Introduction
SOLID TUMORS, DNA DAMAGE, DRUG INTERACTION, ARREST
Cyclin-dependent kinase 1 (CDK1; also known as cell division cycle 2 protein [CDC2]) drives a cell from the G2 phase of the cell cycle into mitosis. In response to DNA damage, the nuclear tyrosine kinase Wee1 inhibits CDK1 to prevent the cell from dividing until the damaged DNA is repaired (G2 checkpoint arrest) [Fully functional CDK1- and CDK2-mediated checkpoints are necessary for the DNA damage response (DDR) to minimize replication stress for proliferating cells [Adavosertib has been evaluated as mono- and combination therapy with chemotherapy, olaparib, and durvalumab in numerous phase I and II studies in patients with a wide variety of solid tumors [The primary objective of this prospective, two-period, open-label, drug–drug interaction (DDI) study (NCT03333824) was to determine whether there was a clinically significant increase of exposure to substrates for CYP1A2 (caffeine), CYP2C19 (omeprazole), and CYP3A (midazolam) in the presence of adavosertib, and if co-administration of the probe CYP substrates had a clinically meaningful effect on adavosertib pharmacokinetics (PKs) [