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Relationship between Pharmacokinetics and Pharmacodynamic Responses in Healthy Smokers Informs a Once-Daily Dosing Regimen for Nemiralisib.

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Affiliations

  • 1. Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage (M.Be., J.N.H., A.A., E.M.H.); GlaxoSmithKline, Stevenage (R.W., J.G., K.F., A.C.); GlaxoSmithKline, Stockley Park, Uxbridge (M.M., A.D., S.W., Y.C.); GlaxoSmithKline, Ware (G.D., S.A.); Babraham Institute, Babraham (A.K., J.C.); and Hammersmith Medicines Research, London (M.Bo.), United Kingdom.
      Authors
    • Begg M 1
    • Wilson R 1
    • Hamblin JN 1
    • Montembault M 1
    • Green J 1
    • Deans A 1
    • Amour A 1
    • Worsley S 1
    • Fantom K 1
    • Cui Y 1
    • Dear G 1
    • Ahmad S 1
    • Kielkowska A 1
    • Clark J 1
    • Boyce M 1
    • Cahn A 1
    (16 authors)
  • 2. Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage (M.Be., J.N.H., A.A., E.M.H.); GlaxoSmithKline, Stevenage (R.W., J.G., K.F., A.C.); GlaxoSmithKline, Stockley Park, Uxbridge (M.M., A.D., S.W., Y.C.); GlaxoSmithKline, Ware (G.D., S.A.); Babraham Institute, Babraham (A.K., J.C.); and Hammersmith Medicines Research, London (M.Bo.), United Kingdom
      Authors
    • Hessel EM 2
    (1 author)

ORCIDs linked to this article

The Journal of Pharmacology and Experimental Therapeutics, 18 Mar 2019, 369(3):337-344
https://doi.org/10.1124/jpet.118.255109 PMID: 30886125 

Abstract 

Nemiralisib (GSK2269557), a potent inhaled inhibitor of phosphoinositide 3-kinase δ (PI3Kδ), is being developed for the treatment of respiratory disorders including chronic obstructive pulmonary disease. Determining the pharmacokinetic (PK) and pharmacodynamic (PD) responses of inhaled drugs early during drug development is key to informing the appropriate dose and preferred dose regimen in patients. We set out to measure PD changes in induced sputum in combination with drug concentrations in plasma and bronchoalveolar lavage (BAL) taken from healthy smokers (n = 56) treated for up to 14 days with increasing doses of inhaled nemiralisib (0.1-6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-(4,5)-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% confidence interval [CI], 11%-34%) and 36% (90% CI, 11%-64%) after a single dose or after 14 days of treatment with nemiralisib, respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of ∼3- to 4.5-fold (peak vs. trough) in plasma exposure after 14 days of nemiralisib treatment. The BAL analysis at trough confirmed higher levels of the drug in the lungs versus plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). A comparison of the drug levels in plasma and the reductions in sputum PIP3 showed a direct relationship between exposure and PIP3 reduction. These results demonstrated target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen.

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