in normal and clinically normal MPTP treated rhesus monkeys. Exp Brain Res 1989;78:69–80
Kuhar MJ, Unnerstall JR, De souza EB. Receptor mapping in neuropharmacology by autoradiography: Some technical problems. NIDA Res Monogr 1985;62:1–12
Morrison DF, Bungay PM, Hsiao JK, Mefford IN, Dykstra KH, Dedrick RL. Quantitative microdialysis. In: Microdialysis in the Neurosciences. Editors Robinson TE, Justice JB, Elsevier 1991:47–80
Turjanski N, Bum DJ, Lammertsma AA, Dolan R, Harding AE, Quinn N, Kennard C, Brooks DJ. PET studies on D1 and D2 receptor status in chorea. NEURA 1993;43:1563–1568
Bench CJ, Lammertsma AA, Dolan RJ, Grasby PM, Warrington SJ, Gunn K, Cuddington D, Turton DJ, Osman S, Fracjowiak RSJ. Dose dependent occupancy of central dopamine D2 receptors by the novel neuroleptic CP-88, 059-01: a study using positron emission tomography and 11-C raclopride PSYCHO 1993;112: 308–314
Miyaoka RS, Lewellen TK, Bice AN. Dynamic high resolution imaging of rats: design considerations IEEE. Trans Nucl Sci 1991;38:670–677
Cutler PD, Cherry SR, Hoffman EJ, et al. Design features and performance of a PET system for animal research. J Nucl Med 1993;33:595–604
Marriott CJ, Cadorette JE, Lecompte R, Scasnar V, Rousseau J, van Lier JE. High Resolution PET imaging and quantitation of pharmaceutical biodistribution in a small animal using avalanche photodiode detectors. J Nucl Med 1994;35:1390–1396
Rogers WL, Slosar J, Hua L, Chiao P, Zhang Y, Clinthorne NH. A high resolution slit aperture for imaging small animal with SPECT. J Nucl Med 1993;34: 9P
Weber DA, Ivanovic M, Franceschi D, Strand S-E, Erlandsson K, Franceschi M, Atkins HL, Coderre JA, Susskind H, Button T, et al Pinhole SPECT: An approach to in vivo high resolution SPECT imaging in small laboratory animals. J. Nucl Med 1994;35:342–348
Palmer J and Wollmer P. Pinhole emission computed tomography method and experimental evaluation. Phys Med Biol 1990;35:339–350
Hichwa R .Are animal scanners really necessary for PET? J Nucl Med 1994;35:1396–1397
Lammertsma AA, Hume SP, Myer SR, Bloomfield PM, Rajeswaran S, Jones T. RAT-PET: a bridge between ex vivo animal and in vivo patient studies. In: Quantification of brain function, tracer kinetics and image analysis in brain PET Editor Uemura K. Amsterdam Elsevier Science Publications 1993: 321–326
Campbell DB. The use of kinetic-dynamic interactions in the evaluation of drugs Psychopharmacology 1990;100:430–450
Campbell DB and Jochemsen R. Animal Pharmacokinetics and Toxicokinetics. In: International Pharmaceutical Product Registration. Editors AC Cartwright and BR Matthews Ellis Horwood 1994:569–639
Campbell DB. Are we doing too many animal biodisposition investigations before Phase I studies in man? A re evaluation of the timing and extent of ADME studies. Euro J Drug Metab Pharmacokinet 1994;19(3):283–293
ICH Toxicokinetics: Guidance on the assessment of systemic exposure in toxicity studies step 5. 1994 ICH secretariat IFPMA 30 Rue de St Jean PO Box 9 1211 Geneva 18 Switzerland
FDA Guideline on the assessment of systematic exposure in toxicity studies; availability. Federal Register 60 040 60 FR 11264 March 1, 1995
Campbell DB. The use of toxicokinetics for the safety assessment of drugs acting in the brain. Molecular Neurobiology. In press 1995
ICH. Pharmacokinetics: Guidance for repeated Dose Tissue Distribution Studies Step 5. 1994. ICH secretariat IFPMA 30 Rue de St Jean PO Box 9 1211 Geneva 18 Switzerland
FDA Guideline on Repeated Dose Tissue Distribution Studies; Federal Register 60 040 60 FR 11274 March 1, 1995
Scheuer J. Animal preparations relevant for study with positron emission tomography or nuclear magnetic resonance. Circulation 1985;72:139–144
Elmaleh DR, Kizuka H, Hanson RN, Jones GS, Herman LW, Strauss HW. Structure- Localization Relationships of 11C-labeled Phentermine Derivatives: Effect of Aromatic Substitution. Appl Radiat Isot 1993;44:821–829
Livini E, Fischman AJ, Ray S, Elmaleh DR, Alpert NM, Weiss S, Correia JA Webb D, Dahl ER, Robeson W, Margouleff D, Liss R, Strauss HW, Rubin RH. Synthesis of 18F-labelled fluconazole and positron emission tomography studies in rabbits. Nucl Med Biol 1992;19:191–199
Livini E, Satterlee W, Robey RL, Alt CA, Van Meter EE, Babich JW, Wheeler WJ, O’Bannon DD, Thrall JH, Fischman AJ. Synthesis of [11C]dapoxetine.HCl, a serotonin re-uptake inhibitor: Biodisposition in rat and preliminary PET imaging in the monkey. Nucl Med Biol 1994;21:669–675
Algbirhio F, Pike VW, Waters SL, Makepease J, Tanner RJ. Efficient and selective labelling of the CFC alternative 1,1,1-2 tetrafluroethane with fluorine-18 in the 1 position. J Chem Soc Chem Commun 1993; 1064–1065
Pike V and Tanner RGM. Study of disposition of a novel drug propellant 1,1,1, tetrafluoroethane in humans by labelling with fluorine-18 and whole body counting. Kluwer Academic Publishers The Netherlands (this journal) 1995
CPMP. Recommendations for the development of Non Clinical Strategies Draft 7 1990
Scales MDC and Mahoney K. Animal toxicological studies on new medicines and their relationship to clinical exposure: a review of international recommendations. Adverse Drug React Toxicol Rev 1991;10:155–168
MHW. General Guidelines for the Clinical evaluation of new pharmaceuticals. 1988. Pharmaceutical Affairs Bureau of the Ministry of Health and Welfare Tokyo 39.
ICH3 (1993) Guidelines on Detection of Toxicity to Reproduction for Medicinal Products, Step 5 ICH secretariat IFPMA 30 Rue de St Jean PO Box 9 1211 Geneva 18 Switzerland
Gatehouse DG. Mutagenicity in International Pharmaceutical Product Registration Editors AC Cartwright and BR Matthews Ellis Horwood 1994:474–553
CPMP. Notes for Guidance on radiopharmaceuticals Pharmacol and Toxicol 1991;68:288–232
Matthews BR. Radiopharmaceutical: International Pharmaceutical Product Registration Editors AC Cartwright and BR Matthews. Ellis Horwood 1994:364–411
FDA. Guidelines for the clinical evaluation of radiopharmaceutical drugs, United States Department of Health and Human Services Public Health Service Food and Drug Administration October 1981
FDA. Draft guideline for submitting supporting chemistry documentation in radiopharmaceutical drug applications, Department of Health and Human Services, Public Health 1991
Myers R. Mitochondrial benzodiazepine receptor ligands as indicators of damage in the CNS: their application in positron emission tomography in Glesen-Crouse E Editor: Peripheral benzodiazepine receptors London: Academic Press 1993:235–273
Suehiro M Scheffel U, Dannals RF, Ricaurte GA, Ravert HT, Wagner HN. A PET radiotracer for studying serotonin uptake sites [11-C]McN-5652-Z. J Nucl Med 1993;34:120–127
Jain RK. Physiological resistance to the treatment of solid tumors in drug resistance in oncology. Editor Teicher BA, Marcel Dekker 1993
Tilsley DWO, Harse RSA, Jones T, Avady F, Luthra SK, Brown G, Price P. New techniques in the pharmacokinetics analysis of cancer drugs in Positron Emission Tomography in pharmacokinetics and cancer chemotherapy. Editors Workman P, Graham MA. Cold Spring Harbor Laboratory Press 1993:425–442
DiChiro G, DeLaPaz RL, Brooks RA, et al. Glucose utilisation of cerebral gliomas measured by 18-F-2-deoxyglucose and PET. Neurobiology 1982;32:1323–1329
Patronas NJ, DiChiro G, Kufta C, et al. Prediction of survival time in glioma patients by means of PET. J. Neurosurg 1985;62:816–882
Price P. The use of labelled drugs at the stage of Phase I/II clinical trials and assessment of therapeutic efficacy of new agents using PET. Kluwer Academic Publishers (this journal) 1995
Peck CC, Barr WH, Benet LZ, Collins J, Desjardins RE, Furst DE, Harter JG, Levy G, Ludden T, et al. Opportunities for the integration of pharmacokinetics, pharmacodynamics and toxicokinetics in rational drug development. Pharm Res 1992;9:826–833
Ponto LB and Ponto JA. Uses and limitations of Positron Emission Tomography in clinical pharmacokinetics/dynamics (Part I). Clin Pharmacokinet. 1992;22:211–222
Ponto LB and Ponto JA. Uses and limitations of Positron Emission Tomography in clinical pharmacokinetics/dynamics (Part II). Clin Pharmacokinet. 1992;22:274–283
Sheiner LB and Benet LZ. Premarketing observational studies of population pharmacokinetics of new drugs. Clin Pharmacol Ther 1985;38:481–487
Harvey C, Lumley CE, Walker SR. A comparison of the review of a cohort of NCEs by four national regulation authorities. J. Pharmaceut Med. 1993;3:65–75
Wagner H. Disease as Dissonance. J Nucl Med 1994;35:13N-26N
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1995 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Campbell, B. (1995). Drug Development and Positron Emission Tomography. In: Comar, D. (eds) PET for Drug Development and Evaluation. Developments in Nuclear Medicine, vol 26. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-0429-6_1
Download citation
DOI: https://doi.org/10.1007/978-94-011-0429-6_1
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-010-4191-1
Online ISBN: 978-94-011-0429-6
eBook Packages: Springer Book Archive