precision of pharmacokinetic parameters in children a systematic review

Abstract The purpose of paediatric pharmacokinetic studies is to provide precise estimates of the true value of pharmacokinetic parameters to inform dosing. We evaluated age-specific estimates of pharmacokinetic parameters in peer-reviewed studies. Systematic reviews of 10 drugs included publications describing >1 pharmacokinetic study in patients <18 years. A pharmacokinetic study was defined as peer-reviewed primary data used to estimate one or more of Volume of distribution (Vd) or Clearance (CL). We defined uncertainty as the width of the 95% confidence interval divided by the population estimate of the study mean. Acceptable uncertainty as uncertainty was defined as <20%. Review of 21594 abstracts identified 137 eligible manuscripts containing 203 pharmacokinetic studies that included 176 Vd and 178 CL parameter estimates. Pharmacokinetic parameter estimates were derived from 2 or more age groups in 227 (64%) estimates. Acceptable uncertainty was found in 59 (34%) Vd and 35 (20%) CL, estimates. Heterogeneity was found with wide prediction intervals reported by drug and parameter. There was limited literature to support allometric dosing in the ten commonly used drugs we studied. There are multiple factors that may contribute to variability. We explore the importance of precise pharmacokinetic data, utility of parameter estimate ranges and the feasibility and extrapolation of pharmacokinetic parameter estimates. Factors contributing to observed uncertainty included modest sample sizes, within sample heterogeneity and dosing that accounts for patient factors in addition to age. These present opportunities to improve the quality and utility of pharmacokinetic data that underpins paediatric dosing.