Pharmacokinetics variability: Why nanoparticles are not just magic-bullets in oncology.

Developing nanoparticles to improve the specificity of anticancer agents towards tumor tissue and to better control drug delivery is a rising strategy in oncology. An increasing number of forms (e.g., conjugated nanoparticles, liposomes, immunoliposomes…) are now available on the shelves and numerous other scaffolds (e.g., dendrimeres, nanospheres, squalenes …) are currently at various stages of development. However, as of today most nanoparticles made available remain lipidic carriers. Pharmacokinetic variability is a major, yet largely underestimated issue with liposomal nanoparticles. A wide variety of causes (e.g., tumor type and disease staging, comorbidities, patient's immune system) can explain this variability, which can in return negatively impact pharmacodynamic endpoints such as poor efficacy or severe toxicities. This review aims to cover the main causes for erratic pharmacokinetics observed with most nanoparticles, especially liposomes used in oncology. Should the main causes of such variability be identified, specific studies in non-clinical or clinical development stages could be undertaken using dedicated models (i.e., mechanistic or semi-mechanistic mathematical models such as PBPK approaches) to better describe nanoparticles pharmacokinetics and decipher PK/PD relationships. In addition, identifying relevant biomarkers or parameters likely to impact nanoparticles pharmacokinetics would allow for either the modification of their characteristics to reduce the influence of the expected variability during development phases or the development of biomarker-based adaptive dosing strategies to maintain an optimal efficacy/toxicity balance. Broadly, we call for the development of comprehensive distribution studies and state-of-the-art modeling support to better understand and anticipate nanoparticle pharmacokinetics in oncology.