Population Pharmacokinetic/Pharmacodynamic Modeling of Guanfacine Effects on QTc and Heart Rate in Pediatric Patients

Using a previously developed population pharmacokinetic model, an exposure-response (ER) model was successfully developed to describe guanfacine plasma concentrations and changes in heart rate (HR) and the QT interval. Guanfacine exposure was associated with small decreases in HR and a small prolongation of the population-corrected QT (QTcP) interval. Based on the final ER model for effect of guanfacine on HR, the estimated population typical decrease in HR would be 2.3% (2.1–2.7%) of the baseline circadian HR for every 1 ng/mL of guanfacine exposure. A QTcP was developed for the analysis using the sampled population. An effect of sex on baseline-corrected QT (BQTP) was the only covariate effect in the final ER model for QTcP, its inclusion resulting in a typical baseline QTcP estimate that is 9 (5–13)?ms higher for females. There was no evidence of QT-RR hysteresis. A linear model was used to relate guanfacine plasma concentrations to QTcP. The typical (95% confidence interval) slope parameter was estimated to be 0.941 (0.62–1.25)?ms/ng/mL. The final model predicted an approximate 1-ms increase from baseline for every 1 ng/mL of guanfacine in plasma. The main predictor of QTcP prolongation was guanfacine exposure, which decreased with body weight and increased with dose.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9645-0) contains supplementary material, which is available to authorized users.KEY WORDS: ADHD, guanfacine, pediatric, pharmacodynamics, pharmacokinetic