Thorough QT /QTc Study

The Importance of Pharmacokinetics in the evaluation of QT/QTc prolongation for investigational drugs (Thorough QT / TQT studies )

 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.

Nuventra takes the approach not only to look vertically at planning a single study (such as a TQT study) but to horizontally integrate clinical pharmacology investigations across a program, thereby evaluating the data as it relates to prior investigations and for informing future decisions within a drug development program.

All PK and PK/PD strategies associated with thorough QT/QTc studies can be reviewed by Nuventra’s experienced clinical pharmacology consultants and pharmacokinetic consultants so please contact us for more details. Click here for a Clinical Pharmacology Plan.

Nuventra Services Provided for Thorough QT / TQT Studies

  • Full clinical protocol development from clinical pharmacology experts
  • Clinical trial design
  • Power calculation for determination sample size
  • PK sampling schedule evaluation
    • Ensure the collection of blood and other samples occur at the right time to allow a good assessment of pharmacokinetics
  • Full PK analysis (PK parameters) conducted in WinNonlin
  • Complete Pharmacokinetic/pharmacodynamic concentration-response relationship (PK/PD) analysis for thorough QT studies.
  • Full or abbreviated PK/PD report to include presentation of ECG data
  • Clinical study reports (CSRs) – with integrated PK & PD data
  • Investigator Brochure (IB) updates to clinical pharmacology and PK data
  • FDA meetings or EMA meetings: Expert clinical pharmacology representation at regulatory meetings (including Briefing packet preparation)
  • Interpretation of PK data to enable next steps in the development program
    • Incorporation of data into model based drug development to allow for better decision making.
    • Impact of study results on other planned clinical studies

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.

For more information or assistance please Contact us or request a quote.

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.

Let Nuventra’s clinical pharmacology consultants, pharmacokineticists, and drug development experts help intelligently integrate this study into your overall development efforts. Click here for a Clinical Pharmacology Plan.

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Contact us or request a quote to help interpret the guidance to industry and with your drug development needs for this type of clinical pharmacology investigation.