59P - The influence of the ABCB1, ABCG2 and OATP1 transporters and the CYP3A enzyme on the bioavailability and tissue distribution of TPX-0131

Background

TPX-0131 is an ALK inhibitor developed for non-small lung cancer (NSCLC) patients that became resistant to first-line treatment. At the moment, pharmacokinetic data for TPX-0131 are still sparse. Therefore, we are interested to gain more insight into the pharmacokinetics of TPX-0131. Based on its structure and previously performed experiments with similar ALK inhibitors, TPX-0131 might be a substrate for the ABCB1, ABCG2, and OATP1 transporters and the CYP3A enzyme. Patients suffering from NSCLC often develop brain metastases. Therefore, the penetration of TPX-0131 into the brain is important to evaluate. Our main interest is therefore gaining more insight into the plasma pharmacokinetics (oral exposure) and the extent of brain penetration of TPX-0131.

Methods

An in vitro transwell experiment and in vivo experiments using genetically modified mouse models will be performed. With the use of a transmembrane in vitro transport assay, the potency of human ABCB1, human ABCG2 and murine Abcg2 to transport TPX-0131 will be evaluated. In vivo, the effect of ABCB1, ABCG2, OATP1 and CYP3A on the bioavailability and tissue distribution of TPX-0131 will be assessed. Different knockout and transgenic mouse models will be used for this purpose. The plasma concentration and tissue-to-plasma ratios of the genetically modified mouse models and wild-type mice will be compared after oral administration of 10 mg/kg TPX-0131.

Results

The in vivo data show that the brain concentration and brain-to-plasma ratio of TPX-0131 were significantly increased in the Abcb1a/b;Abcg2^-/-compared to the wild-type mice. The plasma levels did not show any significant differences between these strains. Secondly, no significant differences could be observed between the Oatp1a/b^-/- and wild-type mice. Furthermore, plasma levels appeared to be similar between Cyp3a^-/-, Cyp3AXAV (expressing transgenic human CYP3A4 in liver and intestine in Cyp3a^-/- background) and wild-type mice.

Conclusions

TPX-0131 might be a substrate for the ABCB1 and ABCG2 transporters. However, TPX-0131 is probably not a substrate for the OATP1 transporter(s) or the CYP3A enzyme.

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.