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Inhalation of [¹²³I]₁-Protease Inhibitor: Toward a New Therapeutic Concept of ₁-Protease Inhibitor Deficiency?

Department of Nuclear Medicine, University Hospital of Technische Universität Dresden, Dresden; Department of Pneumology, University Hospital Essen, Ruhrlandklinik, Essen; Nuclear Medicine, Mainz-Kastel, Mainz; Bayer Vital, Leverkusen; Pharma Research Center, Bayer AG, Wuppertal; and Department of Nuclear Medicine, University Hospital of Bonn, Bonn, Germany

The ₁-protease inhibitor (₁-Pi) is separated from human serum and is therefore extremely expensive. Because only 2%–3% concentrates in the lung after intravenous administration, inhalational therapy for ₁-Pi deficiency would seem likely to be better. The aims of this study were therefore to determine the pattern of deposition of inhaled ₁-Pi labeled with ¹²³I and measure the amount deposited in the lungs. Methods: Eighteen patients with congenital severe ₁-Pi deficiency were enrolled in the study. The low-specific-activity ¹²³I-labeled ₁-Pi aerosol (median particle size ± SD, 3.9 ± 2.5 µm) was generated by an air pressure–driven nebulizer. The patients inhaled for an average of 23.6 ± 8.9 min. Static scintigrams in two projections were acquired immediately after (T₁) and 1 (T₂), 4 (T₃), and 24 h (T₄) after inhalation. The patients were divided into the following three groups according to their forced expiratory volume in 1 s (FEV₁): group I, 40% of predicted normal (n = 8); group II, 40% < FEV₁ 60% of predicted normal (n = 4); group III, >60% of predicted normal (n = 6). Results: The absolute percentage uptake values of ₁-Pi in group I were 12.4 for T₁, 7.3 for T₂, 4.6 for T₃, and 1.2 for T₄; in group II the values were 13.0, 9.6, 6.2, and 2.0, respectively; and in group III, 14.6, 11.4, 6.5, and 3.6, respectively. Differences between the groups were generally statistically significant. Between T₁ and T₂, the probability value was <0.05 for group I versus group II, <0.006 for group I versus group III, and <0.39 for group II versus group III. Between T₁ and T₃, the probability value was <0.29 for group I versus group II, <0.22 for group I versus group III, and <0.94 for group II versus group III. Retention (between T₁ and T₄) was also dependent on the grade of the disease: P < 0.2 for group I versus group II, P < 0.001 for group I versus group III, and P < 0.02 for group II versus group III. Grading of the uptake pattern by three independent experienced investigators (87% agreement) revealed a peripheral deposition that was group dependent. We found that greater peripheral deposition corresponded with lower lung functional impairment: P < 0.5 for group I versus group II, P < 0.01 for group I versus group III, and P < 0.08 for group II versus group III. Degradation also corresponded with functional impairment: P < 0.05 for group I versus group II, P < 0.006 for group I versus group III, and P < 0.3 for group II versus group III. Conclusion: The results of this study show that sufficient amounts of ₁-Pi can be deposited in the periphery of the lung by inhalation at least in patients with low-grade disease. Inhalation of ₁-Pi may thus represent a new and more convenient route of drug administration.

Key Words: ₁-protease inhibitor • antitrypsin • Prolastin • inhalation therapy • ¹²³I-₁-Pi

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