Are Exposure Recommendations for QT Evaluation Being Fulfilled?

Area of Science:

• Pharmacology
• Clinical Development
• Regulatory Science

Background:

• Regulatory agencies recommend high clinical exposure (HCE) for thorough QT (TQT) studies.
• The Q&A 5.1 pathway suggests a two-fold HCE margin for concentration-corrected QT (C-QTc) analysis as an alternative.

Purpose of the Study:

• To evaluate the impact of current regulatory recommendations on drug exposure margins.
• To assess the achievement of HCE in TQT studies and C-QTc analyses for new active substances approved in Japan since 2015.

Main Methods:

• Analysis of exposure margins for 166 new active substances approved in Japan.
• Examination of HCE achievement in conventional TQT studies and C-QTc analyses.
• Assessment of Cmax in single-ascending dose (SAD) and multiple-ascending dose (MAD) studies against HCE targets.

Main Results:

• 28.3% of TQT studies and 50.0% of C-QTc analyses did not meet HCE requirements.
• 51.1% of SAD studies and 47.7% of MAD studies failed to achieve HCE.
• Significant proportions of substances did not reach recommended exposure levels in early clinical phases.

Conclusions:

• Current early clinical study designs often fail to ensure adequate drug exposure.
• A dose-ascending strategy targeting two-fold therapeutic exposure is needed to meet HCE recommendations.
• Optimizing early study designs can prevent TQT study waivers failures and development delays.