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

Drugs with High Extraction Ratios: First-pass Effect and Protein Binding

Clearance of drugs with high extraction ratios depends on hepatic blood flow, which reaches adult rates by around 1 year of life. After nonoral administration of drugs that are not highly protein bound, elimination depends on only age-related changes in hepatic blood flow. For high–extraction ratio drugs administered orally, the effect of age on the activity of hepatic enzymes alters the first-pass effect. Therefore, in children, oral bioavailability of these drugs decreases due to increased activity of CYP1A2, CYP2C9, and CYP3A4; no effect on bioavailability is observed for drugs metabolized by CYP2C19, CYP2D6, NAT2, or UGTs.

For high–extraction ratio drugs, protein binding alters unbound concentrations after nonoral administration. Albumin and α1-acid glycoprotein concentrations are decreased in the premature infant and in neonates and do not reach adult concentrations until approximately 1 year of age. Protein-binding effects are clinically significant for drugs that are highly protein bound and that have high extraction ratios plus a narrow therapeutic window when they are administered nonorally.[71] In this case, the area under the concentration-time curve for the unbound drug can significantly increase when albumin and concentrations of α1-acid glycoprotein are decreased in neonates and thus enhance the pharmacologic effect. High–extraction ratio drugs commonly administered to neonates and infants that are highly protein bound include alfentanil, fentanyl, lidocaine, midazolam, propofol, milrinone, and ropivacaine.

Ropivacaine is metabolized by CYP1A2 and CYP3A4, and 94% of the drug binds to albumin and α1-acid glycoprotein. As predicted, concentrations of unbound ropivacaine after continuous epidural infusion are markedly higher in neonates than in infants.[72] Among children aged 1–9 years given such an infusion, no age dependence was found in unbound clearance.[73] Similar reductions in clearance were observed in neonates receiving intravenous fentanyl,[74] midazolam,[75] or propofol.[76,77] Age-related changes in clearance were not significant for infants and older children given alfentanil,[78–80] intravenous or transdermal fentanyl,[81,82] midazolam,[50] or propofol.[19,83–85]

For nonoral drugs with a high extraction ratio, doses must be decreased only when they are highly protein bound and only in neonates or infants (< 1 yr). After this age, weight-corrected doses may approximate those for adults, according to data from available studies. As described above, when propofol is used in infants, the initial loading doses and initial infusion rate are higher due to effects on volume of distribution.[19]

For drugs with low extraction ratios, protein binding is a factor only when doses are monitored by using total plasma concentrations. In this case, total concentrations cause underestimation of unbound or active concentrations. This has been shown for both phenytoin and valproate given to pregnant women[86] and the elderly;[87,88] however, to our knowledge, no studies have been conducted in neonates and infants.


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