Rujia Xie (1), Jakob Ribbing (2), Peter Milligan (3), Lutz Harnisch (3), Grant Langdon (4)
(1) Clinical Pharmacology & Pharmacometrics, Pfizer (China) R&D, China, (2) Pharmacometrics, Pfizer, Sweden, (3) Pharmacometrics, Pfizer Inc, UK, (4) PTx Solution Ltd. UK
Objectives: The purpose of this analysis was to develop a PK-QT model describing the time-course of QTc interval prolongation following dosing with PH-797804 in healthy volunteers, and aid in dose selection for a thorough QT study.
Methods: Six Phase I studies were included in the analysis with a total of 129 subjects receiving single or multiple oral doses of PH-797804 (range 0.3-60 mg) or placebo. Generally, 3 replicate 12-lead ECG were recorded at each time point. PK-QT analysis was conducted in four steps: 1) nonparametric PK modeling, 2) PK-RR interval analysis; 3) evaluating correction methods using baseline QT data; 4) PK-QTc analysis. QT-triplicate correlation was accounted in residual by using the L2 option in NONMEM. The final PK-QTc model was utilized for trial simulations.
Results: PH-797804 concentrations at QT time points were well predicted by the linear interpolation method. In the RR interval modeling, a negative linear concentration-effect relation was found but 95%CI based on bootstrap included a zero slope; indicating that there was no significant effect on the RR interval.
Five correction methods were evaluated: QTcB, QTcF, QTcP (population), QTcS (study) and QTcI (individual). A model with individual correction and an extra study correction factor for two studies was the best (QTcIS), minimizing any trend between QT and RR interval. All QT data including active treatment and placebo were sufficiently corrected using this method and QTcIS was therefore selected as the dependent variable in developing the concentration effect model.
A step log-linear concentration effect model was the final drug effect model for QTcIS, which consisted of: one cosine circadian term; log-linear concentration effect on QTcIS; and gender effect on baseline. The slope was 1.44 [95%CI: 0.93-1.91] and cut-off concentration was 1.27 [95%CI: 0.22-4.36] ng/ml. Female baseline QTcIS was 7.36 ms longer. There were large replicate variability (within replicate ε correlation r=0.32). Trial simulations indicated that the maximum mean double DQTcI would not be greater than 8.5 ms and the upper 95% CI for the mean would not exceed 10 ms at most of time across a range of supratherapeutic doses up to 24mg.
Conclusions: A modified individual correction method was the best approach. The PK-QTcIS model described QTcIS data well and supported dose selection for the planned TQT study.
Reference: PAGE 22 () Abstr 2875 [www.page-meeting.org/?abstract=2875]
Poster: Safety (e.g. QT prolongation)