Pilot Study with Technosphere/PTH(1 - 34) - A New Approach for Effective Pulmonary Delivery of Parathyroid Hormone (1 - 34)

Abstract

Sequential subcutaneous PTH injection therapy (repeated 14 days of PTH administration and a subsequent treatment pause for a few weeks) is known to increase bone mineral density in patients with osteopenic disorders. Alternative methods of drug delivery may be beneficial in increasing compliance. A pilot study was performed in 10 healthy volunteers (4 female/6-male, age: 25.6 ± 3.5 years, BMI: 22.3 ± 2.4 kg/m², mean ± SD) to assess the pharmacokinetic profiles of 1600 IU of PTH(1 - 34) using the pulmonary Technosphere^TM drug delivery system in comparison to a subcutaneous injection of 400 IU. The treatments were administered in the morning after an overnight fast and blood samples for measurement of PTH(1 - 34), PTH(1 - 84), and calcium and calcitonin were taken over a period of 6 hours. Both injection and pulmonary application of PTH(1 - 34) were well tolerated. After pulmonary administration of Technosphere/PTH(1 - 34), PTH(1 - 34) appeared in the serum with a faster concentration increase (T_max: pulmonary 10 ± 5 min vs. subcutaneous 28 ± 8 min, p < 0.001) and with higher maximal concentrations (C_max: pulmonary 309 ± 215 pmol/l vs. subcutaneous 102 ± 45 pmol/l, p < 0.05) as compared to the subcutaneous injection. The relative bioavailability of pulmonary Technosphere/PTH(1 - 34) was calculated to be 48 %. No differences were seen between pulmonary and subcutaneous application with regard to the PTH(1 - 84), calcitonin and calcium concentrations. In conclusion, pulmonary application of Technosphere^TM/PTH(1 - 34) appears to be an effective and thus attractive candidate for PTH substitution therapy in osteoporosis and other conditions leading to a decrease in bone mineral density.

Key words

Pulmonary Delivery - PTH(1 - 34) - Technosphere

References

• 1 Hodsman A B, Fraher L J, Watson P H. Parathyroid hormone: the clinical experiences and prospects. In: Whitfield JF, Morley P (eds) Anabolic treatments for osteoporosis. Boca Raton FL; CRC Press 1998: 83-108
• 2 Cosman F, Lindsay R. Is parathyroid hormone a therapeutic agent of osteoporosis? A review of the clinical experience.  Calcif Tissue Int. 1998;  62 475-480
• 3 Hodsman A B, Watson P H, Drost D. et al . Assessment of maintenance therapy with reduced doses of PTH(1 - 34) in combination with a raloxifene analogue (LY117018) following anabolic therapy in the ovariectomized rat.  Bone. 1999;  24 445-451
• 4 Lane N E, Sanchez S, Modin G W, Genant H K, Plerini E, Arnaud C D. Parathytroid hormone treatment can reverse corticosteroid-induced osteoporosis.  J Clin Invest. 1998;  102 1627-1633
• 5 Neer R M, Aranud C D, Zanchetta J R, Prince R, Gaich G A, Reginster J Y, Hodsman A B, Eriksen E F, Ish-Shalom S, Genant H K, Wang O, Mitlak B H. Effect of parathyroid hormone (1 - 34) on fractures and bone mineral density in postmenopausal women with osteoporosis.  N Engl J Med. 2001;  344 1434-1441
• 6 Patton J S. Pulmonary delivery of drugs for bone disorders.  Adv Drug Del Rev. 2000;  42 239-248
• 7 Lian H, Steiner S, Sofia R D, Woodhead J H, Wolf H H, White H S, Shen G S, Rhodes C A, McCabe R T. A self-complementary, self-assembling microsphere system: Application of intravenous delivery of the antiepileptic and neuroprotectant compound felbamate.  J Pharm Sci. 2000;  89 867-875
• 8 Mohnike K, Bretschneider D, Brunelle P, Nihoul-Fekete C, Flacke F, Günther G, Pfützner A, Saudubray J M, Steiner S. Continuous s. c. infusion with glucagon and intermittent s. c. treatment with octreotide in persistent hyperinsulinaemic hypoglycemia of infancy (PHHI).  Exp Clin Endocrinol Diabetes. 2000;  108 (Suppl. 1) S127
• 9 Pfützner A, Heise T, Steiner S, Heinemann L, Rave K. Inhaled Technosphere/Insulin shows a low variability in metabolic action in Type 2 diabetes.  Diabetes. 2000;  49 (Suppl. 1) A121
• 10 Pohl R, Muggenburg B A, Wilson B R, Woods R J, Burell B E, Steiner S S. A dog model as predictor of the temporal properties of pulmonary Technosphere/Insulin in humans.  Resp Drug Delivery. 2000;  VII 463-465
• 11 Rave K, Heise T, Pfutzner A, Steiner S, Heinemann L. Results of a dose-response study with a new pulmonary insulin formulation and inhaler.  Diabetes. 2000;  49 (Suppl. 1) A75
• 12 Steiner S, Pfützner A, Rave K, Heise T, Harzer O, Flacke F, Heinemann L. Bioavailability and pharmacokinetic properties of inhaled dry powder Technosphere/Insulin.  Exp Clin Endocrinol Diabetes. 2002;  110 17-21
• 13 Lindsay R, Nieves J, Hennerman E, Shen V, Cosman F. Subcutaneous administration of the amino-terminal fragment of human parathyroid hormone-(1 - 34): kinetics and biochemical responses in estrogenized osteoporotic patients.  J Clin Endocrinol Metab. 1993;  77 1535-1539
• 14 Rucinski B, Mann G N, Epstein S. A new rapid and reproducible homologous immunoradiometric assay for amino-terminal parathyroid hormone in the rat.  Calcif Tissue Int. 1995;  56 83-87
• 15 Patton J S. Breathing life into protein drugs.  Nat Biotech. 1998;  16 141-143
• 16 Patton J S, Platz R M. Pulmonary delivery of peptides and proteins for systemic action.  Adv Drug Deliv Rev. 1992;  8 179-196
• 17 Kohler D. Aerosolized insulin.  J Aerosol Med. 1994;  7 307-314
• 18 Fraher L J, Avram R, Watson P H, Hendy G N, Henderson J E, Chong K L, Goltzman D, Morley P, Willick G E, Whitfield J F, Hodsman A B. Comparison of the biochemical responses to human parathyroid hormone-(1 - 31)NH₂ and hPTH-(1 - 34) in healthy humans.  J Clin Endocrinol Metab. 1999;  84 2739-2743
• 19 Kanzawa M, Sugimoto T, Kobayashi A, Chiara K. Association between parathyroid hormone (PTH)/PTH-related peptide receptor gene polymorphism and the extend of bone mass reduction in primary hyperparathyroidism.  Horm Metab Res. 2000;  32 355-358
• 20 Hodsman A B, Steer B M, Fraher L J, Drost D J. An evaluation of several biochemical markers for bone formation and bone resorption in a protocol utilizing cyclical parathyroid hormone and calcitonin therapy for osteoporosis.  J Clin Invest. 1991;  91 1138-1148
• 21 Howie D C, Bowsher R R, Brunelle R L, Woodworth J R. [Lys(B28), Pro(B29)]-human insulin. A rapidly absorbed analogue of human insulin.  Diabetes. 1994;  43 396-402
• 22 Hodsman A B, Fraher L J, Watson P H, Ostbye T, Stitt L W, Adachi J D, Taves D H, Drost D. A randomized controlled clinical trial to compare the efficiency of cyclical parathyroid hormone versus cyclical parathyroid hormone and sequential calcitonin to improve bone mass in postmenopausal women with osteoporosis.  J Clin Enodcrinol Metab. 1997;  82 620-628