The elimination rate of paracetamol from plasma is close to the adult rate which
may be explained by the compensatory neonatal sulphation pathway which is
operative already du ring the mid-gestational part of foetal development (see above).
Such a quantitative switch between parallel metabolic pathways in different age
groups has been reported also for salicylic acid (Garrettson, Procknal & Levy, 1975).
Pharmacokinetic research in recent time was preceeded ever since the nineteenth
century by much discussion and many suggestions how to dose a drug in the
paediatric patient. The number ofsuggestions testify that this question is complex.
There is still no universal dosage rule that can be recommended. When age is used
as the basis for the dose great errors may be introduced since there is a large
variability in weight between children ofa given age, even ifthey are 'normal'.
have seldom been appropriate. If infants are dosed on the basis of their weight with
the adult dose as standard, they will be underdosed. As a corollary, the adult patient
will be overdosed when the infant dose is used as a standard.
A better estimate ofthe appropriate paediatric dose is given by the 'surface rule'.
Accordingly, the dose is adjusted to the surface area of the individual. The surface
area is greater relative to volume and weight in small individuals than in large. As the
child grows the weight increases and so does the surface area albeit at a slower rate. It
follows that large persons have relatively small surface areas whereas the converse is
true for small persons. In other words , the infant's surface area is greater than would
be expected from his weight and so will the dose ofthe drug be according to this rule .
The surface area may be estimated from the bod y weight and height in nomograms
calculated to follow thc weight to the 0.7 power (Daw son , 1940; Gyllenswärd &
A convenicnt table for calculation of the numerical values of paediatric drug doses
according to the 'surface rule' has been published (Rane, 1978). This rule may be used
for the titration of the initial dose without any clinically important error. However,
it may only scrve as a guide-line and the dose must always be individualized on the
basis ofthe therapeutic response and plasma level monitoring, ifthis is employed.
The rationale for using the 'surface rule' is not completely understood. There is,
however, a close relation between on one hand the 'surface area ' and on the other
many ph ysiological parameters for example cardiac output, rcspiratory metabolism,
blood volume, extracellular water volume, glomerular filtration and renal blood
flow. Man y ofthese have direct or indirect importance for the disposition ofdrugs.
Table 4 Some drugs which are usually given in higher doses (on a weight basis) to children
Many drugs (Table 4) are dosed in children approximately according to the
'surface rule', This is to say that the dose is relatively greater than to adults when
based on the bod y weight. Larger weight related doses of phenytoin are required to
infants (Jalling, Boreus, Rane & Sjöqvist, 1970) and children below the weight of 30
kg (Svensmark & Buchthal, 1964) in order to achieve the same Css as in adults. This
could be explained by a larger Vd but this was ruled out in studies by Loughnan,
Watters, Aranda & Neims (1976) who found similar values of Vd in infants below 4
day s of age, infants between 3 and 96 weeks of age, and adults. The most plausible
explanation is therefore an increased rate of metabolism of this drug at low ages.
Several pharmacokinetic data in the literature (for a review, see Rane & Wilson,
1976) lend support to this theory. A poorer absorption could also contribute to the
low pla sma level-dose relation in ch ildren, although this explanation seems less
Phenobarbitone is also given to infants and children in about twice as high doses as
to adults (Goodman & Gilman, 1975; Nelson, Vaughan & McKay, 1975; Shirkey,
1973). These dose recommendations are commensurate with the early observation
that the plasma level-dose relationship increased with increasing age when the
patients were grouped according to weight (Svensmark & Buchthal, 1964). Similar
observations were also reported by Morselli (1977). These findings may be explained
on the basis of a more rapid clearance and/or a large apparent Vd at low ages,
adults (Morselli, 1977). Therefore, the lower plasma level-dose ratios in infants is
probably due to increased clearance ofthis drug.
The plasma level-dose relationship for carbamazepine was also shown to be lower
in children than in adults (Morselli, 1977). Higher weight-related doses to children
are particularly recommended when the child is on a combined antiepileptic drug
treatment since the average carbamazepine plasma level then is lower than when
carbamazepine is the single drug (Rane, H öjer & Wilson, 1976). Short T'I, (Rane,
Bertilsson & Palmer, 1975; Rane er al., 1976) in ch ildren have been implicated to
reflect a more rapid metabolism of carbamazepine in this age group as compared to
adults. With the use of stable isotope labelIed carbamazepine it was also shown
recently (Bertilsson, H öjer, Tybring, Osterloh & Rane, 1980) that autoinduction of
carbamazepine is pronounced in children. It is discemible already after I day's
treatment and reaches a maximum after several weeks' treatment. The
interindividual variation in carbamazepine metabolism, the autoinduction, and the
The relation between the therapeutic plasma concentration range and the optimal
effect has been incompletely investigated.in children because of ethical and practical
problems and most importantly, difficulties in finding objective measures for
measuring drug effects. When the therapeutic plasma level range is known it is of
great clin ical aid to monitor the drug concentration (Css). Before the correct
interpretation of the Css value can be made it must be ascertained that the blood
sampie was drawn at the end ofthe dosing interval in order to avoid the larger varia-
DRUG METABOLISM IN THE YOUNG 105
tion in plasma concentration in the postabsorptive phase. Secondly, 4-5 half-lives
should have elapsed after the start ofthe treatment or change of dose for a new Css to
be established. It must also be ascertained that the patient has taken the drug as
It is evident that estimation of drug metabolie capacity in infants and children is
investigations in infants and children to a greater extent than hitherto. Increased
pharmacokinetic knowledge is important not only as a basis for a rational drug
therapy but also for evaluating the effect of different disease states on the disposition
ofdrugs in infants and children.
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