Evaluation of delayed cardiac repolarization following administration of an investigational drug must be assessed during the course of a typical drug development program prior to marketing authorization. For most drugs, a standalone “thorough QT/QTc clinical study (TQT study)” is conducted to determine the drug’s effect on cardiac repolarization as assessed by QT/QTc prolongation. Pharmacologic prolongation of the QT/QTc interval can lead to significant and fatal heart arrhythmias.
Pharmacokinetics is an integral part of TQT clinical studies and the pharmacokinetic/pharmacodynamic concentration-response relationship (PK/PD) for QT/QTc prolongation must be characterized during these investigations.
For example, the timing around ECG acquisition should coincide with the expected or known pharmacokinetic behavior of investigational drugs and also an appropriate PK sampling schedule must be devised to adequately characterize the PK/PD concentration-response relationship. If the PK behavior of a drug is known but not well characterized then simulations could be employed pre-study to guide study design and collection of PK data at optimal timepoints.
Another benefit to conducting thorough QT/QTc trials is the ability to obtain a greater understanding of the pharmacokinetic behavior of investigational drugs. With large numbers of subjects typically needed for TQT trials, our consultants at Nuventra view TQT investigations as an opportunity to obtain robust PK data and build a larger portfolio of PK knowledge for a given investigational compound. For example, if a crossover thorough QT/QTc study design is used (see study design below) then intrinsic intra-subject PK variability can be well characterized and applied to future clinical pharmacology studies that require statistical power, such as formal bioequivalence studies needed for drug formulation changes.
Thorough QT/QTc (TQT) Study Design
Thorough QT/QTc investigations can be designed as a double-blind (except for the use of positive control such as moxifloxacin in most studies), randomized, single-site, crossover study in healthy male and female subjects. Parallel study designs for TQT investigations are also a consideration depending on the pharmacokinetics of the investigational drug. For crossover studies, subjects are randomized to 1 of 4 treatments sequences and receive each of the following treatments in random order, with appropriate washout determined by the drug’s pharmacokinetics:
- Treatment 1: Placebo
- Treatment 2: Positive Control (e.g., moxifloxacin 400 mg IV)
- Treatment 3: Therapeutic dose of investigational drug
- Treatment 4: Supratherapeutic dose of investigational drug
Additional methods for assessing cardiac QT/QTc prolongation and the corresponding PK/PD relationships can be employed within the context of other early phase healthy volunteer studies and/or late phase clinical trials, including the use of intensive ECG sampling and the use of pharmacokinetic sparse sampling of blood concentrations in a population PK approach.
If investigational drugs cannot be administered to healthy volunteers (for example oncology drugs are typically cytotoxic and are not administered to healthy volunteers) then other strategies can be employed to gain insight into the potential pharmacologic QT/QTc interval prolongation.
When to Execute Thorough QT (TQT) Studies in Development Programs
A thorough QT/QTc clinical study can be conducted at different stages of a drug development program depending on a variety of factors such as nonclinical data (e.g., hERG assay results) and therapeutic class considerations for potential induction of heart arrhythmias. TQT clinical studies can be conducted early in a development program (i.e., in Phase 1) to de-risk continued development of a compound or a TQT study can be conducted later in a development program if proof-of-concept efficacy data is needed to justify the expense of conducting a TQT study.
Read more in the FDA Guidance “E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.”