Therapeutic Reference Ranges for ADHD Drugs in Blood of Children and Adolescents: A Systematic Review by the AGNP TDM-Task Force

Attention deficit-/hyperactivity disorder (ADHD) medications are commonly prescribed to children and adolescents, but therapeutic reference ranges have not been systematically evaluated yet. This study aimed to establish preliminary therapeutic reference ranges for methylphenidate (MPH), d-amphetamine (d-AMP), atomoxetine (ATX), and guanfacine (GFC), based on a systematic review of the existing relevant literature. Therapeutic reference ranges were calculated based on blood concentrations measured in responder children and adolescents with ADHD. Therapeutic ranges were determined both as mean values plus one standard deviation (SD) and using the 25th/75th IQRs. For MPH, a therapeutic reference range was calculated according to the mean maximum concentration (Cmax)±SD (8.8±7.7 ng/mL) as 1.1–16.6 ng/mL and according to the 25th/75th IQR as 7.2–11.3 ng/mL. The mean d-AMP Cmax concentration±SD was 31.9±15.2 ng/mL, resulting in a range of 16.6–47.1 ng/mL, and the calculated range according to IQR 25th/75th was 18.4–32.5 ng/mL. For ATX, mean maximum concentration at steady state (Cmax,ss)±SD was 589.7±656.3 ng/mL, resulting in a range of 0.0–1245.9 ng/mL, and according to 25th/75th IQR, the range was calculated as 537.0–635.5 ng/mL. For GFC, only one study was eligible, with a mean blood concentration of 7.5 ng/mL in responders. The results provide preliminary recommendations that can serve as reference values for therapeutic drug monitoring in children and adolescents treated with MPH, AMP, ATX, and GFC. Further research is needed to validate or refine the proposed therapeutic ranges.