Session Information
Date: Tuesday, September 24, 2019
Session Title: Parkinsonisms and Parkinson-Plus
Session Time: 1:45pm-3:15pm
Location: Agora 3 West, Level 3
Objective: To characterize the relationship between plasma apomorphine concentrations and QTc (QT interval corrected for heart rate) in patients with Parkinson’s disease (PD) and “OFF” episodes and predict changes in QTc from baseline at clinically relevant apomorphine concentrations.
Background: A thorough QT study was conducted to evaluate the effect of apomorphine sublingual film (APL-130277; APL) on the QT interval in patients with PD and “OFF” episodes..
Method: Concentration-QTc models were developed from 447 time-matched apomorphine concentrations and electrocardiogram data from 39 patients with PD and “OFF” episodes who received APL (10–50 mg) or placebo in a thorough QT study using nonlinear mixed effects modeling methodology as implemented in the NONMEM® software. QTc was assessed using Bazett’s, Fridericia’s (QTcF), and population (QTcP) correction methods. Various models were evaluated. The final model was used to predict changes in QTc from baseline at clinically relevant apomorphine concentrations.
Results: A final linear mixed effects model using QTcP with fixed effects for sex on baseline and random effects on intercept adequately described the relationship between apomorphine concentration and QTc interval. The slope of the QTcP-exposure relationship was minimal with a confidence interval (CI) that included zero (–0.0976 msec·mL/ng [95% CI: –0.8091, 0.6139]), indicating no strong correlation between QT prolongation and increasing apomorphine concentration. A sensitivity analysis with QTcF, which failed to adequately correct for heart rate, resulted in a slope estimate of the concentration-QTcF relationship of 0.274 msec·mL/ng (95% CI: –0.37, 0.92) and demonstrated a nonsignificant plasma concentration-QTc relationship. At the highest proposed therapeutic dose of APL (35 mg), the estimate of the 95% CI upper bound for QTcP change from baseline was 4 msec at the maximum plasma concentration, which is below the regulatory threshold of 10 msec, indicating no clinically relevant effect of APL on QTc.
Conclusion: APL had no clinically relevant effect on QTc prolongation across the proposed therapeutic dose range of 10–35 mg.
To cite this abstract in AMA style:
F. Agbo, Y. Chiu, S. Chapel, G. Galluppi, D. Blum, B. Navia. Population Exposure-Response Modeling of the Effects of Apomorphine Sublingual Film on QTc in Patients With Parkinson’s Disease and “OFF” Episodes [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/population-exposure-response-modeling-of-the-effects-of-apomorphine-sublingual-film-on-qtc-in-patients-with-parkinsons-disease-and-off-episodes/. Accessed June 14, 2025.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/population-exposure-response-modeling-of-the-effects-of-apomorphine-sublingual-film-on-qtc-in-patients-with-parkinsons-disease-and-off-episodes/