Most infants are slow acetylators and may
accumulate toxic levels of those drugs that are
metabolized by this second phase of metabolism
route. Renal perfusion and glomerular filtration
rates (GFR) vary: for the premature, 2–4 ml
min^1 ; for neonates, 25 ml min^1 ; and by 1–1.5
years old, 125 ml min^1 , which is equivalent to
adult clearance rates (Arant, 1978). The potential
toxic implication of renal metabolites and elimina-
tion of unchanged drug in the very young are
obvious (Stewart and Hampton, 1987).
Dosing
Without pediatric PK data, dosing in children has
depended on extrapolations from the adult data,
either by weight or by body surface area. Using
weight may result in overdosing neonates but
underdosing infants and children. Using body sur-
face area may be better because of its linear
increase with age and its good correlation with
cardiac output, renal flow and GFR – more so
than weight. Neither method compensates for the
varying metabolism aforementioned, nor for dif-
ferences in drug disposition between children and
adults.
Concerns in formulations for pediatrics
If a drug is to be given by injection, i.m. or i.v., this
may require only volume variations. But most
drugs developed for adults are given by the oral
route, as tablets, capsules or caplets. The adult
formulation is usually determined by marketing
considerations. Invariably, for children, especially
under age seven years, liquid or syrup must be
formulated. Most drugs taste bitter or unpleasant
(which is why most tablets are sugar coated).
Sometimes, it may be impossible to completely
mask the taste. A commitment to a pediatric for-
mulation requires a whole gamut of testing and the
development of specific product specifications. If
the liquid formulation changes the bioavailability
(faster or slower absorption), then further efficacy
and safety studies may be required. A further
concern is that liquid formulations often have a
shorter shelf life than tablets. Finally, stability
characteristics or other factors may make it impos-
sible to make a liquid or syrup or glycolated elixir,
sprinkle beads or powder sachets, and split or
crushed tablets in apple sauce may be a last resort.
In the latter two cases, an evendistribution of active
compound and other inactive excipients must be
demonstrated. In addition, a lack of effect on bioa-
vailability must be proved if such advice is to
appear in the dosing instructions.Toxicology
The plastic nature of immature organs such as
kidney, liver, brain and lung may indicate the
need for more animal toxicology. Frequently,
neonatal acute and subacute toxicology studies
are undertaken in two animal species. Because
of the small size of both mouse and rat pups, this
may prove a challenge to administer the active
drug. The common ‘mixing with chow’ is inap-
propriate in neonates. Dog pups usually provide
one of the two species, so a special liquid formula-
tion for animals may be required (if the product is
intended for oral delivery), and given by dropper or
gavage.17.5 Clinical studies
Pharmacokinetics (PK)
The traditional PK study volunteer study in
healthy children has proved very hard to set up,
because of the attitude of many parents and over-
viewing independent review boards (IRBs). Even
in pediatric patients, the frequency and total
volume requirements for samples for conventional
PK studies can cause the same refusals. However,
there are pediatric research units that specialize
in these studies, with minimum needle sticks,
minute blood volumes and IRBs sympathetic to
the needs of the pediatric community. The National
Institute of Child Health and Human Development
has set up a ‘network of pediatric pharmacology
units’, usually in academic regional centers, now226 CH17 CLINICAL RESEARCH IN CHILDREN