Manoranjenni Chetty1, Sebastian Polak1, Pavan Vajjah1,3, Masoud Jamei1, Amin Rostami 1,2
(1) Simcyp Ltd (a Certara Company), Blades Enterprise Centre, John St, Sheffield, S2 4SU; School of Pharmacy and Pharmaceutical Sciences, Manchester University, Manchester; (3) Current affiliation: UCB Celltech, 208, Bath road, Slough, SL13WE; UK
Objectives: To evaluate the sex effects on the potential risk of significant QT prolongation using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model.
Methods: The Simcyp Population Based Simulator (version 12 release 1) was used to simulate the concentration-time profiles of quinidine in virtual male and female Caucasian healthy volunteers with a full PBPK model and a systemic clearance of quinidine of 20.59 (CV 38%) L/h1. Clinically observed changes in QT prolongation corrected for heart rate (QTc)2 were used to develop the Emax models with differences in baseline QTc values between males and females obtained from the literature2. Parameter estimation was used to determine the ΔEmax (the maximum value of ΔQTc) and the concentration of quinidine required to produce 50% of the maximum response (EC50). Following evaluation of the developed models to predict clinically observed data, the models were used to simulate PD profiles in 500 males and females respectively. The proportion of subjects of each sex who showed QTc >500ms and hence probably carried a greater risk of experiencing torsade de pointes3, were then estimated.
Results: Visual predictive checks suggested that the PBPK model recovered the clinical PK profiles adequately and there was no significant difference between the PK profiles in males and females. The estimated parameters for the Emax models were not significantly different with respect to the Δ Emax values in males and females (128.9 ms and 130.8 ms respectively) but differed in the values for EC50 (6.28 µM for females and 7.01 µM for males), suggesting a greater sensitivity to change in QT in females. The PBPK/PD model recovered the clinical data adequately. Simulation of QTc in the sexes showed that 56% of females were likely to show maximum QTc > 500ms while the corresponding value for males was 43%.
Conclusions: This PBPK/PD model effectively recovered the higher rate of QT prolongation reported in females and predicted a 1.3 times higher risk of significant QT prolongation in females on quinidine. The estimated sensitivity parameter (EC50) of the PD model suggests a female/male ratio of 0.89. Clinical support for a lower EC50 in Caucasian females comes from the study by Benton and coworkers who reported that at a ‘therapeutic’ concentration of 3µg/mL women are likely to show a 38ms greater increase in QT change than men4. Future PBPK/PD models should include 3-hydroxyquinidine.
References:
[1] The Pharmacological basis of therapeutics.11th ed. Brunton LL, Lazo J and Parker KL ed.2006. 2. Shin et al, Br J Clin Pharmac 2006, 63(2):206. 3.Bednar et al, Prog Cardiovas Dis 2001, 43:1. 4.Benton et al, CPT 1994,67:413.
Reference: PAGE 22 (2013) Abstr 2913 [www.page-meeting.org/?abstract=2913]
Poster: Safety (e.g. QT prolongation)