PK/PD Modeling of the Effect of Intravenous Doses of Anzemet« (dolasetron mesylate) and Its Metabolite (hydrodolasetron) on the QT Interval in Healthy Subjects
Christine Brandquist(1), Daria Stypinski(1), Nathan Teuscher(2), Frederick Girard(3)
(1)Celerion, Lincoln, NE, USA; (2)PK/PD Associates, Fort Worth, TX, USA; (3)sanofi-aventis, Bridgewater, NJ, USA
Objectives: As part of a post-marketing study performed to clarify the potential activity of dolasetron on ventricular repolorization, a secondary objective was to explore whether there was a correlation between plasma concentrations and QT interval prolongation. The PK profile of dolasetron and its metabolite hydrodolasetron following dolasetron mesylate IV administrations (100 mg and 300 mg) was determined along with the QT interval in healthy normal volunteers. The aim of this project was to develop a PK/PD model to quantify the observed effects on QT interval.
Methods: Dolasetron and hydrodolasetron plasma concentrations and ECG data from 78 subjects who received 100 mg (therapeutic dose) and 300 mg (supratherapeutic dose) dolasetron were used in the analysis. Modeling was performed using mixed effect modeling as implemented in NONMEM version VI .
Results: Administration of the 100 mg dose resulted in a moderate and transient, but statistically significant, increase in placebo-corrected QTcF change from baseline (ΔQTcF). Administration of the 300 mg dose resulted in a larger, more sustained, and statistically significant increase in the ΔQTcF. Following 15‑minute IV infusion, the PK relationship between dolasetron and hydrodolasetron was best described by a combined structural PK model, with 1‑compartment for dolasetron and 2‑compartments for hydrodolasetron, with an additive residual error model following an IV bolus administration. The relationship between the QTcF and hydrodolasetron concentrations was best described by a direct response sigmoid Emax model. The prediction estimates for the PD parameters were: E0 = 398 ms, Emax = 65.3 ms, EC50 = 878 ng/mL, and a Hill coefficient of 1.2.
Conclusions: This PK/PD model suggests that the relationship between QTcF and hydrodolasetron is one where there is an increase from baseline QTcF (E0) as a function of the plasma hydrodolasetron concentrations, Emax, and EC50. A QTc change from baseline > 20 ms may have a substantially increased likelihood of being proarrhythmic . Based on the model, as plasma hydrodolasetron concentrations increase, the QTcF value increases to a maximum change of 65.3 ms, and concentrations of 878 ng/mL will result in a 50% of maximal change in QTcF of approximately 33 ms. The model indicates plasma hydrodolasetron concentrations above 159 ng/mL will result in increases in QTcF of 10 ms or greater.
 Nonlinear Mixed Effect Modeling (NONMEM) program (Version VI, Level 2.0, Icon Development Solutions, Ellicott City, MD).
 Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs, October, 2005. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073153.pdf.