Dosing Strategies for High-Alert Medications in Obese Pediatric Patients: A Systematic Review

Abstract

Background/Objective: Childhood obesity induces physiological changes that alter drug distribution and clearance; however, these patients are often excluded from clinical trials, creating a critical safety gap for high-alert medications (HAM). The Objective was to evaluate HAM dosing strategies and pharmacokinetic (PK) alterations in overweight and obese pediatric patients. Methods: A systematic review was conducted and registered in PROSPERO (CRD42023452126). A search of MEDLINE, EMBASE, Web of Science, and Cochrane CENTRAL (1990-March 2026) identified studies reporting dosing strategies or PK of HAM in obese or overweight pediatric patients. Studies were included if they reported dosing recommendations or PK parameters. Eligible designs comprised prospective and retrospective, randomized and non-randomized, observational (cohort, case-control, and cross-sectional), case series, case reports, and narrative and systematic reviews. Study selection, data extraction, and quality assessment were conducted independently by two reviewers. Methodological quality was assessed using validated tools, and results were synthesized qualitatively. Results: Of 5801 records, 91 studies were included, providing evidence for only 27% of the evaluated HAM. Total body weight (TBW) appeared to be appropriate for insulin and vancomycin, although close monitoring was required. TBW-based dosing was associated with approximately 20% overexposure for enoxaparin, supporting the use of fat-free mass (FFM) or reduced dosing strategies. Increased clearance may justify higher doses for amlodipine and consideration of adult-equivalent dosing for metformin in adolescents. For gentamicin, FFM appeared to be the most appropriate descriptor, while adjusted body weight was used for valproic acid. In anesthetics and sedatives, reduced TBW-based dosing may be considered for propofol, whereas ideal body weight (IBW) or FFM were generally preferred for ketamine and dexmedetomidine. Analgesics such as fentanyl and morphine may require IBW- or FFM-based dosing, and maintenance dosing of paracetamol may require adjustment. Conclusions: Evidence remains limited and heterogeneous, with no standardized dosing approach. Model-informed strategies-such as population PK (PopPK) and physiologically based PK model (PBPK) approaches-may be useful for hypothesis generation and exploring PK variability; however, their clinical applicability is constrained by the limited and heterogeneous evidence base, and they should be considered exploratory.