Characterizing Pharmacokinetic-Pharmacodynamic Relationships and Efficacy of PI3Kδ Inhibitors in Respiratory Models of TH2 and TH1 Inflammation.

Robbie L Mcleod,Hani Houshyar,Dapeng Chen,Stephen Alves,Hongshi Yu,Prasanthi Geda,Lauren Dorosh,Khamir Mehta,Michael Caniga,Alan Bass,Malgorzata A Gil,Sanjiv Shah,Jason Katz,Antonio Cabal,Francois Gervais,Gretchen A Baltus,Janice D Woodhouse,Joey Methot,Milenko Cicmil

doi:10.1124/jpet.118.252551

Robbie L Mcleod, Hani Houshyar + Show 17 more

Open Access

https://doi.org/10.1124/jpet.118.252551

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Abstract

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.

Highlights

The use of animal models in drug discovery has historically been integral to the development of novel therapies
We leveraged a clinical pharmacokinetic (PK)/pharmacodynamics (PD)/efficacy relationship established with an oral phosphatidylinositol 3-kinase (PI3K)d inhibitor (Idelalisib) in a nasal allergen challenge study to determine whether a comparable PK/PD/efficacy relationship with PI3Kd inhibitors was observed in preclinical respiratory models of type 2 T helper cell (TH2) and type 1 T helper cell (TH1) inflammation
Respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) continue to be associated with substantial morbidity and mortality with a significant portion of patients being poorly controlled by current standard of care (Grainge et al, 2016; Han et al, 2016; Powell, 2016)

Summary

Introduction

The use of animal models in drug discovery has historically been integral to the development of novel therapies. In many disease areas, the translatability of animal data into the clinical arena has been and continues to be challenging, with notable disconnects between the apparent effectiveness of various pharmacological agents across species, including humans (McGonigle and Ruggeri, 2014; de Caestecker et al, 2015; Gidyk et al, 2015; McNamee et al, 2015) This is true in heterogeneous inflammatory diseases with complex multifaceted pathophysiology such as severe asthma or chronic obstructive pulmonary disease (COPD) (Grainge et al, 2016; Han et al, 2016; Powell, 2016; Vanfleteren et al, 2016). NK1 antagonists with different pharmacokinetic (PK) properties such as Aprepitant (i.e., central nervous system–penetrating capabilities) have successfully entered the human clinical market for chemotherapy-mediated nausea and vomiting (Singh et al., ABBREVIATIONS: APC, allophycocyanin; AUC, area under the curve; BAL, bronchoalveolar lavage; BID, twice per day; Cmax, maximum (or peak) plasma concentration; COPD, chronic obstructive pulmonary disease; FACS, fluorescence-activated cell sorter; HTRF, homogeneous timeresolved fluorescence energy transfer; IL, interleukin; PD, pharmacodynamic; PI3K, phosphatidylinositol 3-kinase; PK, pharmacokinetic; QD, every day; RL, pulmonary resistance; TH1, type 1 T helper cell; TH2, type 2 T helper cell; TID, three times per day; ToT, time on target

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