Optimal Sample Size for Use in Neonatal Pharmacokinetic Studies

Document Type

Journal Article

Publication Date



Therapeutic innovation & regulatory science




Clearance; Model-based; Neonate; Pharmacokinetics; Sample size


BACKGROUND: In recent years, population pharmacokinetics (PK) has been widely used in neonatal pharmacology. However, the sample size selection for neonatal PK studies has been highly variable and without clear consensus, especially for drugs with large individual variability. Therefore, this study's objective was to investigate the optimal sample size for use in neonatal PK studies. METHODS: A comprehensive and reliable population PK model (1631 neonates) of vancomycin was selected as a reference model. The original sparse PK dataset was divided into several sub-datasets according to different sample sizes. NONMEM was used for sub-datasets PK analysis. Statistical powers were calculated to evaluate different sample sizes (> 80% was expected). RESULTS: During population clearance estimations, the average power was 40%, 85%, 100%, and 100% for sample sizes of 10, 25, 50, and 100 neonates, respectively. And the frequency of model-estimated median clearance values within ± 10% (relative errors) of target value (0.057 L/h) were 75.0%, 68.8%, 57.8%, and 35.0%, respectively. Regarding age sub-groups (postmenstrual age (PMA) < or ≥ 37 weeks) clearance estimation, a sample size of 50 was better to complete the assessment of the neonatal age sub-group even in some cases of unbalanced age distribution. CONCLUSION: A sample size of 25 neonates provided a consistent estimation of the overall population (PMA: 23.3-52.4 weeks) clearance for a drug with high individual variability using a sparse PK sampling design. A sample size of 50 was recommended to complete neonatal age sub-group assessments.