Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure-Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

Clinical Pharmacology and Therapeutics

Volumn 104, Issue 6, 2018, Pages 1155-1164

  Palmér, Robert ^a   Mäenpää, Jukka ^a   Jauhiainen, Alexandra ^a   Larsson, Bengt ^a   Mo, John ^a   Russell, Muir ^b   Root, James ^a   Prothon, Susanne ^a   Chialda, Ligia ^c   Forte, Pablo ^c   Egelrud, Torbjörn ^d   Stenvall, Kristina ^a   Gardiner, Philip ^a  

^a ASTRAZENECA R AND D   (Sweden)

^b ASTRAZENECA   (United Kingdom)

^c PAREXEL INTERNATIONAL   (United States)

^d UMEÅ UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

AZD 7986; LEUKOCYTE ELASTASE; PEPTIDE HYDROLASE INHIBITOR; PLACEBO; UNCLASSIFIED DRUG; AZD7986; BENZOXAZOLE DERIVATIVE; CTSC PROTEIN, HUMAN; CYSTEINE PROTEINASE INHIBITOR; DIPEPTIDYL PEPTIDASE I; ELANE PROTEIN, HUMAN; OXAZEPINE DERIVATIVE; SERINE PROTEINASE INHIBITOR;

AREA UNDER THE CURVE; ARTICLE; BRONCHIECTASIS; CHRONIC OBSTRUCTIVE LUNG DISEASE; COHORT ANALYSIS; CONTROLLED STUDY; DESQUAMATION; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG ERUPTION; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; DRY SKIN; ENZYME ACTIVITY; FOLLOW UP; GINGIVA BLEEDING; HUMAN; HYPERKERATOSIS; LICHENOID; MAJOR CLINICAL STUDY; MALE; MAXIMUM CONCENTRATION; MEAN TRANSIT TIME; NEUTROPHIL; PERIPHERAL VOLUME OF DISTRIBUTION; PHARMACODYNAMICS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SINGLE DRUG DOSE; SKIN EXFOLIATION; SKIN HYPERTROPHY; XERODERMA; BIOLOGICAL MODEL; BLOOD; DOSE RESPONSE; DRUG ADMINISTRATION; DRUG EFFECT; ENZYMOLOGY; NONLINEAR SYSTEM; NORMAL HUMAN; ORAL DRUG ADMINISTRATION;

ADMINISTRATION, ORAL; BENZOXAZOLES; CATHEPSIN C; CYSTEINE PROTEINASE INHIBITORS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION SCHEDULE; HEALTHY VOLUNTEERS; HUMANS; LEUKOCYTE ELASTASE; MALE; MODELS, BIOLOGICAL; NEUTROPHILS; NONLINEAR DYNAMICS; OXAZEPINES; SERINE PROTEINASE INHIBITORS;

EID: 85045843887     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1002/cpt.1053     Document Type: Article

References (38)

1. Pham, C.T., Ivanovich, J.L., Raptis, S.Z., Zehnbauer, B. & Ley, T.J. Papillon-Lefevre syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans. J. Immunol. 173, 7277–7281 (2004).
2. Fouret, P., du Bois, R.M., Bernaudin, J.F., Takahashi, H., Ferrans, V.J. & Crystal, R.G. Expression of the neutrophil elastase gene during human bone marrow cell differentiation. J. Exp. Med. 169, 833–845 (1989).
3. Cowland, J.B. & Borregaard, N. Granulopoiesis and granules of human neutrophils. Immunol. Rev. 273, 11–28 (2016).
4. Korkmaz, B., Horwitz, M.S., Jenne, D.E. & Gauthier, F. Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases. Pharmacol. Rev. 62, 726–759 (2010).
5. Dalgic, B., Bukulmez, A. & Sari, S. Eponym: Papillon-Lefevre syndrome. Eur. J. Pediatr. 170, 689–691 (2011).
6. Sørensen, O.E. et al. Papillon-Lefevre syndrome patient reveals species-dependent requirements for neutrophil defenses. J. Clin. Invest. 124, 4539–4548 (2014).
7. Toomes, C. et al. Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat. Genet. 23, 421–424 (1999).
8. Haneke, E. The Papillon-Lefevre syndrome: Keratosis palmoplantaris with periodontopathy. Report of a case and review of the cases in the literature. Hum. Genet. 51, 1–35 (1979).
9. Moss, T.A., Spillane, A.P., Almquist, S.F., McCleskey, P.E. & Wisco, O.J. Palmoplantar keratoderma with progressive gingivitis and recurrent pyodermas. Cutis 93, 193–198 (2014).
10. Hiemstra, P.S., van Wetering, S. & Stolk, J. Neutrophil serine proteinases and defensins in chronic obstructive pulmonary disease: effects on pulmonary epithelium. Eur. Respir. J. 12, 1200–1208 (1998).
11. Park, J.A., He, F., Martin, L.D., Li, Y., Chorley, B.N. & Adler, K.B. Human neutrophil elastase induces hypersecretion of mucin from well-differentiated human bronchial epithelial cells in vitro via a protein kinase C{delta}-mediated mechanism. Am. J. Pathol. 167, 651–661 (2005).
12. Sandhaus, R.A. & Turino, G. Neutrophil elastase-mediated lung disease. COPD 10 Suppl 1, 60–63 (2013).
13. Chalmers, J.D. et al. Neutrophil elastase activity is associated with exacerbations and lung function decline in bronchiectasis. Am. J. Respir. Crit. Care Med. 195, 1384–1393 (2017).
14. Polverino, E., Rosales-Mayor, E., Dale, G.E., Dembowsky, K. & Torres, A. The role of neutrophil elastase inhibitors in lung diseases. Chest 152, 249–262 (2017).
15. Stockley, R.A. Alpha1-antitrypsin review. Clin. Chest Med. 35, 39–50 (2014).
16. Doyle, K. et al. Discovery of second generation reversible covalent DPP1 inhibitors leading to an oxazepane amidoacetonitrile based clinical candidate (AZD7986). J. Med. Chem. 59, 9457–9472 (2016).
17. Gardiner, P., Wikell, C., Clifton, S., Shearer, J., Benjamin, A. & Peters, S.A. Neutrophil maturation rate determines the effects of dipeptidyl peptidase 1 inhibition on neutrophil serine protease activity. Br. J. Pharmacol. 173, 2390–2401 (2016).
18. Guarino, C. et al. Prolonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases. Biochem. Pharmacol. 131, 52–67 (2017).
19. Miller, B.E. et al. Epithelial desquamation observed in a phase I study of an oral cathepsin C inhibitor (GSK2793660). Br. J. Clin. Pharmacol. 83, 2813–2820 (2017).
20. Bergstrand, M., Hooker, A.C., Wallin, J.E. & Karlsson, M.O. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 13, 143–151 (2011).
21. Krzyzanski, W. Interpretation of transit compartments pharmacodynamic models as lifespan based indirect response models. J. Pharmacokinet. Pharmacodyn. 38, 179–204 (2011).
22. Bekkering, S. & Torensma, R. Another look at the life of a neutrophil. World J. Hematol. 2, 44–58 (2013).
23. Summers, C., Rankin, S.M., Condliffe, A.M., Singh, N., Peters, A.M. & Chilvers, E.R. Neutrophil kinetics in health and disease. Trends Immunol. 31, 318–324 (2010).
24. Gunawardena, K.A., Gullstrand, H. & Perrett, J. Pharmacokinetics and safety of AZD9668, an oral neutrophil elastase inhibitor, in healthy volunteers and patients with COPD. Int. J. Clin. Pharmacol. Ther. 51, 288–304 (2013).
25. Vogelmeier, C., Aquino, T.O., O'Brien, C.D., Perrett, J. & Gunawardena, K.A. A randomised, placebo-controlled, dose-finding study of AZD9668, an oral inhibitor of neutrophil elastase, in patients with chronic obstructive pulmonary disease treated with tiotropium. COPD 9, 111–120 (2012).
26. Methot, N. et al. Inhibition of the activation of multiple serine proteases with a cathepsin C inhibitor requires sustained exposure to prevent pro-enzyme processing. J. Biol Chem. 282, 20836–20846 (2007).
27. Christopherson, R.I. & Duggleby, R.G. Metabolic resistance: The protection of enzymes against drugs which are tight-binding inhibitors by the accumulation of substrate. Eur. J. Biochem. 134, 331–335 (1983).
28. Westley, A.M. & Westley, J. Enzyme inhibition in open systems. Superiority of uncompetitive agents. J. Biol Chem. 271, 5347–5352 (1996).
29. Grover, A. & Benet, L.Z. Effects of drug transporters on volume of distribution. AAPS J. 11, 250–261 (2009).
30. Chan, L.M., Lowes, S. & Hirst, B.H. The ABCs of drug transport in intestine and liver: Efflux proteins limiting drug absorption and bioavailability. Eur. J. Pharm. Sci. 21, 25–51 (2004).
31. Lin, J.H. & Yamazaki, M. Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin. Pharmacokinet. 42, 59–98 (2003).
32. de Veer, S.J., Furio, L., Harris, J.M. & Hovnanian, A. Proteases and proteomics: cutting to the core of human skin pathologies. Proteomics Clin. Appl. 8, 389–402 (2014).
33. Nuckolls, G.H. & Slavkin, H.C. Paths of glorious proteases. Nat. Genet. 23, 378–380 (1999).
34. Methot, N. et al. In vivo inhibition of serine protease processing requires a high fractional inhibition of cathepsin C. Mol. Pharmacol. 73, 1857–1865 (2008).
35. Hamon, Y. et al. Neutrophilic cathepsin C is maturated by a multistep proteolytic process and secreted by activated cells during inflammatory lung diseases. J. Biol Chem. 291, 8486–8499 (2016).
36. Hewitt, C. et al. The role of cathepsin C in Papillon-Lefevre syndrome, prepubertal periodontitis, and aggressive periodontitis. Hum. Mutat. 23, 222–228 (2004).
37. Podolin, P.L.B. et al. Cathepsin C inhibition: a novel approach for the treatment of chronic respiratory diseases. In ATS Conference San Francisco (2016).
38. Milara, J., Juan, G., Peiro, T., Serrano, A. & Cortijo, J. Neutrophil activation in severe, early-onset COPD patients versus healthy non-smoker subjects in vitro: effects of antioxidant therapy. Respiration 83, 147–158 (2012).