Epilepsia, 43(Suppl.
3):53–59, 2002
Blackwell Publishing, Inc.
© International League Against Epilepsy
Children Versus Adults: Pharmacokinetic and
Adverse-Effect Differences
Gail D. Anderson
Department of Pharmacy, University of Washington, Seattle, Washington, U.S.A.
Summary: Pharmacokinetic differences may play a part in the
age-related differences in the incidence of adverse effects. The
most common idiosyncratic reaction to lamotrigine (LTG) is
rash, affecting 10–20% of patients. Risk factors are young age,
concurrent valproate (VPA), high starting dose, and rapid
escalation. In children, cytochrome P450 (CYP)-catalyzed me-
tabolism is increased, and uridine diphosphate (UDP)-
glucuronosyltransferase (UGT)-catalyzed metabolism is not
significantly different from that in adults. A CYP-catalyzed
arene oxide intermediate of LTG has been identified. The in-
crease CYP metabolism of LTG in children could result in
increased formation of the reactive metabolite and a higher
incident of rash. Children often received higher milligram per
kilogram doses compared with adults. The higher dose would
cause an increased amount of LTG metabolized to the reactive
arene oxide intermediate. VPA therapy is associated with a
transient elevation in liver-function tests in 15–30% of patients
Many physiologic differences between neonates, in-
fants, children, and adults can affect the absorption, dis-
tribution, metabolism, and excretion of antiepileptic
drugs (AEDs) (Table 1). The purpose of this article is to
(a) provide a brief review of the pharmacokinetic differ-
ences between children and adults, and (b) to theorize
how pharmacokinetic differences may play a part in the
age-related differences in the incidence of adverse ef-
fects. Two idiosyncratic reactions, lamotrigine (LTG)
rash and valproate (VPA) hepatotoxicity are discussed.
For further information about the effects of age on the
pharmacokinetics of AEDs, Battino et al. (1,2) recently
published an extensive review of the pharmacokinetics
of the AEDs in children.
EFFECT OF AGE ON PHARMACOKINETICS
IN CHILDREN
Absorption
Neonates and infants undergo significant maturation
changes in gastric and intestinal pH, gastrointestinal (GI)
Address correspondence and reprint requests to Dr. G. D. Anderson
at Department of Pharmacy Box 357630, University of Washington,
Seattle, WA 98195, U.S.A. E-mail: gaila@u.washington.edu
53
and a rare, fatal hepatotoxicity. Most cases of VPA hepatotox-
icity occurred in children younger than 2 years who had pre-
existing neurologic or other physical defects. Hypotheses
regarding the pathogenesis of the hepatotoxicity include pre-
existing mitochondrial disease or inborn errors of metabolism,
VPA inhibition of ␤-oxidation, and toxicity from VPA metabo-
lites VPA, 4-ene-VPA, and 2,4-diene-VPA. Infants and chil-
dren have higher concentration ratios of 4-ene-VPA to VPA.
Polytherapy with enzyme inducers increases the formation of
the hepatotoxic metabolites. The role of underlying metabolic
disorders associated with hepatodegeneration and intractable
seizures without VPA is a major confounder in identifying risk
factors and demonstrates the difficulty in separating underlying
disease factors in rare idiosyncratic reactions. Key Words: An-
tiepileptic drugs—Pharmacokinetics—Children—Lamotrigine—
Valproate.
emptying time, circulation, enzyme activity, and differ-
ence in GI flora (3,4). However, because of a lack of
clinical studies, relatively little is known regarding the
effects of GI maturation on the rate and extent of ab-
sorption of drugs. There are case reports of possible de-
creased and erratic absorption of phenytoin (PHT) and
phenobarbital (PB) in neonates (5).
Distribution
The plasma concentration that results from a loading
dose of a drug is inversely proportionate to the volume of
distribution (Vd) of a drug. Age-related changes in Vd
will alter loading doses. In neonates and infants, in-
creased total body water–to–body fat ratio, decreased
plasma-binding proteins (albumin and ␣ 1 -acid-
glycoprotein), and differences in tissue binding can alters
the volume of distribution (Vd) of drugs (3,4). The di-
rection of the change (i.e., increase or decrease in Vd)
will depend on the physiochemical characteristics of the
drug. The Vd of PB and PHT is larger in neonates than in
older infants and children (5), whereas the Vd of diaze-
pam (DZP) and lorazepam (LZP) is approximately the
same. Therefore, neonates will need larger loading doses
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54 G. D. ANDERSON

TABLE 1. Age effects on pharmacokinetic parameters biotics including LTG. The UGT2 family is more in-
(compared with adult values) volved in the glucuronidation of endobiotics including
Neonates/Infant Children Adults steroids and bile acids, but also some drugs, like VPA
and morphine. Unlike the CYPs, there is considerable
Renal ⇓ ⇔ ⇔
Metabolism overlap in substrate selectivity between the human
CYP ⇓ ⇑ ⇔ UGTs. In most cases, multiple UGTs can catalyze the
UGT ⇓ ⇔ ⇔ conjugation of one substrate. UGT1A4 is an exception.
Albumin ⇓ ⇔ ⇔
UGT1A4 is the only UGT isoform that catalyzes the
CYP, cytochrome P450; UGT, uridine diphosphate, glucuronosyl formation of quaternary ammonium-linked glucuronides,
transferase.
including lamotrigine (10).
The influence of age on hepatic metabolism is depen-
(mg/kg) of PHT or PB to attain similar therapeutic con- dent on the family of enzymes involved. The develop-
centrations as an adult; loading doses of LZP or DZP mental pattern of the CYPs is significantly different from
should be the same. that of the UGTs. CYP-dependent metabolism is low at
The decreased protein binding alters the ratio of un- birth, ∼50–70% of adult levels; however, by 2–3 years,
bound to total plasma concentrations for the highly enzymatic activity exceeds adult values (3,4). Therefore,
protein-bound AEDs, PHT, and VPA. In the neonates young children have an increased ability (greater than
and young infants, total concentrations are not reliable that of adults) to metabolize drugs eliminated by CYP-
for therapeutic drug monitoring and will underestimate dependent metabolism. By puberty, CYP enzymatic ac-
the unbound or active concentration of AEDs. For PHT, tivity has decreased to adult levels. Clinical studies with
unbound plasma concentrations are needed to prevent drugs metabolized predominantly by different CYP iso-
dose-dependent adverse events. zymes suggest that the increase in activity occurs with
several of the CYP isozymes, including CYP1A2,
Elimination
CYP2C, and CYP3A. Carbamazepine (CBZ) is predomi-
Elimination occurs by either renal excretion of un-
nantly metabolized to its active metabolite, carbamaze-
changed parent drug or hepatic biotransformation to both
pine epoxide (CBZE). The formation of CBZE is
inactive and active metabolites. Renal function is ∼25–
catalyzed by CYP3A4 with minor metabolism by
30% of adult values at birth, increases to 50–75% by 6
CYP1A2 and CYP2C8 (11). Children have an increased
months, and reaches full maturation by age 2–3 years
total body clearance and higher CBZE-to-CBZ ratio
(3,4). Doses of drugs excreted predominantly unchanged
compared with adults (Table 2) (2,12). PHT is eliminated
by the kidneys will need to be reduced for neonates and
predominantly by CYP2C9- and CYP2C19-dependent
infants to prevent adverse effects.
hepatic metabolism to its primary inactive metabolite,
Metabolism para-hydroxyphenytoin (HPPH) (13). Young children
Biotransformation of most of the commonly used have a significantly higher mean Vmax (maximal rate of
AEDS is catalyzed by the cytochrome P450 (CYP) and metabolism) than adults, which progressively declines
uridine diphosphate glucuronosyltransferase (UGT) en- during childhood to reach adult levels at after puberty
zymes. Some of the more recently released AEDs [gaba- (Table 3).
pentin (GBP), levetiracetam, oxcarbazepine (OCBZ), Mechanistically, it is unclear as to why metabolic
and zonisamide (ZNS)] are eliminated by renal, mixed, clearance is higher in children than in adults with drugs
and non-CYP or UGT pathways. CYPs are a family of
multiple enzymes, with the individual isozymes being
composed of three major families (CYP1, CYP2, and TABLE 2. Effect of age on the ratio of carbamazepine
CYP3). Eight primary isozymes are involved in the he- epoxide to carbamazepinea
patic metabolism of most drugs: CYP1A2, CYP2A6, Mean ± standard
CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and Age groups No. Formulation deviation Reference
CYP3A4 (8,9). The most abundant isozyme, CYP3A4, 2 wk–1 yr 6 Variable 0.44 ± 0.2 Korinthenberg
which accounts for ∼30% of the total hepatic CYP (8), et al.a (12)
1–5 yr 9 0.28 ± 0.1
has the broadest substrate specificity and is involved in 5–10 yr 23 0.24 ± 0.1
the metabolism of >50% of all drugs (9). UGTs are a 11–15 yr 14 0.18 ± 0.1
family of enzymes that catalyze the transfer of a gluc- 1–7 yr 15 Syrup 0.30 ± 0.04 Lanchote
et al. (55)
uronic acid moiety from a donor cosubstrate UDGP-GA 1–7 yr 5 Tablet 0.20 ± 0.01
to an aglycone. The UGT family can be separated into 8–15 yr 4 Syrup 0.13 ± 0.02
two distinct families, UGT1 and UGT2, with eight iso- 8–15 yr 7 Tablet 0.23 ± 0.08
>15 yr 24 Tablet 0.16 ± 0.01
zymes identified in each family. UGT1A isozymes are
capable of glucuronidating a variety of drugs and endo- a
Also include 16 receiving polytherapy.

Epilepsia, Vol. 43, Suppl. 3, 2002


ADVERSE-EFFECTS DIFFERENCES IN CHILDREN
TABLE 3. Effect of age on phenytoin pharmacokineticsa
Age (yr) No. Vmax (mg/kg/day) Km (␮g/ml)
0–3 12 18.3 ± 9.9 6.6 ± 10.3
4–6 7 18.5 ± 7.5 13.9 ± 0.4
7–9 9 10.1 ± 5.4 9.1 ± 8.7
10 ± 18 8 11.9 ± 5.3 13.1 ± 8.9
a
Suzuki Y, et al. (56).
catalyzed by the CYPs. A study evaluating maximal
catalytic activity of six CYP isozymes, CYP1A2,
CYP2E1, CYP3A4/3A5, CYP2C8, and CYP2C9, did not
find a difference in activity in pediatric liver (younger
than 10 years) compared with adult livers (14). Small
studies also failed to demonstrate a relation between age
and hepatic microsomal P450 activity (8). Similarly, a
lack of association between age and maximal catalytic
activity in elderly versus younger adults has been noted,
even though CYP activity levels decline in the elderly
(15,16). The increased ratio of liver size to body size in
children has been proposed as a possible explanation for
the increased metabolic activity. However, this does not
explain the differential effect on UGTs compared with
CYPs.
Neonates have deficient glucuronidation ability at
birth due to low levels of UGTs, which appear to reach
adult levels by at least age 3–4 years (17). Very few
studies demonstrated the approximate age of maturation.
Studies with morphine have found that the formation of
morphine glucuronide reaches adult levels by 6 months
to 2.5 years (18). LZP is eliminated predominantly by
glucuronide conjugation. Neonates have a significantly
decreased clearance (7,19). LZP metabolic clearance in a
group of children aged 7–19 years was found to be ap-
proximately the same as that reported in adults (20). LTG
is extensively metabolized by UGT1A4 to the 2-N and
5-N glucuronide metabolites, which account for the ma-
jority of the dose recovered in the urine (10). Studies
with LTG reported conflicting results regarding age-
related effects on total clearance. Some studies reported
a trend toward a decreased concentration-to-dose ratio in
children compared with adults; however, few of the chil-
dren were receiving LTG monotherapy (21). The con-
founding effect of induction potential on age is not
known. Studies with VPA in children receiving poly-
therapy have shown that children may have significantly
higher levels of induction than do adults (22,23). There
was no correlation with age and VPA dose/concentration
ratios in children receiving VPA monotherapy (22). It is
possible that lower LTG concentration/dose ratios in
children taking enzyme-inducing drugs are explain by an
age-related increased induction of the UGT enzymes
compared with that in adults. Chen et al. (24) compared
the oral clearance in a group of 12 children in the absence
of other AEDs after a single dose of LTG. Even though
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55
there was a trend toward an increased oral clearance
(Cl/F) in the four children younger than 6 years (0.5–1.1
ml/min/kg) compared with the eight children aged 6–11
years (0.18–0.88 ml/min/kg), there was large intersubject
variability. Overall, the single-dose Cl/F in the children
was 0.64 ± 0.26 ml/min/kg. This was not significantly
different from the Cl/F found after single-dose LTG in
normal subjects in several studies (Table 4) (25–28).
VPA is another AED that undergoes extensive me-
tabolism, with <5% of the dose exceted unchanged in the
urine (29). Major metabolism occurs by UGT-catalyzed
glucuronide conjugation and ␤-oxidation, with minor
CYP-dependent metabolis (29). VPA plasma clearance is
increased in young children compared with that in adults;
however, glucuronidation does not appear to be respon-
sible for the increased clearance. Reith et al. found that
the proportion of dose recovered as VPA glucuronide in
children less than 10 years was lower, not greater, than in
children greater than 10 years (30). Other investigators
found an increase in the formation of oxidative metabo-
lites of VPA in children compared with adults (31), but
the data are limited. In summary, UGT-catalyzed me-
tabolism of the AEDs does not appear to be significantly
increased in children.
LAMOTRIGINE AND RASH
The most common idiosyncratic reaction to LTG is
rash, affecting 10–20% of patients. The rashes typically
are maculopapular or morbilliform in appearance and
occur generally within 2–6 weeks of initiating therapy.
Risk factors for the rash are young age (children), con-
current VPA therapy, high starting dose, and rapid esca-
lation (32). Schlienger et al. (33) reviewed the
descriptions of case reports of 26 patients and concluded
that the characteristics of the syndrome associated with
LTG were consistent with the anticonvulsant hypersen-
sitivity syndrome, also induced by CBZ, PHT, and PB.
Studies in rats have demonstrated formation of a reactive
arene oxide intermediate whose formation is blocked by
the CYP450 inhibitor, ketoconazole (Fig. 1) (34). In a
TABLE 4. Effect of age on lamotrigine clearance:
single-dose monotherapy
Mean ± SD (range)
No. ml/min/kg Reference
Children
3.8–5.9 yr 4 0.82 ± 0.25 (0.5–1.1) Chen et al. (24)
6–11.3 yr 8 0.55 ± 0.22 (0.18–0.88)
Adults
35–57 yr 11 0.50 ± 0.11 Wooten et al. (57)
20–32 yr 6 0.37 ± 0.11 Yuen et al. (58)
26–36 yr 12 0.59 ± — Posner et al. (26)
19–61 yr 9 0.61 ± 0.10a Posner et al. (27)
19–61 yr 10 0.58 ± 0.14a Cohen et al,. (25)
a
Data corrected for mean body weight (kg).
Epilepsia, Vol. 43, Suppl. 3, 2002

56 G. D. ANDERSON
case report of a patient in whom a febrile maculopapular
exanthema and later desquamation of the face developed
1 month after being started on LTG therapy (with con-
current VPA), a lymphocyte stimulation test was positive
FIG. 2. Proposed mechanism for increased incidence of la-
motrigine (LTG) rash in patients receiving concurrent valproate
(VPA). VPA inhibits the UGT1A4-catalyzed formation of LTG-
glucuronide (1), resulting in an increased LTG concentration-to-
dose ratio (2) and increased fraction of the LTG dose (3)
available to be metabolized to the arene oxide intermediate (4),
and results in an increased rash (5).
Epilepsia, Vol. 43, Suppl. 3, 2002
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FIG. 1. UGT1A4-catalyzed metabolism of la-
motrigine (LTG) (a) to LTG glucuronide (b) and cy-
tochrome P450 (CYP)-dependent formation of an
arene oxide intermediate (c). Biliary metabolites (d,
e) recovered in rats administered [14C]LTG and glu-
tathione (GSH). Adapted from Maggs et al. (34), with
permission.
(35). This assay has been used to assess the risk of other
anticonvulsant hypersensitivity reactions to CBZ, PHT,
and PB (36) and suggests a similar mechanism for the
LTG hypersensitivity syndrome.
As shown in Fig. 2, VPA inhibition of the UGT1A4
catalyzes the formation of LTG N-glucuronides and in-
creases the fraction of the LTG dose that can be me-
tabolized to the reactive arene oxide intermediate. This
can result in increased incidence of rash. Concurrent
administration of the enzyme-inducing AEDs (CBZ,
PHT, PB) is associated with an increased incidence of
rash compared with LTG monotherapy; but less than the
incidence found in patients receiving VPA plus LTG.
The enzyme-inducing AEDs induce both CYPs and
UGTs; however, the induction of CYPs is significantly
greater than that of UGTs. Therefore, there would still
be an increased fraction of the LTG dose that can be
metabolized to the reactive arene oxide intermediate
compared with that with LTG monotherapy (Fig. 3).
In children, UGT-catalyzed metabolism of LTG is not
significantly different from that in adults; however,
CYP metabolism is in general increased. As the CYP
pathway is a minor pathway, an increased in CYP me-
tabolism would not result in an increased total body

ADVERSE-EFFECTS DIFFERENCES IN CHILDREN
FIG. 3. Proposed mechanism for increased incidence of la-
motrigine (LTG) rash in patients receiving concurrent enzyme
inducers compared with LTG monotherapy and decreased inci-
dence compared with LTG/valproate polytherapy. Broad-
spectrum enzyme inducers increase cytochrome P450 activity
greater than UGT activity (1), resulting in an increased fraction of
LTG dose (2) available to be metabolized to the arene-oxide
intermediate (3) and increased rash (4).
clearance of LTG. However, the increased CYP metabo-
lism of LTG in children could result in increased forma-
tion of the reactive metabolite and therefore a higher
incidence of rash (Fig. 4). A confounding factor is that
children received higher milligram-per-kilogram doses
compared with adults in the clinical trials because of the
lack of the 5-mg formulation of LTG (37). The higher
dose also would cause a higher amount of LTG to be
metabolized to the reactive arene oxide intermediate.
One possible hypothesis for the effect of rate of esca-
lation on the incidence of rash is the role of the time-
dependent autoinduction by LTG. LTG induces its own
UGT metabolism (autoinduction) as well as VPA gluc-
uronidation. In a study of 18 normal volunteers, Yau et
al. (28) found that the elimination half-life of LTG de-
creased by 25%, and the oral plasma clearance increased
by 37% after 14 days of LTG treatment. Coadministra-
FIG. 4. Proposed mechanism for increased incidence of la-
motrigine (LTG) rash in children compared with adults. Children
with increased cytochrome P450 activity and approximately the
same UGT activity compared with adults (1); results in an in-
creased fraction of the LTG dose metabolized to the arene oxide
intermediate (2), and increased incidence of rash (3).
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57
FIG. 5. Proposed mechanism for decreased incidence of la-
motrigine (LTG) rash in patients in whom therapy is initiated
slowly. LTG induces UGT1A4 (1), resulting in an increased LTG-
glucuronide formation (2), and decreased LTG available (3) to
form the reactive arene oxide intermediate (4), and decreased
incidence of rash (5).
tion of LTG also results in an increase in VPA clearance
by ∼25% (38) and an increased excretion of VPA gluc-
uronide (30). Mechanistically, starting with a lower dose
of LTG and increasing at a slow rate would allow time
for the autoinduction of UGT metabolism of LTG to the
nontoxic N-glucuronide metabolites. This would then re-
sult in a lower fraction of the dose metabolized to the
reactive metabolite (Fig. 5). Other immune-mediated
mechanisms also may explain the role of initial dose and
rate of escalation.
Even though the hypersensitivity syndrome induced
by LTG is similar to that reported for CBZ, PHT, and PB
(33), children do not have a higher incidence of rash with
the older AEDs. One hypothesis for the difference be-
tween LTG and the older AEDs is demonstrated in Fig.
6. For CBZ, PHT, and PB, total body clearance through
major pathways of elimination are increased in children
compared with adults. This is in contrast to the lack of a
significant difference in LTG total body clearance be-
tween children and adults. Therefore, for CBZ, PHT, and
PB, the fraction of the AED available for metabolism to
the reactive arene oxide intermediate in children may not
be increased compared with that in adults.
VALPROATE AND HEPATOTOXICITY
VPA therapy is associated with both transient eleva-
tion in liver-function tests in 15–30% of patients and a
rare, fatal hepatotoxicity (39). The typical histologic
findings are microvesicular steatosis accompanied by ne-
crosis of hepatocytes. Most cases of VPA hepatotoxicity
occurred in children younger than 2 years who had pre-
existing neurologic or other physical defects. Many were
developmentally delayed. A precipitating illness, possi-
bly viral, occurred in many children. Dreifuss et al. (40)
demonstrated that both age and polytherapy are associ-
ated with significantly increased prevalence, and both
Epilepsia, Vol. 43, Suppl. 3, 2002

58 G. D. ANDERSON
risk factors have continued to be reported in subsequent
cases worldwide (41–44). There have been many hypoth-
esis regarding the pathogenesis of the hepatotoxicity in-
cluding preexisting mitochondrial disease or inborn
errors of metabolism (45), VPA inhibition of ␤-oxidation
(46), and toxicity from the unsaturated metabolites of
VPA, 4-ene-VPA and 2,4-diene-VPA (47). Infants and
children have higher concentration ratios of 4-ene-VPA
to VPA (48). Polytherapy with enzyme inducers in-
creases the formation of the hepatotoxic metabolites
(49). There is a case report of fatal VPA hepatotoxicity in
a patient with medium acyl-coenzyme A (CoA) dehy-
drogenase (MCAD), one of the more common inborn
errors of metabolism (50). VPA has been shown to in-
hibit four types of the MCAD enzymes involved in
branched-chain amino acids, short and medium chain
fatty acids in patients receiving VPA monotherapy, and
polytherapy with CBZ or PHT without evidence of hep-
atotoxicity (51). A recent case report described an adult
with a mitochondrial disorder, chronic progressive exter-
nal ophthalmoplegia (CPEO), who was treated with
VPA, which resulted in a fatal hepatotoxicity (52). In
several of the children with fatal VPA-induced hepato-
toxicity, their precipitating factor may have been viral
infection. Stephens et al. (53) demonstrated that VPA
enhances the lethality of tumor necrosis factor ␣ (TNF␣)
in rats. The role of underlying metabolic disorders asso-
ciated with hepatodegeneration and intractable seizures
without VPA is a major confounder in identifying risk
factors and demonstrates the difficulty in separating un-
derlying disease factors and drug effects in rare idiosyn-
cratic reactions. Bickenese (54) described four unrelated
children with early childhood hepatocerebral degenera-
tion misdiagnosed as VPA hepatotoxicity and two sib-
lings with a related diagnosis without exposure to VPA.
Appleton et al. (45) described two unrelated children in
whom liver failure developed while receiving VPA, with
Epilepsia, Vol. 43, Suppl. 3, 2002
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FIG. 6. Proposed mechanism for children not hav-
ing an increased incidence of rash while receiving
the traditional antiepileptic drugs (carbamazepine,
phenytoin, phenobarbital). In children, the major
pathways of elimination also are induced, resulting
in little or no change in the arene oxide intermediate.
Metabolic scheme adapted from Shear et al. (36),
with permission.
siblings in whom hepatic steatosis and intractable sei-
zures also developed without being exposure to VPA. If
patients were screened for underlying metabolic disor-
ders, the use of VPA in young children without concur-
rent metabolic disease might be safer than originally
estimated.
In conclusion, children are at a higher risk of some
idiosyncratic reactions. Age-related changes in pharma-
cokinetics may play a role in some cases. Age-related
immunologic differences and underlying diseases are im-
portant factors to be considered.
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