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.

A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials.

INTRODUCTION: Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4ß7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. OBJECTIVE: The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. METHODS: A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. RESULTS: Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. CONCLUSION: We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs.