Cardiovascular safety monitoring during oncology drug development and therapy.
Assessments of cardiac and cardiovascular toxicity are prominent components of drug safety endeavors during drug development and clinical practice. Oncologic drugs bring several challenges to both domains. First, during drug development, it is necessary to adapt the ICH E14 "Thorough QT/QTc Study" because the cytotoxic nature of many oncologics precludes their being administered to healthy individuals. Second, appropriate benefit-risk assessments must be made by regulators: given the benefit these drugs provide in life-threatening illnesses, a greater degree of risk may be acceptable when granting marketing authorization than for drugs for less severe indications. Third, considerable clinical consideration is needed for patients who are receiving and have finished receiving pharmacotherapy. Paradoxically, although such therapy has proved very successful in many cases, with disease states going into remission and patients living for many years after cessation of treatment, cardiotoxicities can manifest themselves relatively soon or up to a decade later. Oncologic drugs have been associated with various off-target cardiovascular responses, including cardiomyopathy leading to heart failure, cardiac dysrhythmias, thromboembolic events, and hypertension. Follow-up attention and care are, therefore, critical. This article reviews the process of benefit-risk estimation, provides an overview of nonclinical and preapproval clinical assessment of cardiovascular safety of oncology drugs, and discusses strategies for monitoring and management of patients receiving drugs with known cardiotoxicity risk. These measures include cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogs and cardioprotectants, and early detection of myocardial cell injury using biomarkers.
1Quintiles Cardiac Safety Center of Excellence, Durham, NC; 2Quintiles Cardiac Safety Services, Mumbai, India; 3Quintiles Therapeutic Delivery Unit, Durham, NC; and 4Quintiles Oncology Therapeutic Area, Rockville, MD.
J Rick
JR
Turner
Gopi Krishna
GK
Panicker
Dilip R
DR
Karnad
Christopher H
CH
Cabell
Ronald
R
Lieberman
Snehal
S
Kothari
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D066126:Cardiotoxicity / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D015195:Drug Design; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D018570:Risk Assessment / Q000379:methods; D013997:Time Factors
D000970:Antineoplastic Agents