Concentration-QTc (C-QTc) modeling

While C-QTc modeling offers a streamlined path, it is rarely as straightforward as it appears. Have you accounted for the nuances of diurnal variation or the impact of food effects on your cardiac safety signals?

The potential of a drug to delay cardiac repolarization is conventionally evaluated in a resource-intensive TQT study. Such studies expose participants to a supratherapeutic dose of the investigational drug, as well as to a QT-prolonging drug which serves as a positive control. Following ICH E14 Q&A updates, C-QTc modeling of Phase I data can be submitted to the regulatory authorities, together with nonclinical data, to request a waiver for a dedicated TQT study.

At Pharmetheus, we manage these complexities to ensure your early clinical PK and QTc data provide a definitive alternative to a dedicated TQT study.

Why Pharmetheus is your partner of choice:

• Trusted scientific method: key contributor in the research and development of C-QTc modeling.
  
• Regulatory track record: extensive experience in delivering robust C-QTc analyses for complex client projects.

We offer extensive expertise in the design, analysis, and reporting of C-QTc modeling, having supported clients with successful FDA and other health authority submissions. Our experience has been shared through a tutorial in CPT:PSP ( developed in collaboration with our partners, exemplified across various therapeutic areas (ref 1, 2, 3, 4, 5, 6, 7, and 8) and more recently expanded upon in our Journal of Pharmacokinetics and Pharmacodynamics (JPKPD) research paper which highlights the risks of overlooking diurnal variation and food effects in Phase I-based C-QTc analyses.

In addition to expert knowledge and practical experience from numerous client projects, we have developed efficient internal workflows, including specialized scripts and templates. These tools ensure robust, high-quality analyses that allow us to submit results to regulatory authorities with full confidence.

• From TQT study waiver strategy to end-to-end submission ready C-QTc analysis, we are your partner. 
• We can empower your teams in conducting C-QTc analyses, and offer support through technical advice and workshop training. 
• Planning for regulatory interaction, we can support you with the strategy, meeting preparation, and participation in person. 
  

We support your clinical, clinical pharmacology, and pharmacometrics teams with:

• High-quality and timely design, analysis, and reporting of C-QTC modeling projects.
• Strategic and technical advice, plus training workshops to empower your teams in C-QTC analysis.
• Expert regulatory interaction, including use of the ICH M15 framework, preparation of briefing books and meeting materials, and representation at regulatory meetings.

Affiliated publications and abstracts

• Meyer C et al. How to Successfully Generate an Alternative Approach to a Thorough QT Study: GLPG1972 as an Example. CPT. 2023 Feb;113(2):310-320.
• Brooks L et al. Concentration QTc Analysis of Giredestrant: Overcoming QT/heart rate Confounding in the Presence of Drug-Induced Heart Rate Changes. CTS. 2023 May;16(5): 823-834.
• Vaddady P et al. Concentration-QTcF Analysis of Quizartinib in Patients With Newly Diagnosed (ND) Acute Myeloid Leukemia (AML). ACoP13 (Nov 2022). Poster M-034.
• Vaddady P et al. Concentration- QTcF analysis of quizartinib inpatients with newly diagnosed FLT3-internal-tandem-duplication- positive acute myeloid leukemia. CTS 2024 Nov;17(11): 1-12.
• Henrich A et al. PK/PD modeling of a clazosentan thorough QT study with hysteresis in concentration-QT and RR-QT. JPKPD. 2021;48(2), 213–224.
• Schilling U et al. Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis. CDI. 2021;41(8):711-721.
• Tanneau L et al. Exposure–safety analysis of QTc interval and transaminase levels following bedaquiline administration in patients with drug-resistant tuberculosis. CPT-PSP. Dec 2021;10(12): 1445-1587.
• Tanneau L et al. Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens. CPT. 2022;112(4):873-881.
• Bardol M et al. Risks encountered when not adjusting for diurnal variation and food effect in QTcF analysis based on phase I data. JPKPD. 2026; 53(6).

Our commitment to advancing the field of pharmacometrics is demonstrated through our active participation in scientific research and publication. This work not only contributes to the broader scientific community but also ensures our partners benefit from the most current and validated methodologies.

Whether you are in early-stage strategic planning or preparing for regulatory submission, our experts are ready to discuss how our Concentration-QTc (C-QTc) modeling can optimize your program. 

Ready to accelerate your cardiac safety strategy?

Contact us to discuss your needs

• Engage us for expert advice on strategic, regulatory, or technical matters at any stage of your study or program.
• Contract with us for milestone projects to perform specific analyses, such as a complete model-based bioequivalence analysis.
• Hire an embedded scientist to work as part of your team, either full- or part-time, giving you hands-on support guided by our senior consultants.
• Empower your in-house team with customized training workshops tailored to their specific background and needs.