Getting the dose right

children taking medicine, vintage style drawing

Children should not just be considered “small adults” when it comes to prescribing medications, say Australian researchers

A new British Journal of Clinical Pharmacology article by researchers from the University of Sydney Discipline of Pharmacology has looked at drug dosage guidelines for infants and children.

The researchers reviewed 454 dosage guidelines and found most drug treatments (63%) have the same mg/kg dose for all age/weight groups.

Paediatric dosage guidelines were found to be based on simply formulas (such as mg/kg), available dosing formulations, and prior patterns of use.

Only 2% are dosed according to body surface area (BSA).

Meanwhile two-fold or more variation from doses that would be predicted by allometric scaling are common, as are arbitrary large shifts in recommended doses at age thresholds.

Many dosage guidelines also make the assumption that children are equivalent to “small adults” physiologically, physicochemically and biochemically, say the authors.

However there are large differences in physiological characteristics between children and adults, they point out, most notably in body composition, differential liver and kidney functioning, and drug-metabolising capacity.

Some metabolising enzymes are also only a fraction of adult levels during infancy, leading to decreased drug clearance and dosage requirements in this age group.

“Commonly a switch between the dosing regimens (set dose to mg/kg or vice versa) will occur at a particular age cut off somewhere between infancy and children, or childhood and adolescence,” say the authors.

“While these age cut-offs are designed to account for developmental changes in drug metabolism, in the real world the dosing regimen changes seem rather arbitrary, and titration between on developmental stage and another is not apparent.

“While doses may be safely approximated for drugs with large therapeutic margins, accurate dose estimation for drugs with narrow therapeutic margin is imperative in order to minimise the risk of drug toxicity.”

When used in children, a significant proportion of medications are used on an off-label basis, they add, citing study results that show levels of off-label prescriptions in hospitals ranging from 25.7% to 47%.

For some drug treatments, the BSA equivalent doses best demonstrate opportunity for fairly consistent dosing across children of different age groups, says the study.

However there are drawbacks, including that it is prone to errors due to the complexity of the mathematical calculations involved.

Formularies can be improved by utilising model-based methods to determine optimal paediatric dosage of existing drugs, the authors argue.

“In an ideal world, pharmacokinetic and pharmacodynamics profiles for every paediatric drug would be established and the results would inform dosage guidelines,” they say.

“Drugs used to treat childhood leukaemia are routinely dosed using BSA, which has contributed to achieving impressive improvement in outcomes in recent years.

“In absence of pharmacokinetic and pharmacodynamics studies, further research is required to determine if better outcomes could be achieved … by adopting biologically based scaling of paediatric doses.”

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  1. Peter Crothers

    Not much new here actually. You could have written this article 40 years ago and it would have fairly accurately reflected what we knew then.

  2. Ron Batagol

    Also, dosage guidelines specifically for infants and children, written by experts in the field are readily available. Thus, two of the most useful resources, the Royal Childrens Hospital Clinical Practice Guidelines, and the AMH Childrens Dosing Companion are available online. Just as is the case in the obstetric medication area, I think it’s critically important to emphasise to pharmacists that they shouldn’t rely solely on proprietary guides, which will reflect TGA-approved indications and dosage, but that in a specialised practice areas such as this, to go to the source or sources which provide the best evidence-based and clinical experience-based information and guidance.

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