Discussion
The present study showed that CYP2D6 genotype has a great impact
on atomoxetine exposure, where IM and PM patients have 1.9-fold and
9.6-fold higher serum concentrations of atomoxetine per mg dose compared
to NMs/UMs. When adding CYP2C19 genotype as a factor of relevance for
personalised atomoxetine dosing, CYP2C19*2 carriers had 1.5-fold
higher serum concentrations of atomoxetine per mg dose than non-carriers
regardless of CYP2D6 genotype. CYP2D6 PMs and IMs carrying theCYP2C19*2 allele should have doses equivalent to ≤10% and 35%
of the normal starting dose, respectively, to target the same exposure
as CYP2D6 NMs not carrying the CYP2C19*2 allele. These findings
suggest that pre-emptive genotyping of CYP2D6/CYP2C19 should be
performed to individualise atomoxetine dosing and minimise the risk for
adverse effects.
According to CPIC dosing recommendations for
atomoxetine12, dosing for CYP2D6 PMs should be reduced
to approximately half of the approved dose in the product label
information. Our study, however, suggests that an even lower dose (i.e.,
≤10% of the starting dose) should be used in CYP2D6 PMs to avoid
potential dose-dependent adverse effects. In practice, starting dose
selection will be limited by available formulation and lowest available
dose, with only oral solution forms suitable for the lowest doses.
Further, our study suggests that for CYP2D6 IMs, a dose reduction
equivalent to 50% of the recommended dose should be considered to
target the same drug exposure as NMs, consistent with results from a
previous study18. An even larger dose-reduction is
warranted if the CYP2D6 PMs and IMs are carrying the CYP2C19*2allele (dose reduction of ≥90% and 65%, respectively), compared to
CYP2D6 NMs not carrying the CYP2C19*2 allele. There was no
significant interaction effect between the various CYP2D6 genotype
subgroups and CYP2C19*2 allele carriers (p≥0.13), thus,
indicating an additive effect on atomoxetine exposure ofCYP2C19*2 allele variant carriers regardless of CYP2D6 genotype.
In addition, our study shows that the quantitative differences in
atomoxetine exposure between the various CYP2C19 andCYP2D6 genotypes were similar regardless of age. In patients who
are CYP2D6 UM, very limited data exists, but it is unlikely these
patients would achieve adequate serum concentrations with standard
atomoxetine dosing12,19. Indeed, we showed that CYP2D6
UMs had a higher probability of having at least one undetectable
atomoxetine concentration (three out of four patients) compared to all
other CYP2D6 genotypes, which indicates higher risk of
undetectable levels and therapeutic failure. However, due to the low
numbers of CYP2D6 UMs in the present study, no statistically significant
differences were observed between NMs and UMs for C
D-1 ratio, absolute concentrations and daily dose of
atomoxetine, as well as risk of undetectable samples in the mixed model
analyses. The CPIC’s recommendations are based on studies showing
superior treatment response and compliance in CYP2D6 PMs versus NMs. It
is therefore likely that the CYP2D6 PMs in the present study may have
experienced improved therapeutic response but also increased
dose-dependent side effects compared to the other CYP2D6 genotype
subgroups. It is possible that this superior treatment response also
resulted in better treatment adherence and fewer undetectable
atomoxetine samples. Unfortunately, clinical data on therapeutic
response were unavailable. A study based on pooled data from clinical
trials conducted by Michelson et al.20 found that PMs
showed a greater clinical improvement, measured by ADHDRS-score, and
lower treatment drop-out than patients with normal CYP2D6 activity.
Interestingly, but unsurprisingly, these patients also had higher serum
levels of atomoxetine (Cmax sampled 1-hour post-dose,
PMs vs NMs: approx. 3300 vs 650 nM on the same dose) and risk of adverse
effects, including raised pulse and diastolic blood pressure, tremor,
decreased appetite and insomnia. Trzepacz, PT et al. found a
significant difference in weight, BMI and pulse in two open-label phase
3 studies but, conversely, no differences in clinical effect were
observed between the CYP2D6 genotype
subgroups9. Fijal, BJ et al. studied the effect
of CYP2D6 activity and safety associated with atomoxetine treatment in
adult patients over a period of 25 weeks at multiple international
centers21. In addition to comparing NM and PM
phenotypes, as in earlier studies, they distinguished between patients
with UM and IM phenotypes. The study found an increased risk of adverse
effects in patients with poor CYP2D6 activity, including reduced
appetite, dry mouth, erectile dysfunction, hyperhidrosis, insomnia and
urinary retention. Diastolic blood pressure and pulse were also
significantly higher, while BMI was significantly lower. Patients with
IM also had a higher risk of dry mouth and insomnia. Therefore, it is
possible that the higher burden of adverse effects observed in CYP2D6
PMs may outweigh the potential improvement in therapeutic response
compared to NMs.
A strength of the present study was the relatively large dataset, of not
only adult users, but also children and adolescents that are previously
less studied. We also had the possibility to correct the results for
blood sampling time (trough concentrations, blood sampling 4-8 hrs
post-dose). One obvious weakness of the present study was the lack of
clinical information about each patient, including therapeutic
effectiveness and treatment outcome, information on renal and hepatic
status (e.g., Child-Pugh B and C category), as well as existing somatic
comorbidities that would be of value. Concentrations are not corrected
for patient weight as this data was not available. Patient weight may
play a role in atomoxetine pharmacokinetics, especially in younger
patients where weight-corrected dosing is recommended (i.e., patients
under 70 kg in weight). Therefore, the patients’ age was included in the
statistical models as age may account for weight indirectly. In
addition, dose administration intervals were not known and may generate
some noise in the estimates but are unlikely skewed between the variousCYP2D6 genotype subgroups and CYP2C19*2 allele carriers
versus noncarriers. Information about steady-state could not be
confirmed but steady-state is a prerequisite for TDM, and this is
clearly communicated to doctors requesting TDM. It is therefore likely
that the great majority of atomoxetine serum samples are at
steady-state. A higher proportion of males (59%) was observed in the
present study population which reflects the higher proportion of males
diagnosed with ADHD as reported elsewhere1,2. Thus,
the study population is likely representative and comparable to other
studies.
In conclusion, both CYP2D6 and CYP2C19 genotypes have an
impact on atomoxetine exposure regardless of age, where our real-world
data suggest atomoxetine dose requirements to be equivalent to ≤10% and
35% of the starting dose in CYP2D6 IM and PM patients carrying theCYP2C19*2 allele variant versus CYP2D6 NM patients not carrying
the CYP2C19*2 allele variant, respectively, to target the same
atomoxetine exposure. These findings suggest that pre-emptive genotyping
of CYP2D6 /CYP2C19 should be performed to individualize
atomoxetine dosing and prevent adverse effects.