Found in Translation: Maximizing the Clinical Relevance of Nonclinical Oncology Studies

Abstract

The translation of nonclinical oncology studies is a subject of continuous debate. We propose that translational oncology studies need to optimize both pharmacokinetic (drug exposure) and pharmacodynamic (xenograft model) aspects. While improvements in pharmacodynamic translatability can be obtained by choosing cell lines or patient-derived xenograft models closer to the clinical indication, significant ambiguity and variability exists when optimizing the pharmacokinetic translation of small molecule and biotherapeutic agents. In this work, we propose a pharmacokinetic-based strategy to select nonclinical doses for approved drug molecules. We define a clinically relevant dose (CRD) as the dosing regimen in mice that most closely approximates the relevant pharmacokinetic metric in humans. Such metrics include area under the time-concentration curve and maximal or minimal concentrations within the dosing interval. The methodology is applied to six drugs, including targeted agents and chemotherapeutics, small and large molecules (erlotinib, dasatinib, vismodegib, trastuzumab, irinotecan, and capecitabine). The resulting efficacy response at the CRD is compared with clinical responses. We conclude that nonclinical studies designed with the appropriate CRDs of approved drug molecules will maximize the translatability of efficacy results, which is critical when testing approved and investigational agents in combination. .

How well are Phase 2 cancer trial publications supported by preclinical efficacy evidence?

“…Many human protection policies emphasize the importance of preceding human trials with promise of efficacy and safety in preclinical studies . Though animal models of cancer are widely recognized as imperfect, as suggested by recent reviews of various models, several studies suggest that preclinical efficacy studies, when designed and interpreted properly, are predictive of response in clinical trials . Preclinical efficacy evidence thus furnishes an ethical basis for exposing patients to unproven interventions.…”

Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies

“…However, direct comparison of plasma exposure associated with a measured clinical activity in humans (a clinical pharmacodynamic response) to an exposure observed in nonclinical models which used doses and routes of administration that differ from clinical use can assist the interpretation of pharmacodynamic results in the animal model. In this regard, Spilker et al (21) have recently proposed a rigorous strategy by which human PK parameters can be utilized in conjunction with mouse PK studies to determine the doses and routes of administration that can most closely mimic the clinically relevant exposures in the animal model.…”

“…While AUC can be useful to compare exposure following different routes of administration or formulations, it is particularly useful to translate the exposure achieved in humans to that seen in animal models. Modifying the dose or route in animals to mimic more closely the AUC observed in the clinic, using a protocol such as suggested by Spilker et al (21), may provide a more relevant drug exposure in the model and help to avoid high exposures which would not be tolerated in humans or that may lead to off-target activities of the drug.…”

“…The therapeutic effects of many of the agents are likely due to repeated administration of these doses using a variety of schedules which may lead to accumulation, so some agents may achieve higher exposures at steady-state. Consideration of these clinically achievable exposures in conjunction with animal studies to characterize the PK in the model species, such as described by Spilker et al (21) and including dose-response curves, will ultimately improve the translation of pharmacological activity in the model back to the clinic. We expect the greatest utility of this report will be a source from which an upper boundary on the clinically achievable plasma concentrations of anti-cancer agents can be readily applied to in vitro studies.…”

Clinical Pharmacology: a Discipline at the Nexus Between Translational Science and Precision Medicine: Commentary on “Enhancing Value of Clinical Pharmacodynamics in Oncology Drug Development: An Alliance Between Quantitative Pharmacology and Translational Science”

“…As we mentioned earlier, some of the challenges outlined by the authors amount to timely reminders: one of them is the free drug hypothesis, and the need to properly correct for interspecies differences during preclinical to clinical translation, which has been demonstrated for many oncology drugs. 7 An important, but addressable, challenge is to account for small molecule drug binding in tissue matrix, which is important for characterization of pharmacokinetic (PK)-PD, but seldom done. However, given the current limitations in translational oncology and in clinical trial design, some challenges will likely remain for the foreseeable future.…”