Evaluation of QT Liability for PF‐05251749 in the Presence of Potential Circadian Rhythm Modification

Figures

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  Figure 1. Model‐derived ∆∆QTcF vs. PF‐05251749 concentration plot across different types of models. Blue line and shaded regions represent mean prediction and 90% confidence intervals (CIs), red arrow is upper bound of 90% CI at mean steady‐state maximum concentration (Cmax) for lowest therapeutic dose (50 mg), purple dashed arrow is for highest therapeutic dose (400 mg), and green dotted arrow is for supratherapeutic dose (750 mg). LME, linear mixed effect; NLME, nonlinear mixed effect; QTcF, Fridericia corrected QT interval; ∆∆QTcF, placebo‐corrected QTcF change from baseline.

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  Figure 2. Two scenarios of drug‐induced QTcF circadian rhythm change. hr, hour; QTcF, Fridericia corrected QT interval.

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  Figure 3. Box and whisker plots of the estimation errors for slope parameters in both LME and NLME models across different phase‐ delay scenarios. Boxes denote the 25th and 75th percentiles, and the closed circles denote the median. Whiskers represent the 5th and 95th percentiles. hr, hour; LME, linear mixed effect; NLME, nonlinear mixed effect.

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  Figure 4. Box and whisker plots of the estimation errors for slope parameters in both LME and NLME models across different period lengthening scenarios. Boxes denote the 25th and 75th percentiles and the closed circles denote the median. Whiskers represent the 5th and 95th percentiles. LME, linear mixed effect; NLME, nonlinear mixed effect.

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  Figure 5. False‐negative study rate for clinically meaningful QT prolongation case (upper bound of 90% confidence interval for ∆∆QTcF ≥ 10 milliseconds) in both LME and NLME models across different scenarios of QTcF circadian rhythm change. hr, hour; LME, linear mixed effect; NLME, nonlinear mixed effect; QTcF, Fridericia corrected QT interval; ∆∆QTcF, placebo‐corrected QTcF change from baseline.

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  Figure 6. False‐positive slope rate for no QT prolongation case in both LME and NLME models across different scenarios of QTcF circadian rhythm change. hr, hour; LME, linear mixed effect; NLME, nonlinear mixed effect; QTcF, Fridericia corrected QT interval.