The Right Dose: From Phase I to Clinical Practice

Abstract

To realize the full potential of promising new anticancer drugs, it is of paramount importance to administer them at the right dose. The aim of this educational article is to provide several opportunities to optimize anticancer drug dosing, focusing on oral targeted therapies. First, therapeutic drug monitoring can optimize exposure in individual patients, if the optimal concentration is known. This approach is of particular interest in regard to oral kinase inhibitors with high interindividual pharmacokinetic variability. If exposure is related to response, then therapeutic drug monitoring is potentially feasible, although the clinical utility of this approach has not yet been established. Other approaches to reduce variability include administration of more frequent, smaller doses and administration under optimal prandial conditions. However, for many drugs, the labeled dose has not been demonstrated to be the optimal dose; for such agents, the vast majority of patients may be receiving excessive doses, which results in excessive toxicity. Furthermore, administration of lower off-label doses may reduce both medical and financial toxicity. These strategies should be applied from registration studies to clinical practice, with the goal of better optimizing anticancer treatment.

Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development

“…For example, small patient populations and high variability of diseases and patients in early clinical trials can lead to opportunities for adaptive trial designs, contextualization in reference to real‐world data, Bayesian approaches, patient stratification, and biomarker‐assisted trials 22–26 . Moreover, the evolving mindset of oncologists, which places greater emphasis on patient safety and the need for rigorous evaluation of drug benefit–risk profiles, highlights the importance of optimizing doses and treatment regimens to ensure the best possible outcomes for patients 27,28 . Poor dose optimization can lead to adverse consequences for patients, primarily due to toxicity, resulting in a reduced quality of life, frequent dose adjustments at the approved dose, diminished treatment efficacy due to patients' inability to continue therapy or receive subsequent treatment because of toxicities, and challenges in developing combination regimens.…”

Call to Action for Improving Oral Anticancer Agent Adherence

“…In addition, poor adherence in clinical trials may affect the body of knowledge supporting the benefit of investigational agents and lead to the abandonment of their development programs. 18,19 Improving Adherence This section presents an action plan to improve oral anticancer agent adherence. Although patients play a central role in working with their cancer care team to adhere to treatment, the burden of optimizing adherence lies with the stakeholders in the health care system.…”

“…In addition, poor adherence in clinical trials may affect the body of knowledge supporting the benefit of investigational agents and lead to the abandonment of their development programs. 18,19…”

“…Reliance on MTD contributes to labeled doses being unnecessarily high, leading to off-target toxicity, dosage reduction and discontinuation, and poor long-term tolerability. 18…”

“…Reliance on MTD contributes to labeled doses being unnecessarily high, leading to off-target toxicity, dosage reduction and discontinuation, and poor long-term tolerability. 18 To identify the optimal dose, pharmaceutical companies should expand investment in molecular biology and pharmacology to identify more selective and potent oral anticancer agents with reduced off-target effects and optimize dose throughout development. 24 Additional strategies to establish more complete premarket knowledge about optimal dose should include testing more than one dose in earlyphase studies, leveraging exposure-response relationships, and using pharmacokinetic and pharmacodynamic modeling and simulation, adaptive trial design, and drug interaction studies.…”