Optimizing Pediatric Dosing: A Developmental Pharmacologic Approach

Gail D. Anderson, Ph.D.; Anne M. Lynn, M.D.


Pharmacotherapy. 2009;29(6):680-690. 

In This Article


Gastric pH is increased in neonates, infants, and young children and reaches adult pH values by 2 years of age. Gastrointestinal motility is decreased in neonates and reaches adult levels in infants and children. The age at which this occurs is unclear.

Bioavailability of enterally administered weak acids, such as phenytoin and phenobarbital, may be reduced in infants and young children because of their heightened gastric pH. Bioavailability of the enteral formulation of phenytoin is 75% in neonates and infants (aged 1–121 days) compared with nearly complete absorption in adults.[9] After a single oral dose of phenobarbital, the time to peak concentrations is significantly delayed in neonates.[10] In a population pharmacokinetic study of children and adolescents (median age 7.4 yrs, range 0.5–16.9 yrs), the bioavailability of ganciclovir, another weak acid, was approximately 50% lower than that reported in adults.[11] Children required higher oral doses than adults to achieve target serum concentrations.

Metabolism and active efflux transporters in the gastrointestinal tract can also affect bioavailability.[12] Immature intestinal CYP3A4 metabolism of midazolam reduces clearance in preterm infants.[13] Gabapentin is renally excreted as unchanged drug, and its bioavailability is dose dependent because of saturable transport by the L-amino acid transporter in the gastrointestinal mucosa. Oral clearance of gabapentin is 33% higher in children younger than 5 years than in older children or adults. Because renal clearance reaches adult levels at 1–2 years of age, and because gabapentin is not protein bound, this effect on oral clearance is not due to altered clearance but decreased bioavailability resulting from immature activity of the L-amino acid transporter, which limits absorption.

Oral clearance of fexofenadine depends on the efflux transporters P-glycoprotein[14] and organic anion-transporting peptides[15] in the gastrointestinal tract. A population pharmacokinetic analysis of fexofenadine in infants and children aged 6 months–12 years revealed no significant effect of age on oral clearance.[16] This observation suggests that efflux transporters mature as soon as 6 months of age. Bioavailability of drugs affected by pH, gastrointestinal motility, efflux transporters, and/or intestinal metabolism should be close to adult values by the age of 5 years and possibly earlier than this for some drugs. However, the data are too limited to permit definitive conclusions.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.