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

Abstract

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. Results from an in vitro rat blood basophil (CD63) activation assay were used as a PD biomarker. IC 50 values for PI3Kd inhibitors, MSD-496486311, MSD-126796721, Idelalisib, and Duvelisib, were 1.2, 4.8, 0.8, and 0.5 mM. In the ovalbumin Brown Norway TH2 pulmonary inflammation model, all PI3Kd 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 PI3Kd 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 PI3Kd inhibitors on eosinophils is supported by a PK target with a ToT over the course of treatment close to the PD IC 50 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 IC 50 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.

Projected Dose Optimization of Amino- and Hydroxypyrrolidine Purine PI3Kδ Immunomodulators

“…For compound 3c, the human whole blood CD63 inhibition potency was IC 50 = 50 nM (unbound uIC 50 = 36 nM), consistent with the inhibition of CD69 surface biomarker upregulation by anti-CD76b. We used the Brown Norway rat model for allergic rhinitis and asthma, and results with 3c was published in greater detail elsewhere 20 (where 3c was identified as MSD-496486311). Rats were presensitized for 14 days by daily treatment with ovalbumin (0.020 mg ip).…”

PI3Kδ Inhibition as a Potential Therapeutic Target in COVID-19

“…An ex vivo full-blood basophil (CD63) activation assay confirmed that PI3Kδ was engaged in their study performing observation/measurement periods. McLeod and collaborators identified the potency and selectivity of four in vitro enzyme and cellular assay inhibitors (MSD-496486311, MSD-126796721, Idelalisib, and Duvelisib) (67). Cytokine imbalance and cell migration to inflammatory tissues are features of the lung damage observed in severe COVID-19; the same condition is also evident in allergic diseases, where the activation of pro-inflammatory cells plays a key role in the inflammatory response.…”

“…For this reason, at this time, the ACE2 inhibitor approach does not appear to be the best therapy for COVID-19. Together with PI3Kδ inhibitor Idelalisib, Ebastine treatment in COVID-19 also appears to be an excellent inhibitory drug approach to T-cell pro-inflammatory cytokines IL-6 and TNF-α as demonstrated in allergic diseases (67,68). Ebastine may cause improvement in the patient's breathing with COVID-19 pulmonary symptoms.…”

Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review

“…Blockade of PI3 kinase also improved rodent models of arthritis, asthma, and systemic lupus erythematosus. Inhibition of PI3 decreased bronchoalveolar lavage eosinophils in a murine pulmonary inflammation model [117]. d.…”