Exposure-response relationship in adults and children for pediatric dose adjustment

Abstract

Pediatric dosing aims to produce similar drug exposure to that of adults, provided that children and adults have similar exposure‐response (ER) relationships. We examined ER similarities between adult and pediatric populations using in‐house NDA data. All NDAs that included pediatric uses were screened, from which 10 NDAs that contained the following parameters and indices (P&I) were analyzed: pharmacokinetics (PK), ER, drug‐related adverse events (ADR), and efficacy (E) after administration of various formulations/dosage regimens. Pediatric‐to‐adult ratios (PTA) of these P&I were calculated for various pediatric age groups (3 mo‐16 yrs). Trend analysis did not reveal a consistent pattern relating drug exposure to ADR or E P&I. Pediatric exposure levels were higher than adults (Cmax ratios = 0.33 ‐ 2.58, AUC ratios = 0.43 ‐ 2.25) but resulted in less than comparable response (E ratios = 0.18 ‐ 1.36). Although the PTA ADR ratios were comparable to adults, ranging from 0.25 to 4.24, 3 drugs manifested serious adverse events (SAE) in children only. In general, the difference in ADR and E P&I are inversely related to age. Detailed age‐group analysis will be presented. PTA E or ADR ratios among therapeutically‐similar drugs could not be extrapolated. The lack of PTA similarity observed in this study implies that pediatric PK studies may provide key information for dose adjustment but incorporation of ADR and E data is critical. Clinical Pharmacology & Therapeutics (2004) 75, P75–P75; doi: