How to Estimate the Dose to Be Given for the First Time to Pediatric Patients

Abstract

Current FDA guidance (Food and Drug Administration, Guidance for Industry: General considerations for pediatric pharmacokinetic studies for drugs and biological products. U.S. Department of Health and Human Services, Rockville, MD, November 1998) recommends administration of a fraction of an adult dose to pediatric patients based on mg/kg of bodyweight (BW) or mg/m² of body surface area extrapolation of adult doses. However, children are not small adults, and it is recommended to use the systemic exposure [usually the area under the curve (AUC)] to guide the starting dose selection in pediatrics. Systemic exposure is typically the AUC observed at the therapeutic dose in adults. This approach implies the ability to predict the pharmacokinetics in pediatric patients. There are several techniques to predict the pharmacokinetics in children based on knowledge of the pharmacokinetics in adults. The preferred approach is physiologically based pharmacokinetic (PBPK) modeling. PBPK models account for developmental differences between adults and children of differing ages and incorporate known maturation and variability in clearance processes and distribution. However in cases when the PBPK approach is not possible, the recommendation is to use allometry. In the case of larger molecules (for example, with biological products), an mg/kg or allometric scaling approach may be appropriate, unless there is prior information that provides a more drug-specific way to calculate the starting dose. Additional information like the use of a safety factor and other approaches to estimate the starting dose in pediatrics will be described in this chapter.