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J Pharmacol Exp Ther. 2019 Mar 18. pii: jpet.118.255109. doi: 10.1124/jpet.118.255109. [Epub ahead of print]

Relationship between pharmacokinetics and pharmacodynamic responses in healthy smokers informs a once daily dosing regimen for nemiralisib.

Author information

1
GlaxoSmithKline.
2
Charles River.
3
Babraham Institute.
4
Hammersmith Medicines Research.
5
GlaxoSmithKline; edith.m.hessel@gsk.com.

Abstract

Nemiralisib (GSK2269557) is a potent inhaled inhibitor of phosphoinositide 3-kinase delta (PI3Kδ) which is being developed for the treatment of respiratory disorders including COPD (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 mg to 6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% CI 11-34%) and 36% (90% CI 11-64%) following single dose or 14 days of treatment with nemiralisib respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of ~3-4.5-fold (peak vs. trough) in plasma exposure following 14 days of nemiralisib treatment. BAL analysis at trough confirmed higher levels of drug in lung vs. plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). Comparison of drug levels in plasma and reductions in sputum PIP3 show a direct relationship between exposure and PIP3 reduction. In conclusion, these results demonstrate target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen.

KEYWORDS:

drug design; drug development; inhaled drugs; kinases; pharmacodynamics; pharmacokinetics; phosphatidylinositol-3,4,5-trisphosphate; phospholipids; respiratory pharmacology

PMID:
30886125
DOI:
10.1124/jpet.118.255109
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