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.

Figure 1

Summary of physiologically‐based pharmacokinetic (PBPK) strategy for predicting the exposure of trazodone in children. CYP, cytochrome P450; DDI, drug–drug interaction; fm_CYP3A4, CYP3A4 contribution.

Figure 2

Predicted (black line represents mean, and gray lines represent individual trials) and observed (circles; (a–d) 31, (e) 32, (f) 25, 32) trazodone plasma concentration profiles following the administration of different doses and formulations. ER, extended release; IR, immediate release; q.d., once a day; TID, three times a day.

Figure 3

Predicted median total plasma concentration‐time profiles of trazodone following the respective predicted final doses in 2–6, >6–12, and > 12–17 year olds. These were based on matching the adult C_max following 30 mg IR q.d. for 7 days (a,b), 75 mg IR q.d. for 7 days (c,d), and 150 mg IR q.d. for 7 days (e,f). h, hour; yrs, years.