Evident bias in a paracetamol metabolite population pharmacokinetic model applied to an external dataset

Paracetamol (acetaminophen) is commonly used to manage mild and moderate pain in neonates 1 . There has been extensive work exploring the pharmacokinetics of paracetamol in neonates, but few studies have also evaluated the metabolites in conjunction with the parent drug. A recently published population pharmacokinetic model successfully characterized the pharmacokinetics of paracetamol and its metabolites in the plasma and urine of preterm and term neonates and indicated that both weight and postnatal age played an important role in describing the interindividual variability 2 . The FDA suggests that an external validation is the most ‘stringent’ form of validation for a pharmacokinetic model 3 . Therefore, this analysis sought to validate the previously published model with an external cohort of preterm and term neonates to verify the extrapolation of this model to broader clinical settings.