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dependent upon functional CYP2D6 activity for conversion to the
pharmacologically active species, such as codeine and tramadol.
110,111
Infants
and children appear capable of converting codeine to morphine,
112
achieving
morphine-to-codeine ratios comparable to those of adults.
113
However, in one
study, morphine and its metabolites were not detected in 36% of children
receiving codeine, and codeine analgesia was found to be unreliable in the
studied pediatric population and not related to CYP2D6 phenotype.
114
At the
other end of the phenotypic spectrum, an ultrarapid metabolizer genotype and
phenotype has been associated with much greater morphine formation from
codeine than anticipated, with potentially fatal consequences. The index case
for this phenomenon was a child exposed to excessively high morphine
concentrations through breast milk from his codeine-treated mother with three
functional CYP2D6 alleles.
105
Since the initial case report, several additional
case reports and case series or morphine toxicity from codeine prescribed to
children have been reported. Due to the potential for both lack of efficacy and
serious adverse events, the U.S. FDA limits the use of codeine and tramadol to
patients older than 18 years (https://www.fda.gov/drugs/drug-safety-andavailability/fda-drug-safety-communication-fda-requires-labeling-changesprescription-opioid-cough-and-cold). CPIC guidelines for codeine and
tramadol have been published and updated,
115
but do not reflect the most recent
(2018) FDA recommendations.
In addition to the codeine example described above, CYP2D6
pharmacogenomics has been incorporated into dosing algorithms for additional
medications, including atomoxetine and pimozide. One of the more relevant
examples for pediatrics is atomoxetine, a nonstimulant drug used in the
treatment of attention-deficit/hyperactivity disorder (ADHD). Atomoxetine
pharmacokinetics is associated with CYP2D6 genotype, and increased
incidence of a number of adverse drug reactions have been observed in children
taking atomoxetine who are CYP2D6 poor metabolizers, but concern has also
been raised that extensive and ultrarapid CYP2D6 metabolizers may be at risk
for poor response and require doses greater than approved doses.
116
As such,
CPIC has published genotype-stratified guidelines for initial atomoxetine doses
in children, and time until dosage escalation can proceed.
117
The genotypestratified dosing recommendations for all CYP2D6-based CPIC guidelines are
based on the concept of activity score, an ordinal system that converts CYP2D6
genotype calls into a predicted phenotype based on the relative activity the
CYP2D6 protein encoded by the allelic variant, with values of “0” assigned to
nonfunctional alleles, such as *3, *4, *5, and *6; a value of “0.5” assigned to
partial function alleles *9, *17, *29, and *41; and a score of “1” assigned to
fully functional *1, *2, and *35 alleles.
118,119
Each allele in the diplotype is
assigned a value, such that poor-metabolizer individuals with two nonfunctional
alleles (e.g., CYP2D6 diplotypes such as CYP2D6*3/*4, CYP2D6*4/*6, or
CYP2D6*5/*5) are assigned an activity score of 0, whereas individuals with
diplotypes consisting of fully functional *1, *2, or *35 alleles (e.g.,
CYP2D6*1/*2, CYP2D6*2/*35) are assigned an activity score of 2. For gene
duplication/multiplication events, the allele value is multiplied by the number of
copies present: CYP2D6*1/*2x2 would be assigned an activity score of *1 = 1
plus *2×2 = 1×2 for a total activity score of 1+2 = 3. Similarly, a CYP2D6
diplotype of CYP2D6*4x2/*17 would have a score of 0×2 = 0 plus 0.5 for a
total score of 0.5. In 2019, the score assigned to *10 was downgraded from a
partial function allele with a value of 0.5 to a new value of 0.25,77 and a recent
study confirms that inclusion of structural variants in the calculation of the
activity score provides an improved estimate of activity from genotype data.
120
CYP3A4, CYP3A5, and CYP3A7
The CYP3A subfamily consists of four members in humans (CYP3A4,
CYP3A5, CYP3A7, and CYP3A43) and is quantitatively the most important
group of CYPs in terms of human hepatic drug biotransformation. These
isoforms catalyze the oxidation of many different therapeutic entities, several of
which are of potential importance to pediatric practice. CYP3A7 is the
predominant CYP isoform in fetal liver and can be detected in embryonic liver
as early as 50 to 60 days’ gestation.
121,122
CYP3A7 activity is maximal in the
early neonatal period with a progressive decline thereafter. In contrast,
CYP3A4 activity, the major CYP3A isoform in adults, is essentially absent in
fetal liver but increases during the first week of postnatal life.
123,124
CYP3A4 is
also abundantly expressed in the intestine where it contributes significantly to
the first-pass metabolism of orally administered substrates, such as midazolam
and tacrolimus.
125–127
Similar to the liver, the ontogeny of CYP3A4 protein
expression in the intestine has also been described as progressively increasing
in the first few years of life before plateauing to levels comparable to those
seen in adults.
128
Several methods have been proposed for CYP3A phenotyping, and the
advantages and limitations of each have been reviewed in detail.
38,39
Using these
various phenotyping probes, CYP3A4 activity has been reported to vary widely
(up to 50-fold) among individuals, but the population distributions of activity
are essentially unimodal and evidence for polymorphic activity has been
elusive. Several allelic variants have been identified
(https://www.pharmvar.org/gene/CYP3A4; see Table 5.1), but they occur
relatively infrequently, and data are conflicting regarding clinical significance.
One variant that has received attention is CYP3A4*22, originally reported as an
intronic SNP associated with improved clinical response to simvastatin, a
CYP3A4 substrate,
129
and subsequently reported to be associated with reduced
expression of CYP3A4 protein in vitro
130
and activity in vivo.
131
The potential
effect of CYP3A4*22 on tacrolimus exposure and response has been described
in several studies since the original report,
132
but currently, the CPIC guideline
for tacrolimus dosing does not include any recommendations CYP3A4*22
genotype.
133
Prospective studies will need to be conducted to validate whether
inclusion of CYP3A4*22 allele truly has a clinically meaningful role in
achieving appropriate systemic tacrolimus exposure. In the interim, the
Immunosuppressive Drugs Scientific Committee of the International Association
of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) has
recognized the potential importance of the *22 allele and recommend its
inclusion as a covariate of interest in future pharmacokinetic studies to
determine the drivers of interindividual variability in tacrolimus disposition
and guide dose selection.
134
Of interest to pediatrics is the CYP3A4*1B allele present in the CYP3A4
promoter region.
135,136
The clinical significance of this allelic variant appears
limited with respect to drug biotransformation activity,
137–139
despite being
associated with two-fold increased activity over the wild-type CYP3A4*1
allele in reporter gene assays in vitro.
140
Although there does not appear to be
an association between the CYP3A4*1B allele and age of menarche as recalled
in adulthood in one study,
141
a significant relationship does exist between the
number of *1B alleles and onset of puberty as defined by Tanner breast score
(odds ratio = 3.21; 95% confidence interval 1.62–6.89).
142
In this study, 90% of
9-year-old girls with a CYP3A4*1B/*1B genotype had a Tanner breast score ≥2
compared to 56% of CYP3A4*1A/*1B heterozygotes and 40% of girls
homozygous for the CYP3A4*1A allele. Since CYP3A4 plays an important role
in testosterone catabolism, the authors of the latter study proposed that the
estradiol-to-testosterone ratio may be shifted toward higher values in the
presence of the CYP3A4*1B allele and trigger the hormonal cascade that
accompanies puberty.
CYP3A5 is polymorphically expressed, being present in approximately
25% of adult liver samples studied in vitro.
143,144
Expression of CYP3A5 is
greatest in individuals of African ancestry, and loss of function in Caucasian
livers is largely due to an SNP in intron 3 that creates a cryptic splice site and
gives rise to splice variants that carry premature stop codons.
144
Even more so
than with CYP3A4, genetic polymorphisms in CYP3A5 have shown to be
associated with tacrolimus pharmacokinetics, but as with CYP3A4, IATDMCT
guidelines do not currently include CYP3A5 genotype in the dosage selection
process.
134
Conversely, the guidelines issued by CPIC call for increasing the
starting dosage of tacrolimus, in conjunction with TDM, in adult CYP3A5
intermediate and normal metabolizers relative to CYP3A5 nonexpressers.
133
While CPIC has not released official CYP3A5 genotype–guided
recommendations for tacrolimus dosing in the pediatric population, they
conclude that based on the available data, extrapolation of the adult
recommendations to children “seems appropriate.”
133
CYP3A7 is unusual in that it is expressed at high levels in human fetal
liver
124
and plays a critical role during pregnancy through the formation of the
16α-hydroxy metabolite of dehydroepiandrosterone sulfate (DHEA-S), the
process by which a third hydroxyl group is added to DHEA-S prior to final
formation of estriol by placental syncytiotrophoblasts. Other substrates of
CYP3A7 include retinoic acid and a wide range of foreign compounds that gain
access to the fetus from the maternal circulation. Many drugs prescribed during
pregnancy, such as glyburide for gestational diabetes, have been shown to cross
the placenta, and residual drug in the child following delivery may be
dependent on CYP3A7 for metabolic clearance.
145
Therefore, variability in
CYP3A7 activity following delivery may be a determinant of postnatal
hypoglycemia in neonates exposed to glyburide in utero. Genetic
polymorphisms have been identified in CYP3A7 that have yielded conflicting
results regarding their contribution to enzymatic function. A notable example is
the CYP3A7*2 allele that occurs at a relatively low frequency in Caucasians
(8%) and Asians (28%) compared with Africans (68%). Although the
CYP3A7.2 protein product has been associated with 20% to 25% higher
activity than the CYP3A7.1 enzyme in vitro,
146
no significant differences in
DHEA 16α-hydroxylation activity were observed in livers genotyped for
CYP3A7*1 and CYP3A7*2.
147
Given the recent observation of sex-dependent
effects of genetic variants in CYP3A4 and CYP3A7,
148
the functional
consequences of genetic variation in fetal liver CYP3A7 warrant further
investigation. Persistence of fetal CYP3A7 mRNA in adult liver has been
partially attributed to the CYP3A7*1C allele in which a set of seven tightly
linked variants essentially replace 60 bp of the CYP3A7 promoter with the
identical sequence from CYP3A4.
144
Glucuronosyl Transferases
The UGT gene superfamily catalyzes the conjugation of substrates with
glucuronic acid. The ontogeny of protein abundance for several UGTs in the
human liver has been characterized, with expression of UGT1A1, UGT1A4,
UGT1A6, UGT1A9, UGT2B7, and UGT2B15 all reported to increase with
age.
149
Both drugs and endogenous compounds
150
have been identified as
substrates for UGTs, and the implications of genetic variation in UGTs on drug
dosing have been extensively reviewed.
151
UGT1A1 is the major UGT gene
product responsible for bilirubin glucuronidation, and more than 60 genetic
alterations have been reported, most of which are rare and are more properly
considered mutations rather than gene polymorphisms. Inheritance of two
defective alleles is associated with reduced bilirubin-conjugating activity and
gives rise to clinical conditions such as Crigler-Najjar syndrome and Gilbert
syndrome. More frequently occurring polymorphisms involve a dinucleotide
(TA) repeat in the atypical TATA box of the UGT1A1 promoter. The wild-type
UGT1A1*1 allele has six repeats (TA6), and the TA5 (UGT1A1*33), TA
7
(UGT1A1*28), and TA8 (UGT1A1*34) variants are all associated with reduced
activity. UGT1A1*28 is the most frequent variant and is a contributory factor to
prolonged neonatal jaundice
152,153
and toxicity of the irinotecan-active
metabolite, SN-38.
154,155
Currently, the FDA recommends reductions in
irinotecan dose in patients who are homozygous for the *28 allele.
156
The
antiretroviral, atazanavir, is known to inhibit UGT1A1 and lead to
hyperbilirubinemia. This adverse event is more common in poor metabolizers,
presumably due to reduced basal UGT1A1-mediated clearance of bilirubin.
157
As such, CPIC has issued a recommendation that atazanavir not be used in
adults who possess two reduced function alleles.
158
While specific pediatric
recommendations are not included, they state that the adult guidelines may be
directly adapted to children.
158
Polymorphisms in UGT1A4 have also been identified, with the UGT1A4*2
allele resulting in the substitution of a proline to a threonine residue upstream of
the normal cleavage site for the formation of the mature protein. Diminished
catalytic activity has been observed for the mature UGT1A4*2 protein
product.
159
Conversely, another variant allele, UGT1A4*3, may have enhanced
activity of its mature protein product. The UGT1A4*3 allele has been
associated with increased glucuronidation of olanzapine and 25-hydroxyvitamin
D3.
160,161
However, one study evaluating the effects of the UGT1A4*3 allele on
dose-normalized concentrations of lamotrigine in children yielded conflicting
results, complicating the interpretation of the genotype–phenotype
relationship.
162
Several allelic variants of other important UGTs involved in
drug biotransformation (UGT1A6 and UGT2B7) have also been reported,
151
but
the lack of isoform-specific probe compounds analogous to dextromethorphan
for CYP2D6 has precluded a clear understanding of the clinical impact of
polymorphisms in these genes, with some exceptions80; issues related to
developmental trajectory adding further complexity to genotype–phenotype
associations. Nevertheless, from a pediatric perspective, genetic variation in
the promoter region of UGT1A9 has been reported to influence glucuronidation
of acetaminophen in newborns administered intravenous acetaminophen.
Specifically, insertion of an extra thymidine in a run of nine sequential
thymidine residues (T9) to form a T10 motif was associated in a 42% reduction
in the formation of acetaminophen glucuronide.
163
Expression of UGT2B17
protein is perhaps the most variable of the UGTs in children and adolescents,
being influenced by sex (~2.6-fold higher in males and females), age (minimally
expressed in children less than 9 years of age and increases during puberty),
and genetic variation (SNPs and CNV).
164
Its primary function is sex hormone
homeostasis, especially androgens such as testosterone and dihydrotestosterone.
Although a limited number of drugs are also UGT2B17 substrates, the
consequences of variable activity on clearances of these agents have not been
investigated in pediatric patients.
Arylamine N-Acetyltransferases
One the earliest discovered and most widely recognized genetic polymorphisms
is the arylamine N-acetyltransferase-2 (NAT2) polymorphism. Approximately
50% of Caucasians and African Americans residing on the North American
continent are phenotypically slow metabolizers placing a substantial number of
individuals at increased risk for the development of adverse drug effects, such
as sulfasalazine-induced hemolysis, hydrazine- or arylamine-induced peripheral
neuropathy, procainamide- or isoniazid-induced lupus erythematosus, and
Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN)
associated with sulfonamide administration.
165
NAT2 function is inherited in an
autosomal dominant manner with the inheritance of two “slow” alleles required
for expression of the slow-metabolizer phenotype. The relative proportion of
rapid and slow metabolizers varies considerably with ethnic or geographic
origin. For example, the percentage of slow acetylators among Canadian
Eskimos is 5% but approaches 90% in some Mediterranean populations.
166
According to the standardized NAT2 nomenclature, the wild-type and three
additional “fast” alleles give rise to the rapid acetylator phenotype, while nine
“slow” alleles have been described.
82
In vivo, using caffeine as a phenotyping probe, all infants between the ages
of 0 and 55 days appear to be phenotypically slow acetylators, while 50% and
62% of infants between the ages of 122 to 224 and 225 to 342 days,
respectively, can be characterized as fast acetylators.41 Several independent
studies indicate that maturation of the NAT2 phenotype occurs during the first 4
years of life.
40,167,168
Thus, phenotype–genotype discordance is likely to be most
apparent in the first 2 to 4 months of life, and drugs highly dependent on NAT2
function for their elimination should be used with caution.
Thiopurine S-methyltransferase
TPMT is a cytosolic enzyme that catalyzes the S-methylation of aromatic and
heterocyclic sulfur-containing compounds, such as 6-mercaptopurine,
azathioprine, and 6-thioguanine, that are used in the treatment of several
pediatric diseases and disorders including acute lymphoblastic anemia (ALL),
inflammatory bowel disease, and juvenile arthritis and to prevent renal allograft
rejection. To exert its cytotoxic effects, 6-mercaptopurine requires metabolism
to thioguanine nucleotides (TGNs) by a multistep process that is initiated by
hypoxanthine guanine phosphoribosyl transferase. TPMT prevents TGN
production by methylating 6-mercaptopurine (Fig. 5.5A). TPMT activity is
usually measured in blood with activity in erythrocytes reflecting that found in
other tissues, including liver and leukemic blasts. While approximately 89% of
Caucasians and African Americans have high TPMT activity and 11% have
intermediate activity, 1 in 300 individuals inherit TPMT deficiency as an
autosomal recessive trait (Fig. 5.5B).83 In patients with intermediate or low
activity, more drug is shunted toward production of cytotoxic TGNs. TPMT can
also methylate 6-thioinosine 5′-monophosphate (TIMP) to generate a methylated
metabolite that is capable of inhibiting de novo purine synthesis (Fig. 5.5C).
Figure 5.5 The 6-thioinosine 5′-monophosphate (TPMT) polymorphism. A: 6-Mercaptopurine (6MP)
undergoes metabolism to thioguanine nucleotides (TGNs) to exert its cytotoxic effects. TPMT and xanthine
oxidase reduce the amount of 6MP available for the bioactivation pathway to TGNs. TPMT can also
methylate TIMP to generate a methylated compound capable of inhibiting de novo purine synthesis. B :
Distribution of TPMT activity in humans. In all, 89% of the population has high activity, while 11% have
intermediate activity. Approximately 1 in 300 individuals. A is homozygous for two loss of functional alleles
and thus has very low activity. C: Correlation between TPMT genotype and intracellular TGN
concentrations. In TPMT poor metabolizers, more 6MP is available to go down the bioactivation pathway to
form TGNs and is associated with an increased risk of myelosuppression. D: The most common variant
TPMT allele is the result of two mutations that give rise to an unstable protein product that undergoes
proteolytic degradation. (Modified with permission from Nature Reviews Cancer 1:99–108 copyright 2001,
Macmillan Magazines Ltd; Kim SH, Kim M, Lee KW, et al. HLA-B*5901 is strongly associated with
methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Pharmacogenomics
2010;11:879–884.)
Conflicting relationships between age and TPMT activity have been
reported in children. In one study, peripheral blood TPMT activity in newborns
was reported to be 50% greater than in race-matched adults and demonstrated a
distribution of activity consistent with the polymorphism characterized in
adults.
169
In contrast, TPMT activities were comparable to previously reported
adult values in a population of Korean school children (n = 309) aged 7 to 9
years
170
and in French Caucasian children (n = 165) hospitalized for day
surgery.
171
Considerable interindividual variability in TPMT activity exists for
both pediatric and adult populations consistently, with genetic variation being
the primary driver of the observed variability.
Several genetic variants contribute to the TPMT poor-metabolizer
phenotype. The *2, *3A, *3B, *3C, and *4 alleles are all considered
nonfunctional and clinically actionable under CPIC thiopurine dosing
guidelines.
172
Although the *3A allele has only a frequency of 0.03% in the
general population, it is the most common variant and represents 55% of all
mutant alleles. TMPT*3A is characterized by two nucleotide transition
mutations, G460A and A719G, that lead to two amino acid substitutions
Ala154Thr and Tyr240Cys (Fig. 5.5D). Either variant alone results in loss of
functional activity through the production of unstable proteins that are subject to
accelerated proteolytic degradation.
173,174
Less frequent allelic variants involve
SNPs that produce amino acid substitutions in the coding region and defective
intron–exon splicing.
A polymorphic locus has been identified in the promoter region of the
TPMT gene involving a variable number of tandem repeats (VNTR) in which
three to nine repeats of a specific nucleotide sequence occur in tandem.
175,176
The VNTR polymorphism modulates TPMT activity when expressed in vitro,
177
apparently by a mechanism involving gene transcription.
178
In vivo, the VNTR