title: Population Pharmacokinetics: Some Observations in Pediatric Modeling for Drug Clearance.
abstract: The objective of this study is to evaluate the predictive performance of several models to predict drug clearance in preterm and term neonates. Five models using different types of allometric and linear models were developed. Two sets of data were used to develop these models (data from preterm neonates to adults and data from preterm and term neonates). Models were also developed with (normalized to 70 kg) or without body weight normalization (body weight 1 kg). From the literature, clearance values for four drugs from neonates to adults were obtained. External data were used to evaluate the predictive performance of these models in preterm and term neonates. The results of the study indicated that (1) normalization to a standard body weight had no impact on the predictive performance of the models, (2) the model developed from preterm neonates to adults using fixed exponent 0.75 provided inaccurate estimate (overestimation) of drug clearance in neonates, (3) a far superior prediction of clearance was observed with the model when the exponents of allometry were estimated than the model using exponent 0.75, (4) linear models with the exception of the model with intercept provided comparable results to the estimated exponent model and were superior in their predictive performance to the model using exponent 0.75, and (5) when the models were developed from neonate data, the predictive performance of all models were similar. Overall, the study indicated that body weight normalization had no impact on the performance of model prediction, the exponents of allometry in pharmacostatistical models should be estimated rather than fixed, and more studies are needed to evaluate the suitability of linear models for the prediction of drug clearance in neonates.
authors.affiliation: Office of Tissue and Advance Therapeutics, Center for Biologics Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA. Iftekhar.mahmood@fda.hhs.gov.
authors.forename: Iftekhar
authors.identifier: 0000-0003-1311-4237
authors.initials: I
authors.lastname: Mahmood
authors.affiliation: Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Million A
authors.initials: MA
authors.lastname: Tegenge
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D016014:Linear Models; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D010599:Pharmacokinetics; D055815:Young Adult
chemical_list: D004364:Pharmaceutical Preparations