Pharmacokinetic interaction of entinostat and lapatinib following single and co-oral administration in rats

Abstract

1.?Entinostat, also known as SNDX-275 or MS-275, is a novel, potent, orally bioavailable, class I selective histone deacetylase inhibitor. Pre-clinical data has show that MS-275 can enhance the activity of lapatinib in HER²⁺ metastatic inflammatory and non-inflammatory breast cancer. This study examined whether oral administration of MS-275 to the rats with lapatinib led to any pharmacokinetic interactions.

2.?To evaluate pharmacokinetic interaction of MS-275 and lapatinib in rat, a sensitive and simple LC-MS method was developed to simultaneously determine MS-275 and lapatinib in rat plasma with carbamazepine as internal standard (IS). Eighteen rats were divided randomly into three groups, lapatinib group (lapatinib 15?mg/kg, n?=?8), MS-275 group (MS-275 15?mg/kg, n?=?8) and co-administration group (MS-275 15?mg/kg and lapatinib 15?mg/kg, n?=?8).

3.?There was no statistical pharmacokinetics difference for MS-275 in MS-275 group and co-administration group; the lapatinib could not influence the pharmacokinetic profile of MS-275 in rats. However, there is a statistical pharmacokinetics difference between lapatinib in the lapatinib group and co-administration group, when co-oral administration MS-275 with lapatinib, AUC increased from 2375.5 to 9900.3?ng/mL h (p?C_max increased from 538.0 to 2578.2?ng/mL (p?p?4.?These data indicate MS-275 could obviously influence the pharmacokinetic profile of lapatinib in rats, which might cause drug–drug interactions in humans when using lapatinib with MS-275. Further investigations should be carried out to elucidate the synergistic mechanisms between the two drugs.