A lesser known use of imaging studies in drug development is to determine the patterns of deposition, biodistribution, and regional kinetics of drugs in the body. This kind of study is of most interest when the drug is intended for local action following topical administration by inhalation. Imaging provides a convenient noninvasive method for observing initial deposition patterns and their variations caused by variables of the drug’s formulation and delivery method. Though planar gamma imaging is the method that has most often been used, recent years have seen promising demonstrations of SPECT and PET imaging to provide three-dimensional and quantitative measurements of drug deposition. When the goal of a drug is direct local treatment of diseased tissue, delivery of that drug is an important therapeutic variable. Imaging studies allow the drug delivery to be measured and optimized before a drug formulation is committed to clinical trials.
Rohatagi S, Rhodes GR, Chaikin P.Absolute oral versus inhaled bioavailability: significance for inhaled drugs with special reference to inhaled glucocorticoids. J Clin. Pharmacol. 1999; 39(7):661-663.
2.
Gonda I.The ascent of pulmonary drug delivery. J Pharm Sci. 2000; 89(7):940-945.
3.
Gonda I, Schuster JA, Rubsamen RM, et al. Inhalation delivery systems with compliance and disease management capabilities. J Controlled Release.1998; 53(1-3):269-274.
4.
Jendle J, Karlberg BE, Persliden J, et al. Delivery and retention of an insulin aerosol produced by a new jet nebulizer. J Aerosol Med. 1995; 8(3):243-254.
5.
Newman SP, Steed KP, Hardy JG, et al. The distribution of an intranasal insulin formulation in healthy volunteers: effect of different administration techniques. J Pharm Pharmacol. 1994; 46(8):657-660.
6.
Berridge MS, Lee Z, Heald DL. Regional distribution and kinetics of inhaled pharmaceuticals. Curr Pharm Des. 2000; 6(16):1631-1651.
7.
Newman SP, Wilding IR. Imaging techniques for assessing drug delivery in man. Pharm Sci Tech Today. 1999; 2(5):181-189.
8.
Davis SS, Hardy JG, Newman SP, et al. Gamma scintigraphy in the evaluation of pharmaceutical dosage forms. Eur J Nucl Med. 1992; 19(11):971-986.
9.
Newman SP, Pavia D.Aerosol deposition in man. In: Moren F, Newhouse MT, Dolovich M, eds. Aerosols in Medicine, Principles, Diagnosis and Therapy. New York, NY: Elsevier Science Publishers, 1985. pp. 193-215.
10.
Newman SP. Scintigraphic assessment of therapeutic aerosols. Crit Rev Ther Drug Carrier Syst. 1993; 10(1):65-109.
11.
Harris D, Fell JT, Sharma HL, et al. Assessment of gastric emptying using gamma scintigraphy. J Clin Pharm Ther. 1987; 12(5):343-346.
12.
Parr AF, Beihn RM, Franz RM, et al. Correlation of ibuprofen bioavailability with gastrointestinal transit by scintigraphic mnitoring of 171Er-labeled sustained-release tablets. Pharm Res. 1987; 4(6): 486-489.
13.
Ishibashi T, Pitcairn GR, Yoshino H, et al. Scintigraphic evaluation of a new capsule-type colon specific drug delivery system in healthy volunteers. J Pharm Sci. 1998; 87(5):531-535.
14.
Kenyon CJ, Brown F, McClelland GR, et al. The use of pharmacoscintigraphy to elucidate food effects observed with a novel protease inhibitor (saquinavir). Pharm Res. 1998; 15 (3):417-422.
15.
Adkin DA, Kenyon CJ, Lerner EI, et al. The use of scintigraphy to provide “proof of concept” for novel polysaccharide preparations designed for colonic drug delivery. Pharm Res.1997; 14 (1):103-107.
16.
Brown J, Hooper G, Kenyon CJ, et al. Spreading and retention of vaginal formulations in postmenopausal women as assessed by gamma scintigraphy. Pharm Res. 1997; 14(8):1073-1078.
17.
Williams CN, Haber G, Aquino JA. Double-blind, placebo-controlled evaluation of 5-ASA suppositories in active distal proctitis and measurement of ex-tent of spread using 99mTc-labeled 5-ASA suppositories. Dig Dis Sci. 1987; 32(12 Suppl):71S-75S.
18.
Ogoshi T, Usui N.Distribution of inhaled aerosol using nasal nebulizer. Nippon Jibiinkoka Gakkai Kaiho. 1991; 94(1):51-56.
19.
Berridge MS, Heald DL, Muswick GJet al. Biodistribution and kinetics of nasal [11C]-triamcinolone acetonide. J Nucl Med. 1998; 39(11):1972-1977.
20.
Berridge MS, Lee Z, Heald DL. Pulmonary distribution and kinetics of inhaled [11C]triamcinolone acetonide. J Nucl Med. 2000; 41(10):1603-1611.
21.
Pauwels R, Newman S, Borgstrom L.Airway deposition and airway effects of antiasthma drugs delivered from metered-dose inhalers. Eur Respir J.1997; 10(9):2127-2138.
22.
Lipworth BJ, Clark DJ. Early lung absorption profile of non-CFC salbutamol via small and large volume plastic spacer devices. Br J Clin Pharmacol. 1998; 46(1):45-48.
23.
Fiel SB, Fuchs HJ, Johnson C, et al. Comparison of three jet nebulizer aerosol delivery systems used to administer recombinant human DNase I to patients with cystic fibrosis. The Pulmozyme rhDNase Study Group. Chest. 1995; 108(1):153-156.
24.
Hardy JG, Harvey WJ, Sparrow RA, et al. Localization of drug release sites from an oral sustained-release formulation of 5-ASA (Pentasa) in the gastrointestinal tract using gamma scintigraphy. J Clin Pharmacol. 1993; 33(8):712-718.
25.
Atherton JC, Washington N, Bracewell MA, et al. Scintigraphic assessment of the intragastric distribution and gastric emptying of an encapsulated drug: the effect of feeding and of a proton pump inhibitor. Aliment Pharmacol Ther. 1994; 8(5):489-494.
26.
Sun JX, Walter B, Sandefer EP, et al. Explaining variable absorption of a hypolipidemic agent (CGP 43371) in healthy subjects by gamma scintigraphy and pharmacokinetics. J Clin Pharmacol. 1996; 36(3):230-237.
27.
Kenyon CJ, Nardi RV, Wong D, et al. Colonic delivery of dexamethasone: a pharmacoscintigraphic evaluation. Aliment Pharmacol Ther. 1997; 11(1): 205-213.
28.
Kosoglou T, Kazierad DJ, Schentag JJ, et al. Effect of food on the oral bioavailability of isosorbide-5-mononitrate administered as an extended-release tablet. J Clin Pharmacol. 1995; 35(2):151-158.
29.
Marathe PH, Sandefer EP, Kollia GE, et al. In vivoevaluation of the absorption and gastrointestinal transit of avitriptan in fed and fasted subjects using gamma scintigraphy. J Pharmacokinet Biopharm.1998; 26 (1):1-20.
30.
Newman SP. A comparison of lung deposition patterns between different asthma inhalers. J Aerosol Med. 1995;8(Suppl 3):S21-6; discussion S27: S21-6
31.
Borgstrom L, Bondesson E, Moren F, et al. Lung deposition of budesonide inhaled via Turbuhaler: a comparison with terbutaline sulphate in normal subjects. Eur Respir J. 1994; 7(1):69-73.
32.
Carter NJ, Page CJ, Eustance CN, et al. Evaluating the Swirler nebulizer: a user’s perspective. Nucl Med Commun. 1998; 19(6):599-604.
33.
Pitcairn GR, Lim J, Hollingworth A, et al. Scintigraphic assessment of drug delivery from the Ultrahaler dry powder inhaler. J Aerosol Med. 1997; 10(4):295-306.
34.
Cass LM, Brown J, Pickford M, et al. Pharmacoscintigraphic evaluation of lung deposition of inhaled zanamivir in healthy volunteers. Clin Pharmacokinet. 1999; 36(Suppl 1):21-31.
35.
Summers QA, Fleming JS, Dai Y, et al. The pulmonary deposition of two aerosol preparations of nedocromil sodium delivered by MDI assessed by single photon emission computed tomography. J Aerosol Med. 1996; 9(Suppl 1):S93-S109.
36.
Fok TF, al-Essa M, Kirpalani H, et al. Estimation of pulmonary deposition of aerosol using gamma scintigraphy. J Aerosol Med. 1999; 12(1):9-15.
37.
Foster WM, Stetkiewicz PT, Freed AN. Retention of soluble 99mTc-DTPA in the human lung: 24-h postdeposition. J Appl Physiol. 1997; 82(4):1378-1382.
38.
Pitcairn GR, Newman S.The F2 metric to validate radiolabelling methods used in lung deposition studies. [Abstract]J Aerosol Med. 1999; 12(2):134
39.
Durak H, Sayit E, Aktogu S, et al. Lung clearance of inhaled 99mTc-erythromycin lactobionate in nonsmokers and smokers. Nucl Med Commun. 1996; 17(10):895-901.
40.
Calmanovici GP, Boccio JR, Lysionek AE, et al. 99mTc-ENS: a new radiopharmaceutical for aerosol lung scintigraphy. Comparison between different freeze-dried formulations. J Nucl Med. 1999; 40(6):1080-1083.
41.
Calmanovici G, Zubillaga M, Lysionek A, et al. 99mTc-ENS, a new radiopharmaceutical for aerial lung scintigraphy: comparative studies in rats. Nucl Med Biol. 1998; 25(5):511-513.
42.
Virgolini I, Kurtaran A, Leimer M, et al. Inhalation scintigraphy with iodine-123-labeled interferon gamma-1b: pulmonary deposition and dose escalation study in healthy volunteers [see comments]. J Nucl Med. 1997; 38(9):1475-1481.
43.
Bennett WD, Scheuch G, Zeman KL, et al. Regional deposition and retention of particles in shallow, inhaled boluses: effect of lung volume. J Appl Physiol.1999; 86(1):168-173.
44.
Olseni L, Palmer J, Wollmer P.Quantitative evaluation of aerosol deposition pattern in the lung in patients with chronic bronchitis. Physiol Meas. 1994; 15(1):41-48.
45.
Saari SM, Vidgren MT, Koskinen MO, et al. Regional lung deposition and clearance of 99mTc-labeled beclomethasone-DLPC liposomes in mild and severe asthma. Chest. 1998; 113(6):1573-1579.
46.
Chan HK, Daviskas E, Eberl S, et al. Deposition of aqueous aerosol of technetium-99m diethylene triamine penta-acetic acid generated and delivered by a novel system (AERx) in healthy subjects. Eur J Nucl Med. 1999; 26(4):320-327.
47.
Lee Z, Berridge MS, Heald D.Corrections in gamma scintigraphy. [In Press] J Aerosol Med. 2001.
48.
Buvat I, De-Sousa MC, Di-Paola M, et al. Impact of scatter correction in planar scintimammography: a phantom study. J Nucl Med. 1998; 39(9):1590-1596.
49.
Miller C, Filipow L, Jackson S, et al. Planar imaging quantification using 3D attenuation correction data and Monte Carlo simulated buildup factors. Phys Med Biol. 1996; 41(8):1401-1423.
Buvat I, RodriguezVM, Todd PA, et al. Comparative assessment of nine scatter correction methods based on spectral analysis using Monte Carlo simulations. J Nucl Med. 1995; 36(8):1476-1488.
52.
el-Fakhri GN, Buvat I, Pelegrini M, et al. Respective roles of scatter, attenuation, depth-dependent collimator response and finite spatial resolution in cardiac single-photon emission tomography quantitation: a Monte Carlo study. Eur J Nucl Med.1999; 26(5):437-446.
53.
Perring S, Summers QA, Fleming JS, et al. A new method of quantification of the pulmonary regional distribution of aerosols using combined CT and SPECT and its application to nedocromil sodium administered by metered dose inhaler. [Abstract]Br J Radiol. 1994; 67:46-53.
54.
Chan HK, Eberl S, Daviskas E, et al. Dynamic SPECT of aerosol deposition and clearance in healthy subjects. [Abstract] J Aerosol Med. 1999; 12(2):135.
55.
Fleming JS, Halson P, Conway J, et al. Three-dimensional description of pulmonary deposition of inhaled aerosol using data from multimodality imaging. J Nucl Med. 1996; 37(5):873-877.
56.
Watanabe N, Inoue T, Tomioka S, et al. Discordant findings between krypton-81m gas and Tc-99m labeled ultrafine aerosol lung ventilation SPECTin two patients with idiopathic pulmonary fibrosis. Clin Nucl Med. 1995; 20(4):315-317.
57.
King MA, Tsui BM, Pan TS. Attenuation compensation for cardiac single-photon emission computed tomographic imaging: Part 1. Impact of attenuation and methods of estimating attenuation maps. J Nucl Cardiol. 1995; 2(6):513-524.
58.
King MA, Tsui BM, Pan TS, et al. Attenuation compensation for cardiac single-photon emission computed tomographic imaging: Part 2. Attenuation compensation algorithms. J Nucl Cardiol. 1996; 3(1):55-64.
59.
King GG, Eberl S, Salome CM, et al. Airway closure measured by a technegas bolus and SPECT. Am J Respir Crit Care Med. 1997; 155(2):682-688.
60.
Svartengren K, Philipson K, Svartengren M, et al. Clearance in smaller airways of inhaled 6-micron particles in subjects with immotile-cilia syndrome. Exp Lung Res. 1995; 21(5):667-682.
61.
Eberl S, Chan HK, Daviskas E, et al. Assessment of lung radioaerosol deposition and clearance with simultaneous emission-transmission dynamic SPECT. [Abstract] J Nucl Med. 1999; 40(5):95.
62.
Bergstrom M, Cass LM, Valind S, et al. Deposition and disposition of [11C]zanamivir following administration as an intranasal spray. Evaluation with positron emission tomography. Clin Pharmacokinet. 1999; 36(Suppl 1):33-39.
63.
Lee Z, Berridge MS, Heald DL. Evaluation of planar gamma scintigraphy vs. PET imaging used for pulmonary deposition of inhaled aerosols. Int J Nucl Med. http://63.96.40.23/2000; 1:25
64.
Farr SJ. The physicochemical basis of radiolabelling metered dose inhalers with 99mTc. J Aerosol Med. 1996; 9(Suppl 1):S27-S36
65.
Langenback EG, Davis JM, Robbins C, et al. Improved pulmonary distribution of recombinant human Cu/Zn superoxide dismutase, using a modified ultrasonic nebulizer. Pediatr Pulmonol. 1999; 27(2):124-129.
66.
Dolovich M, Inman M, Wahl L, et al. 3D Imaging of the lung: PET scanning and aerosols. [Abstract]Am J Respir Crit Care Med. 1998; 157:A78
67.
Dolovich M, Nahmias C, Thompson M, et al. Positron emission tomographic (PET) imaging of the lung in cystic fibrosis:3D assessment of the distribution of inhaled therapy. [Abstract]Am J Respir Crit Care Med. 1999; 159:A687
68.
Ojima F, Ido T, Hatazawa J, et al. Development of a new method for simultaneously evaluating mucociliary clearance and pulmonary epithelial permeability in rabbit experiments by means of 18FDG, three-dimensional positron emission tomography and rectilinear scan. Ann Nucl Med. 1998; 12(5):231-235.
69.
Berridge MS, Cassidy EH, Bordeaux KG. Preparation of [11C] triamcinolone acetonide. Appl Radiat Isot. 1994; 45:91-95.
70.
Pike VW, Aigbirhio FI, Freemantle CA, et al. Disposition of inhaled 1,1,1,2-tetrafluoroethane (HFA134A) in healthy subjects and in patients with chronic airflow limitation. Measurement by18F-labeling and whole-body gamma-counting. Drug Metab Dispos.1995; 23(8):832-839.
71.
Aigbirhio FI, Carr RM, Pike VW, et al. Automated radiosynthesis of no-carrier-added [S-fluoro-methyl-18F]fluticasone propionate as a radiotracer for lung deposition studies with PET. J Lab Comp Radiopharm. 1997; 39:567-584.
72.
Bergstrom M, Nordberg A, Lunell E, et al. Regional deposition of inhaled 11C-nicotine vapor in the human airway as visualized by positron emission tomography. Clin Pharmacol Ther. 1995; 57 (3):309-317.
