Characterizing Pharmacokinetic–Pharmacodynamic Relationships and Efficacy of PI3Kδ Inhibitors in Respiratory Models of TH2 and TH1 Inflammation
| Autor: | Jason D. Katz, François G. Gervais, Lauren Dorosh, Milenko Cicmil, Khamir Mehta, Joey L. Methot, Janice D Woodhouse, Hongshi Yu, Hani Houshyar, Prasanthi Geda, Gretchen A. Baltus, Malgorzata A Gil, Antonio Cabal, Sanjiv J. Shah, Robbie L. McLeod, Dapeng Chen, Alan S. Bass, Stephen E. Alves, Michael Caniga |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pharmacology biology Chemistry Area under the curve Cmax Basophil 03 medical and health sciences Cmin Ovalbumin 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Pharmacodynamics Blood plasma medicine biology.protein Molecular Medicine IC50 030217 neurology & neurosurgery |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 369:223-233 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship established with an oral phosphatidylinositol 3-kinase (PI3K)δ inhibitor (Idelalisib) in a nasal allergen challenge study to determine whether a comparable PK/PD/efficacy relationship with PI3Kδ inhibitors was observed in preclinical respiratory models of type 2 T helper cell (TH2) and type 1 T helper cell (TH1) inflammation. Results from an in vitro rat blood basophil (CD63) activation assay were used as a PD biomarker. IC50 values for PI3Kδ inhibitors, MSD-496486311, MSD-126796721, Idelalisib, and Duvelisib, were 1.2, 4.8, 0.8, and 0.5 μM. In the ovalbumin Brown Norway TH2 pulmonary inflammation model, all PI3Kδ inhibitors produced a dose-dependent inhibition of bronchoalveolar lavage eosinophils (maximum effect between 80% and 99%). In a follow-up experiment designed to investigate PK attributes [maximum (or peak) plasma concentration (Cmax), area under the curve (AUC), time on target (ToT)] that govern PI3Kδ efficacy, MSD-496486311 [3 mg/kg every day (QD) and 100 mg/kg QD] produced 16% and 93% inhibition of eosinophils, whereas doses (20 mg/kg QD, 10 mg/kg twice per day, and 3 mg/kg three times per day) produced 54% to 66% inhibition. Our profiling suggests that impact of PI3Kδ inhibitors on eosinophils is supported by a PK target with a ToT over the course of treatment close to the PD IC50 rather than strictly driven by AUC, Cmax, or Cmin (minimum blood plasma concentration) coverage. Additional studies in an Altenaria alternata rat model, a sheep Ascaris-sensitive sheep model, and a TH1-driven rat ozone exposure model did not challenge our hypothesis, suggesting that an IC50 level of TE (target engagement) sustained for 24 hours is required to produce efficacy in these traditional models. We conclude that the PK/PD observations in our animal models appear to align with clinical results associated with a TH2 airway disease. |
| Databáze: | OpenAIRE |
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