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By: Konstantine W. Skordos

Preclinical akon-skordos_photond early clinical development in oncology are among the most challenging of any therapy area. Once potential compounds demonstrate a measure of promise with in vitro and in vivo disease models, a race begins to deliver it to patients in desperate need of new therapies. Rarely are compound properties fully explored in early trials involving healthy volunteers, historically due to safety considerations for cytotoxic agents potentially active in malignant neoplastic disease. Even in the setting of favorable safety profiles for some molecularly targeted agents, it will rarely be ethical to delay entry into patients who may benefit from the potential medicine.

Additionally, patient selection may be informed by genetic screening for trials involving molecularly targeted agents. Because patients likely to respond can be identified with precision, the potential exists for very early evidence of target validation and clinical response. Therefore, trial complexity has increased dramatically with numerous endpoints including but not limited to safety, pharmacokinetics (PK), pharmacodynamics (PD), biomarkers, and of course efficacy. There are many serious challenges for preclinical and early clinical development of oncology therapies. For instance, oncology patients experience comorbidities, some of which will require management using prescription and nonprescription drugs. Therefore, drug interaction liabilities must be managed based exclusively on preclinical in vitro data and associated risk assessment. Orally administered drugs have the additional complexity of food interactions, which may alter PK. However, fasting requirements may affect drug tolerability, administration convenience, and ultimately compliance. Additional sources of PK variability must be minimized and controlled to reliably ascertain a PK/PD relationship

If clinical proof of concept is achieved, confirmatory trials to support registration of the new drug are started with urgency, and clinical pharmacology studies to support the eventual label must also be started with urgency.

Given both the pace and complexity of oncology discovery and development, the need for quantitative clinical pharmacology thinking and expertise have likely never been higher, especially with novel treatment modalities, including immunotherapies where classical approaches to dose and regimen may no longer be operative. This continuum of knowledge from clinical development to drug discovery is in constant demand, and as a translational discipline, clinical pharmacologists are uniquely positioned to contribute.

Learn more about these challenges in the December AAPS Newsmagazine cover story The Changing Role of the Clinical Pharmacologist in the Advancing Landscape of Cancer Therapy.

Konstantine W. Skordos is presently director, Clinical Pharmacology, Translational Clinical Oncology at Novartis, where he leads a group responsible for the clinical pharmacology aspects (PK, PK/PD, and DDI) for early clinical development assets in oncology. He maintains a strong focus on drug interaction prediction; particularly for complex drug interactions involving combination drug development.