Characterizing the Sources of Pharmacokinetic Variability for TAK-117 (Serabelisib), an Investigational Phosphoinositide 3-Kinase Alpha Inhibitor: A Clinical Biopharmaceutics Study to Inform Development Strategy.

TAK-117 (also known as MLN1117 or serabelisib) is an orally available inhibitor of phosphoinositide 3-kinase alpha being developed for treatment of solid tumors. This clinical study in healthy subjects assessed the relative bioavailability of a TAK-117 tablet compared with a capsule formulation (part 1) and the effect of food (part 2) and intragastric pH modulation (part 3) on TAK-117 pharmacokinetics. In part 1, subjects received single doses of 900 mg TAK-117 under fasting conditions as capsules and tablets on 2 different occasions in random order. In part 2, subjects received a single dose of 600 mg TAK-117 under fed (high-fat meal) or fasted conditions on 2 different occasions in random order. In part 3, subjects received a single dose of 900 mg TAK-117 alone and in combination with lansoprazole in a fixed sequence. Blood samples were collected up to 72 hours after each TAK-117 dose. The geometric mean ratios (90% confidence intervals) for the area under the TAK-117 plasma concentration-time curves were 1.53 (0.93-2.51) for tablets versus capsules, 1.50 (1.00-2.25) for fed versus fasted, and 0.02 (0.01-0.04) for TAK-117 plus lansoprazole compared with TAK-117 alone. The most common adverse event was nausea, the incidence of which was reduced when TAK-117 was administered with food despite the increased systemic exposure. The incidence of all adverse events was reduced when TAK-117 was administered with lansoprazole, which was consistent with the substantial reduction in bioavailability. Intersubject variability of TAK-117 was high. Careful management of intragastric pH-modulatory concomitant medications and food intake may be required.