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ANNEX 3. Pharmacology of antimalarial medicines

a3.15 pharmacology of antimalarials in special groups and conditions

A3.15.1 Safety and tolerability of antimalarials in infants

Infants under 12 months of age constitute a significant proportion of patients in malaria
endemic countries. Yet few studies focus specifically on this age range, partly because
of ethical dilemmas and also owing to technical difficulties with sampling. Very young
children cannot report adverse effects themselves, so detection of these is dependent
upon parents and health professionals making observations. In addition, pre-marketing
clinical trials for new drugs are not represented by important subpopulations including A3
infants (79), yet there are potentially important pharmacokinetic differences in infants
compared to older children and adults (80).

Drug absorption

The gastric pH at birth is usually 6–8 but within a few hours falls to 2 and then rises
again until virtual achlorhydria occurs for several days. As the gastric mucosa develops,
the acidity increases again until 3 years of age when adult values are attained. The gastric
emptying time is prolonged (up to 8 h) in neonates and approaches adult values only after
6 months. Intramuscular injections can also be problematic in young children. Infants
with acute or severe malaria may become extremely “shut down” whereby visceral,
muscle and skin blood flow is reduced. This may result in slow, erratic or incomplete
drug absorption and the consequent delay in achieving therapeutic drug levels at a time
when speed and adequacy of drug delivery are crucial.

Distribution

Relatively large total and extracellular body water compartments in infancy lead to larger
apparent volumes of distribution. Total body lipids rise steadily after birth for the first 9
months of life but then decrease until adolescence. These changes in body composition
can modulate volume of distribution and clearance. Liver mass per body weight is higher
in infants than adults and the liver undergoes rapid growth during the first 2 years.
The brain is disproportionately large in young children, and the blood brain barrier
relatively immature, making a further contribution to volume of distribution. Finally drug
distribution is also affected by lower protein binding in infancy with more free drug and
thus increased clearance. The former might also lead to a greater risk of toxicity.

Drug metabolism
The cytochrome P450 mixed function oxidase system is the most important
biotransformation system incorporating many enzymes and isoenzymes. In general,
these enzyme systems are immature at birth. There is therefore relatively slow clearance
of most metabolized drugs in the first 2–3 months of life. Between 2 and 6 months
clearance is more rapid than in adults and even more so for most drugs from 6 months

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