65P - Influence of efflux and uptake transporters on the pharmacokinetics of the SYK inhibitors entospletinib and lanraplenib

Background

Spleen tyrosine kinase (SYK) is a cytoplasmic nonreceptor tyrosine kinase important for signaling through multiple immunoreceptors across different immune cell types, including B cell receptor (BCR). Inhibition of SYK significantly inhibits the functioning of immunity. The SYK inhibitors entospletinib (IC₅₀ = 7.6 nM) and lanraplenib (IC₅₀ = 120 nM) are highly selective and disrupt kinase activity. Entospletinib (800 mg twice daily) could be beneficial for the treatment of a variety of B cell malignancies, whereas lanraplenib (30 mg once daily) could be used for systemic lupus erythematosus (SLE) and lupus nephritis (LN). Pharmacokinetic data are still limited for entospletinib and lanraplenib. Therefore, we are interested to gain insights into the impact of the efflux transporters P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2) and influx transporters organic anion transporting polypeptides (OATP’s) on the pharmacokinetics of these SYK inhibitors.

Methods

We used wild-type, single and combined Abcb1a/1b and/or Abcg2, and Oatp1a/1b deficient mouse strains. Entospletinib (10 mg/kg) and lanraplenib (10 mg/kg) were administered simultaneously to the mice by oral gavage. At several time points, blood samples were collected via the tail vein and the experiment was terminated using cardiac puncture followed by cervical dislocation.

Results

A slight increase in plasma exposure of entospletinib was observed in Abcb1a/1b;Abcg2^-/- compared to wild-type, but not for lanraplenib. Brain exposure of both drugs was clearly restricted by ABC transporters, with a 3.6-fold increase in brain penetration for entospletinib and 12.1-fold for lanraplenib comparing the knockout strain with wild-type. We observed only a slight influence of OATP transporters on the tissue distribution of lanraplenib, but not of entospletinib.

Conclusions

ABC transporters play an important role in the brain disposition of entospletinib and lanraplenib, although they have only a slight impact on the plasma exposure of entospletinib. The role for the OATP uptake transporters seems to be less prominent for both drugs, but they might be involved in the tissue disposition of lanraplenib, but not of entospletinib.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Schinkel Group.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.