Study design considerations to assess the impact of potential drug–drug interactions in first‐in‐human studies in oncology drug development

First-in-human studies are limited to patients with serious diseases for which no curative therapies are available to ensure that the benefits outweigh the risks. First-in-human (FIH) studies in oncology are usually conducted in patients to provide early access to potentially effective drugs in the absence of available therapies and to identify the recommended dosages for the intended patient population. 10 This study was used as the basis for PBPK modeling and simulations to predict the effect of ivosidenib as a CYP3A inducer: multiple doses of ivosidenib could reduce the single-dose exposure of a CYP3A4 sensitive substrate, such as midazolam by 83%, and the steady-state exposure of itraconazole (also a CYP3A4 substrate) by 90%. 10 The PBPK modeling formed the basis for the ivosidenib labeling recommendations to healthcare providers to avoid co-administration of azole antifungals that are CYP3A4 substrates, including itraconazole and ketoconazole, as it may result in a loss of antifungal efficacy, and to reduce the dose of ivosidenib when co-administered with a strong CYP3A inhibitor as it may increase exposure of ivosidenib and potentially increasing the severity and incidence of adverse reactions, including QT interval prolongation. 10 CONCLUSION During drug development, it is critically important to identify the optimal doses of the new therapeutic for patients to assure safety and efficacy.