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. 2016 Aug;173(15):2390-401.
doi: 10.1111/bph.13515. Epub 2016 Jul 7.

Neutrophil Maturation Rate Determines the Effects of Dipeptidyl Peptidase 1 Inhibition on Neutrophil Serine Protease Activity

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Free PMC article

Neutrophil Maturation Rate Determines the Effects of Dipeptidyl Peptidase 1 Inhibition on Neutrophil Serine Protease Activity

P Gardiner et al. Br J Pharmacol. .
Free PMC article

Abstract

Background and purpose: Neutrophil serine proteases (NSPs) are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. The effects of neutrophil turnover rate on NSP activity following DPP1 inhibition was studied in a rat pharmacokinetic/pharmacodynamic model.

Experimental approach: Rats were treated with a DPP1 inhibitor twice daily for up to 14 days; NSP activity was measured in onset or recovery studies, and an indirect response model was fitted to the data to estimate the turnover rate of the response.

Key results: Maximum NSP inhibition was achieved after 8 days of treatment and a reduction of around 75% NSP activity was achieved at 75% in vitro DPP1 inhibition. Both the rate of inhibition and recovery of NSP activity were consistent with a neutrophil turnover rate of between 4-6 days. Using human neutrophil turnover rate, it is predicted that maximum NSP inhibition following DPP1 inhibition takes around 20 days in human.

Conclusions and implications: Following inhibition of DPP1 in the rat, the NSP activity was determined by the amount of DPP1 inhibition and the turnover of neutrophils and is thus supportive of the role of neutrophil maturation in the activation of NSPs. Clinical trials to monitor the effect of a DPP1 inhibitor on NSPs should take into account the delay in maximal response on the one hand as well as the potential delay in a return to baseline NSP levels following cessation of treatment.

Figures

Figure 1
Figure 1
Time course for onset of inhibition of NE and PR3 activities in blood and bone marrow after oral administration of the DPP1 inhibitor AZ1 to rats, (a–d) NE and PR3 activities in bone marrow and blood in onset 1, (e and f) NE and PR3 activities in blood in onset 2. The horizontal lines represent the median value in each group, the percent inhibition is the median value in the respective group compared with the median value in the vehicle‐treated group, the dotted line represents the buffer signal, V = vehicle and BM = bone marrow.
Figure 2
Figure 2
Time course for recovery of (a) NE, (b) PR3 and (c) CatG activities in bone marrow in AZ2‐treated and vehicle‐treated (control) rats. The DPP1 inhibitor AZ2 or vehicle control was administered orally twice daily for 8 days, the first dose in the morning and the second 8 h later. The rats were killed at 9 day intervals on day 0, 9 or 18 after the end of the treatment. The horizontal line represents the median value in each group, the percent inhibition is the median value in the respective group compared with the median value in the matched vehicle‐treated group, the dotted line represents the buffer signal, V = vehicle and BM = bone marrow.
Figure 3
Figure 3
(a) Simulated time course of concentration of AZ1 after an oral dose (3.6 mg·kg−1) in rat with markers showing dose‐adjusted observed pharmacokinetic data, 0–8 h. (b) Simulated time course of concentration of AZ1 and fraction of DPP1 inhibition after twice daily oral dose (3.6 mg·kg−1 and 10.7 mg·kg−1 after 8 h) in rat 0–8 days. (c) Best fit to the observed time course of NSP inhibition after oral administration of AZ1 in the onset study. Note: observed CatG inhibition data from the onset study were not included in the fitting.
Figure 4
Figure 4
(a) Simulated time course of concentration of AZ2 and fraction of DPP1 inhibition after twice daily oral administration (10 mg·kg−1) in rat. Markers show exposure data in rats in the recovery study. (b) Best fit to the observed time course of NSP inhibition after oral administration of AZ2 in the recovery study in rat.
Figure 5
Figure 5
(a) Left‐hand panel shows simulated time course of concentration of AZ2 and fraction of DPP1 inhibition following once daily oral administration in human at a dose that is predicted to give a steady state average concentration of 3 × IC50 and inhibits DPP1 by 75%. Right‐hand panel shows simulated time course of NSP inhibition in human after oral administration of AZ2. (b) Simulated effect of a missed dose on day 24 (typically after steady state is reached). (c) Simulated recovery of NSP activity following the discontinuation of treatment with AZ2.
Figure 6
Figure 6
Illustration of neutrophil maturation and when NSP processing is thought to occur (modified from Bekkering and Torensma, 2013).

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References

    1. Alexander SPH, Fabbro D, Kelly E, Marrion N, Peters JA, Benson HE et al. (2015). The concise guide to PHARMACOLOGY 2015/16: Enzymes. Br J Pharmacol 172: 6024–6109. - PMC - PubMed
    1. Bekkering S, Torensma R (2013). Another look at the life of a neutrophil. World J Hematol 2: 44–58.
    1. BoChiba M, Ishii Y, Sugiyama Y (2009). Prediction of hepatic clearance in human from in vitro data for successful drug development. AAPS J 11: 262–276. - PMC - PubMed
    1. Dancey JT, Deubelbeiss KA, Harker LA, Finch CA (1976). Neutrophil kinetics in man. J Clin Invest 58: 705–715. - PMC - PubMed
    1. Elborn JS, Perrett J, Forsman‐Semb K, Marks‐Konczalik J, Gunawardena K, Entwistle N (2012). Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis. Eur Respir J 40: 969–976. - PubMed
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