Clinical Pharmacology Tools and Evaluations to Facilitate Comprehensive Dose Finding in Oncology: A Continuous Risk‐Benefit Approach

Abstract

Targeted therapies are now considered an integral component in the treatment armamentarium for many malignancies, and the approach to developing these drugs needs to be refined from the previous cytotoxic paradigm of toxicity-guided dose finding and identification of maximum tolerated dose to a paradigm driven by target activity. Moving away from the toxicity-driven dose finding and justification model requires an integrated approach in order to adequately characterize the risk-benefit of a drug. This approach starts with understanding the importance of collecting samples for pharmacokinetic and pharmacodynamic assessments in all phases of clinical development to fully characterize the pharmacokinetics and identify covariates and then correlating exposure to key markers of safety and efficacy in pharmacometric analyses to perform a robust risk-benefit assessment and establish the right dose. In addition, for oral agents, decisions on administering the drug with respect to food can impact dose among other clinical trial outcomes such as tolerability and patient compliance. Understanding the importance of model-based drug development as a decision-making tool to support drug development through incorporation of all relevant data allows for a robust risk-benefit assessment at key decision points. Utilization of clinical pharmacology tools and assessments throughout development will provide the key components of a successful oncology development program.

Phase I study assessing the mass balance, pharmacokinetics, and excretion of [14C]-pevonedistat, a NEDD8-activating enzyme inhibitor in patients with advanced solid tumors

“…Evaluation of the effects of intrinsic (e.g., functional capacity of eliminating organs) and extrinsic (e.g., drug-drug interactions) factors on PK is a crucial component of the clinical pharmacology characterization of anticancer agents to inform appropriate dosing and administration across patient populations and clinical contexts of use [18,19]. Radiolabeled mass balance studies play an important role in quantitatively defining routes of elimination and clearance mechanisms, thereby providing valuable inputs to inform a scientifically guided and rational approach to evaluating intrinsic/extrinsic factor effects on PK [20].This study evaluated the mass balance, PK, routes of elimination, and safety of the NAE inhibitor pevonedistat in 8 patients with advanced solid tumors.…”

Model‐Based Meta‐Analysis: Optimizing Research, Development, and Utilization of Therapeutics Using the Totality of Evidence

“…With the emergence of highly active and innovative therapies in areas of high unmet medical need, dose and regimen optimization may not be complete prior to initial approval, especially in the context of accelerated regulatory approvals and adaptive licensing pathways. For example, recent reviews have identified several examples of ongoing postmarketing optimization of the initial approved doses of anticancer drugs . In this context, exposure/dose‐response MBMA models can be valuable in identifying the determinants of therapeutic index of approved drugs (e.g., optimal dose/schedule, risk factors for adverse events of clinical importance).…”

“…For example, recent reviews have identified several examples of ongoing postmarketing optimization of the initial approved doses of anticancer drugs. [53][54][55] In this context, exposure/doseresponse MBMA models can be valuable in identifying the determinants of therapeutic index of approved drugs (e.g., optimal dose/ schedule, risk factors for adverse events of clinical importance). Such findings can result in hypotheses for enhancing postapproval dose optimization efforts and risk management guidance.…”

Toward Dynamic Prescribing Information: Codevelopment of Companion Model‐Informed Precision Dosing Tools in Drug Development

“…Either way, patient safety must be ensured without choking innovation. Finally, further clinical pharmacology expertise is required (1) in drug development to influence the major decision makers, and (2) in clinical practice to train clinicians about MIPD and to determine a framework of quality control at the point of care.…”