Estimation of an Appropriate Dose of Trazodone for Pediatric Insomnia and the Potential for a Trazodone–Atomoxetine Interaction

Abstract

There is a paucity of clinical trials for the treatment of pediatric insomnia. This study was designed to predict the doses of trazodone to guide dosing in a clinical trial for pediatric insomnia using physiologically‐based pharmacokinetic (PBPK) modeling. Data on the pharmacokinetics of trazodone in children are currently lacking. The interaction potential between trazodone and atomoxetine was also predicted. Doses predicted in the following age groups, with exposures corresponding to adult dosages of 30, 75, and 150 mg once a day (q.d.), respectively, were: (i) 2‐ to 6‐year‐old group, doses of 0.35, 0.8, and 1.6 mg/kg q.d.; (ii) >6‐ to 12‐year‐old group, doses of 0.4, 1.0, and 1.9 mg/kg q.d.; (iii) >12‐ to 17‐year‐old group, doses of 0.4, 1.1, and 2.1 mg/kg q.d. An interaction between trazodone and atomoxetine was predicted to be unlikely. Clinical trials based on the aforementioned predicted dosing are currently in progress, and pharmacokinetic data obtained will enable further refinement of the PBPK models.

Pediatric insomnia: Treatment

“…29 Additionally, development of a physiologically based pharmacokinetic model to inform trazodone dosing for youth with insomnia is underway. 30 Some studies in adolescents with depression suggest that caution should be used when combining trazodone with medications that inhibit CYP2D6. In the Treatment of SSRI-Resistant Depression in Adolescents study, none of the patients who were treated with trazodone (vs other soporifics) improved.…”

Physiologically Based Pharmacokinetic Models Are Effective Support for Pediatric Drug Development

“…The conduct of a clinical trial in pediatric patients was based on previous dose predictions endorsed by the European Medicines Agency. Ethical and regulatory approvals for the clinical trial were also based on the doses predicted in this analysis ( 16 ). The pediatric PBPK model in combination with the population pharmacokinetics (PopPK) model could be further used to guide dose selections for treatment ( 92 ).…”

“…The PBPK model has been widely applied as a tool for decision making, study optimization, and data analysis by academia, the pharmaceutical industry, and the regulatory agencies of pediatric drug development and therapy (11)(12)(13). The PBPK model has a variety of applications, such as guiding first dosing (14)(15)(16), predicting tissue drug concentration (17), estimating potential drug-drug interactions (DDIs) in pediatric patients, and describing the effects of organ impairment on pediatric pharmacokinetics (18).…”

Physiologically‐based pharmacokinetic modeling to predict drug interactions of lemborexant with CYP3A inhibitors

“…This PBPK modeling approach has been used previously to inform drug labels, and is recognized by the European Medicines Agency and the US Food and Drug Administration (FDA) as an appropriate tool for DDI predictions in the absence of complete clinical trial data. [13][14][15][16][17][18] The objectives of this work were to develop and verify a PBPK model for lemborexant using the Simcyp populationbased simulator, 19 and to apply the model to predict DDIs of lemborexant with additional moderate and weak inhibitors of CYP3A. These predictions were to provide considerations for lemborexant dosing when co-administered with known CYP3A inhibitors.…”

“…To complement the existing lemborexant clinical DDI information, we developed a physiologically‐based pharmacokinetic (PBPK) model incorporating in vitro data on plasma protein binding, information on physicochemical properties, and human oral clearance data. This PBPK modeling approach has been used previously to inform drug labels, and is recognized by the European Medicines Agency and the US Food and Drug Administration (FDA) as an appropriate tool for DDI predictions in the absence of complete clinical trial data 13‐18 …”