Operational Characteristics of Linear Concentration‐QT Models for Assessing QTc Interval in the Thorough QT and Phase I Clinical Studies

Concentration‐QTc (C‐QTc) analysis can be used as an alternative to the standard statistical methods in clinical QT studies. Pharmacokinetic/pharmacodynamics (PK/PD) simulations were performed to assess the operating characteristics of four C‐QTc models. False negatives were 2–6% for crossover and 2–9% for parallel studies, with 12 to 60 subjects per treatment for a dose with 10‐ms mean effect. All C‐QTc models tested gave less than +1 ms mean bias in the ΔΔQTc max prediction. The power to exclude 10 ms was >80% across all study designs and sizes, for a dose with 3‐ms mean effect. The study demonstrates that linear C‐QTc models have adequate sensitivity and specificity when the simulation and data analytical models are the same. C‐QTc models that incorporate time‐ and treatment‐specific terms give the least biased ΔΔQTc max predictions under scenarios of model‐misspecifications and offer an advantage when applying to real clinical data where the underlying relationship is not known.