The AAPS Journal

, Volume 16, Issue 6, pp 1237–1246 | Cite as

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

  • William Knebel
  • James Ermer
  • Jaideep Purkayastha
  • Patrick Martin
  • Marc R. Gastonguay
Research Article

Abstract

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.

KEY WORDS

ADHD guanfacine pediatric pharmacodynamics pharmacokinetic 

Supplementary material

12248_2014_9645_Fig4_ESM.gif (85 kb)
Supplemental Fig. 1

Image shows a predictive check for median heart rates with distributions of simulated median heart rates (bpm) within each individual (Cmed) compared to the actual observed distribution of Cmed values from the population pharmacodynamic database and a predictive check for maximum population corrected QT (QTcP) intervals (ms) compared to the actual observed distribution of QTcP intervals from the population pharmacodynamic database. Quantile-quantile plots for each of the 100 simulation replicates are depicted by a gray dashed line and are overlaid on this plot. The black solid line represents a reference line of identity. Top image shows heart rate and bottom image shows QTcP intervals. (GIF 84 kb)

12248_2014_9645_MOESM1_ESM.tiff (49.1 mb)
High resolution. (TIFF 49.0 MB)
12248_2014_9645_Fig5_ESM.gif (72 kb)
Supplemental Fig. 2

Image shows change in QTcP at steady-state Cmaxversus weight for clinical trial simulations in pediatric ADHD patients receiving 2 or 4 mg of guanfacine. Simulated change in QTcP at steady-state Cmax is plotted against corresponding weight (kg). Values are plotted as open circles. Solid black line is reference for weight of 20 kg in 6-year old, dashed line is reference for weight of 50 kg in 12-year old, and dotted line is reference for weight of 65 kg in 17-year old. Left panel shows 2 mg dose and right panel shows 4 mg dose. (GIF 71 kb)

12248_2014_9645_MOESM2_ESM.tiff (31.6 mb)
High resolution. (TIFF 31.5 MB)

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Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • William Knebel
    • 1
  • James Ermer
    • 2
  • Jaideep Purkayastha
    • 2
  • Patrick Martin
    • 2
  • Marc R. Gastonguay
    • 1
  1. 1.Metrum Research Group, LLCTarifvilleUSA
  2. 2.Shire Development LLCWayneUSA

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