Regulatory agencies such as the Food and Drug Administration (FDA), European Medicines Agency (EMA), Health Canada, and the Japanese Pharmaceutical and Medical Device Agency (PMDA) provide scientific and public health guidance with cardiac safety being paramount in drug development of new investigational products (IP). Cardiac safety is not a singular undertaking but rather encompasses many elements to be considered beyond measurement of the QT interval before a candidate drug receives regulatory approval. These safety assessments may include evaluation of additional targeted and non-targeted cardiovascular effects such as whether the IP mediates cardiac or pericardial inflammation or affects blood pressure, the coronary or systemic vasculature, heart valves, or cardiac muscle. Historically, the primary cardiac safety concern of regulators was the proarrhythmic risk of new chemical entities and has been centered on the QT interval as a marker of a drug's ability to delay ventricular repolarization and its potential to precipitate lethal ventricular rhythms. Beyond this biomarker, there has only been tangential focus on the PR and QRS intervals, conduction disturbances and supraventricular arrhythmias, and formal regulatory guidance pertaining to these findings has not been published. Hence, this review is designed to expand the myopic view of cardiac safety beyond the QT interval and highlight the importance of clinical nonlethal arrhythmias and conduction abnormalities involving novel non-antiarrhythmic small molecules for which more robust monitoring and surveillance should be contemplated.
ABSTRACT Early clinical development of anticancer drugs traditionally focused on exploring candidate treatments in patients. For instance, due to their cytotoxic action, administration of chemotherapies to healthy volunteers (HVs) for evaluation of their pharmacokinetic profiles was not considered feasible nor ethical from a safety and tolerability perspective. With the introduction of more targeted anticancer agents, such as the tyrosine kinase inhibitors (TKIs), enrolment of HVs in clinical pharmacology trials has become an advantageous alternative to early, non‐therapeutic testing in cancer patients. Futibatinib (Lytgobi) is a TKI acting upon the fibroblast growth factor receptor (FGFR) 1–4 and is approved for the treatment of patients with locally advanced or metastatic intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions or other rearrangement. During its clinical development, a series of studies were conducted enrolling HVs, for example, to evaluate pharmacokinetic properties (ADME), drug–drug interaction (DDI) potential and QT liability. In this review article, we will discuss when and why enrolment of HVs can be considered for small molecule anticancer drug trials and touch upon the risks and limitations as well as the advantages of administering this type of drugs to HVs. The case of futibatinib provides an illustrative example of the opportunities and challenges for exploring an anticancer small molecule in HVs.
Omaveloxolone is approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years. It is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro. Two drug-drug interaction studies (NCT04008186 and NCT05909644) were performed to evaluate (1) the effect of drug-metabolizing enzymes (DMEs) and drug transporter (DT) modulators on the pharmacokinetics of omaveloxolone and (2) the effect of omaveloxolone on the pharmacokinetics of DME and DT substrates. Additionally, the safety of coadministering these drugs with omaveloxolone was assessed. Coadministration of the strong CYP3A4 inhibitor itraconazole significantly increased omaveloxolone maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) by approximately 3- and 4-fold, respectively. Conversely, coadministration with the moderate CYP3A4 inducer efavirenz decreased Cmax and AUC0-∞ of omaveloxolone by 38.0% and 48.5%, respectively. Omaveloxolone exposure was also increased following coadministration with verapamil, a moderate CYP3A4 and P-glycoprotein (P-gp) inhibitor, but it was unaffected by the strong CYP2C8 inhibitor gemfibrozil. Coadministration of omaveloxolone reduced systemic exposure of the substrates of CYP3A4, CYP2C8, breast cancer resistance protein, and organic anion transporting polypeptide 1B1 but had no effect on those of P-gp and organic cation transporter 1. Omaveloxolone was well tolerated when administered alone and in combination with the DME and DT modulators or substrates. These findings support concomitant medication precautions and dosing recommendations for omaveloxolone when coadministered with a moderate or strong CYP3A4 inhibitor or inducer, as well as the substrates of certain CYP450 enzymes or transporters.
