The past, present, and future of chemotherapy with a focus on individualization of drug dosing.

While there have been rapid advances in developing new and more targeted drugs to treat cancer, much less progress has been made in individualizing dosing. Even though the introduction of immunotherapies such as CAR T-cells and checkpoint inhibitors, as well as personalized therapies that target specific mutations, have transformed clinical treatment of cancers, chemotherapy remains a mainstay in oncology. Chemotherapies are typically dosed on either a body surface area (BSA) or weight basis, which fails to account for pharmacokinetic differences between patients. Drug absorption, distribution, metabolism, and excretion rates can vary between patients, resulting in considerable differences in exposure to the active drugs. These differences result in suboptimal dosing, which can reduce efficacy and increase side-effects. Therapeutic drug monitoring (TDM), genotype guided dosing, and chronomodulation have been developed to address this challenge; however, despite improving clinical outcomes, they are rarely implemented in clinical practice for chemotherapies. Thus, there is a need to develop interventions that allow for individualized drug dosing of chemotherapies, which can help maximize the number of patients that reach the most efficacious level of drug in the blood while mitigating the risks of underdosing or overdosing. In this review, we discuss the history of the development of chemotherapies, their mechanisms of action and how they are dosed. We discuss substantial intraindividual and interindividual variability in chemotherapy pharmacokinetics. We then propose potential engineering solutions that could enable individualized dosing of chemotherapies, such as closed-loop drug delivery systems and bioresponsive biomaterials.