The population pharmacokinetics of guanfacine extended release were characterized in pediatric patients aged 6–17 years using NONMEM and evaluated by predictive check and bootstrap.
Data were described using a one-compartment model. A covariate modeling approach that emphasized parameter estimation rather than stepwise hypothesis testing was implemented. A nonparametric bootstrap procedure and a predictive check method were used to evaluate the final model and parameter estimates.
Typical population pharmacokinetic parameters (95 % confidence interval), given the reference covariates (Caucasian, male, age 12 years, weight 50 kg), were 33.1 (30.2–36.4) L/h for apparent clearance (CL/F), 804 (703–900) L for apparent volume of distribution, 0.552 (0.437–0.670) h−1 for the absorption rate constant, and 0.651 (0.608–0.697) h for absorption lag time.
The pharmacokinetics of guanfacine are similar in pediatric patients compared with adults when appropriately scaled by patient weight. The main predictor of guanfacine exposure, as determined by a change in CL/F, was weight. Effects of the other covariates (age, sex, and race) on CL/F were estimated with reasonable precision; however, the additional effects of age, sex, and race can be considered to have little to no clinical relevance.
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Funding for this research was provided to Metrum by Shire Development LLC. Melissa Brunckhorst, Ph.D., from MedErgy, provided editorial assistance in formatting, proofreading, and copy editing. This support was funded by Shire. Although the sponsor was involved in the design, collection, analysis, interpretation, and fact checking of information, the content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in Clinical Pharmacokinetics were made by all the authors independently.
WK and MRG are employees of Metrum Research Group LLC, which received funding from Shire Development LLC for this study. JE and MC are employees of Shire Development LLC and hold stock/stock options in Shire.
The studies included in the analyses were approved by an ethics committee or institutional review board and were conducted in accordance with the current revision of the Declaration of Helsinki.
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Supplemental Fig. 1. Predictive check for median guanfacine concentrations with distributions of simulated median concentrations within each individual (Cmed) compared to the actual observed distribution of Cmed values from the population pharmacokinetic database. Quantile-quantile plots for each of the 1000 simulation replicates are depicted by a grey dashed line and are overlaid on this plot. The black solid line represents a reference line of identity.(TIFF 1054 kb)
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Knebel, W., Corcoran, M., Ermer, J. et al. Population Pharmacokinetic Modeling of Guanfacine in Pediatric Patients. Clin Pharmacokinet 54, 875–883 (2015). https://doi.org/10.1007/s40262-015-0245-7
- Allometric Model
- Reference Weight
- Nonparametric Bootstrap Procedure
- Reference Covariates