PT  - JOURNAL ARTICLE
AU  - Robbie L McLeod
AU  - Malgorzata A Gil
AU  - Dapeng Chen
AU  - Antonio Cabal
AU  - Jason Katz
AU  - Joey Methot
AU  - Janice D Woodhouse
AU  - Lauren Dorosh
AU  - Prasanthi Geda
AU  - Khamir Mehta
AU  - Milenko Cicmil
AU  - Gretchen A Baltus
AU  - Alan Bass
AU  - Hani Houshyar
AU  - Michael Caniga
AU  - Hongshi Yu
AU  - Francois Gervais
AU  - Stephen Alves
AU  - Sanjiv Shah
TI  - Characterizing Pharmacokinetic-Pharmacodynamic Relationships and Efficacy of PI3Kδ-inhibitors in Respiratory Models of TH2 and TH1 Inflammation
AID  - 10.1124/jpet.118.252551
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.118.252551
4099  - http://jpet.aspetjournals.org/content/early/2019/02/25/jpet.118.252551.short
4100  - http://jpet.aspetjournals.org/content/early/2019/02/25/jpet.118.252551.full
AB  - We leveraged a clinical PK/PD/efficacy relationship established with an oral PI3Kδ inhibitor (Idelalisib) in a nasal allergen challenge study to determine if a comparable PK/PD/efficacy relationship with PI3Kδ inhibitors was observed in preclinical respiratory models of TH2 and 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 uM. In the Ovalbumin Brown Norway TH2 pulmonary inflammation model, all PI3Kδ inhibitors produced a dose dependent inhibition of BAL eosinophils (maximum effect between 80-99%). In a follow-up experiment designed to investigate PK attributes (Cmax, AUC, Time on target (ToT)) that govern PI3Kδ efficacy, MSD-496486311(3 mg/kg, QD and 100 mg/kg QD) produced 16% and 93% inhibition of eosinophils, while doses (20 QD-, 10 BID- and 3 TID -mg/kg) 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 coverage. Additional studies in an A. 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 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.