Search

Aims: This study evaluated drug–drug interactions between the CYP3A4 inhibitor carotegrast methyl and the other CYP3A4 substrates, midazolam, atorvastatin and prednisolone. Methods: A total of 88 healthy volunteers orally received carotegrast methyl 960 mg 3 times daily for 14 days. A single oral (5 mg) or intravenous (0.017 mg kg−1) midazolam, oral (5 mg) prednisolone or oral (10 mg) atorvastatin was administered before, with and after carotegrast methyl treatment. When the 90% confidence interval (CI) for the geometric mean ratios of the pharmacokinetic (PK) parameters with coadministration with carotegrast methyl (Day 14) to those before carotegrast methyl administration was between 0.80 and 1.25, no PK interaction were deemed. Results: The Cmax and AUC0‐t of oral midazolam before administration of carotegrast methyl were 30.9 ± 9.8 ng mL−1 and 74.5 ± 21.9 ng h mL−1, respectively. The geometric mean ratio of the Cmax and AUC0‐t of midazolam on Day 14 to those on Day −1 was 1.86 (90% CI, 1.64–2.11) and 3.07 (90% CI, 2.81–3.35), which did not fall within the range of 0.80–1.25, suggesting that carotegrast methyl had a PK interaction with midazolam. Similar PK interactions were found for intravenous midazolam and atorvastatin, but not for prednisolone. The inhibitory effect of carotegrast methyl on CYP3A4‐mediated metabolism of midazolam and atorvastatin had almost disappeared by 14 days after the end of administration. Conclusion: Carotegrast methyl was classified as a moderate CYP3A4 inhibitor in humans. Carotegrast methyl might enhance the action of drugs that are metabolized by CYP3A4. [ABSTRACT FROM AUTHOR]

Valemetostat is an oral, selective inhibitor of enhancer of zeste homolog‐2 (EZH2) and EZH1. In a first‐in‐human phase‐1 trial, valemetostat capsules were well tolerated and clinically active in patients with relapsed/refractory non‐Hodgkin lymphoma. Subsequently, a film‐coated tablet formulation was developed for future clinical trials and commercialization. We report outcomes from 2 phase 1 trials in healthy Japanese participants, assessing the safety, tolerability, and pharmacokinetics (PK) of valemetostat tablets at single ascending doses (50, 100, and 200‐mg), the relative bioavailability between capsules and tablets, and the effect of food (high‐fat or low‐fat meals) on the PK of valemetostat tablets. In the ascending‐dose study, valemetostat maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) increased dose‐proportionally. Valemetostat plasma PK parameters were similar between the capsule and tablet formulations following a single 200‐mg dose. Administration of valemetostat, 200 mg after a meal, was associated with 50%‐60% lower Cmax, 30%‐50% lower AUC, and a median Tmax delay of 2.5‐3 hours relative to fasted administration. Valemetostat was well tolerated in healthy subjects; treatment‐emergent adverse events were mild (grade 1) in severity. Based on these trials, the tablet formulation of valemetostat is suitable for use in subsequent clinical trials and should be administered under fasted conditions to avoid a negative food effect. [ABSTRACT FROM AUTHOR]