title: Prediction of drug clearance in children: impact of allometric exponents, body weight, and age.
abstract: In recent years, with the advent of pediatric exclusivity and requirements for conducting clinical studies involving children, emphasis has been placed on finding safe and efficacious doses of drugs for children. It has been suggested that one can predict the clearance (CL) of a drug in children according to this equation: CL in the child = Adult CL * (Weight of the child/70)0.75. In light of the controversy surrounding the exponent of 0.75 for the prediction of clearance, the objectives of the study were as follows: (1) to develop allometric equations based on body weight or age to predict clearance of a drug in children; (2) to determine if the fixed exponent of 0.75 is a suitable exponent for the prediction of clearance in children from adult data, as compared with the allometric exponent generated for individual drugs; (3) to determine if the allometric equation generated on the basis of age predicts clearance in children better or worse than the allometric equation generated on the basis of body weight; and (4) to propose a new approach based on the findings of the current evaluation. Five methods were used to predict drug clearance in children. Six drugs were used in the evaluation, and drug clearance in each child was predicted for a given drug. Besides evaluating the exponent of 0.75, allometric equations were developed using double log plots of clearance versus body weight or age. The exponents of the allometric equations were then used to predict drug clearance by replacement of 0.75 in the aforementioned equation. The results of the study indicate that 0.75 is not the best exponent for prediction of drug clearance in children, and a more suitable approach is to develop an allometric relationship for a given drug in children. For all 6 drugs, there were 77 children in whom the clearance was predicted. There were 48 observations for which error in the predicted clearance was 50% or more with use of the exponent 0.75, whereas there were only 13 observations with prediction error > or = 50% when 0.75 was replaced by an allometric exponent developed for a given drug. In order to predict drug clearance in children with reasonable accuracy, an allometric equation should be developed for every drug and the exponent 0.75 should be replaced by the exponent of the allometric equation developed for that drug.
authors.affiliation: From the Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food & Drug Administration, Bethesda, Maryland, USA. lftekhar.mahmood@fda.hhs.gov
authors.forename: Iftekhar
authors.initials: I
authors.lastname: Mahmood
mesh_terms: D000293:Adolescent; D000375:Aging / Q000378:metabolism*; D001835:Body Weight; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D010372:Pediatrics; D010599:Pharmacokinetics