Cytochrome P 450 enzymes
Of the 381 drugs, the labels of 143 have information on various
cytochrome P 450 enzymes of varying levels: actionable, 68 (47.55%);
informative, 47 (32.87%); testing required, 6 (4.20); and testing
recommended, 1 (0.70%). The labels of the remaining 21 drugs (14.69%)
have varying levels of information. The information was about the
enzymes CYP2D6 (n = 90, 54.55%), CYP2C19 (n = 26, 15.76%); CYP3A4 (n =
23, 13.94%), CYP2C9 (n = 17; 10.30%), and others (n = 7, 4.24%).
Fifteen drugs with the information level informative have been approved
by the EMA. However, the information states that “no pharmacogenomics
information is available”. Information on the role of enzymes or
proteins that are involved in the pharmacokinetics of the drug and that
may lead to drug-drug interactions if concomitantly used with other
drugs using the same enzymes or proteins during pharmacokinetic
activities are included in these labels. There are two examples of
different levels of information provided by other agencies (if any),
indacaterol and voriconazole.
For indacaterol, the information in the FDA- and Swiss-approved labels
is also informative but more detailed and states the genotypes that may
lead to pharmacokinetic changes. On the other hand, the information in
the PMDA-approved label is classified as actionable although it is
similar to that provided by other agencies. The labels actually contain
the same information but in worded differently.
The EMA European Public Assessment Report (EPAR) for indacaterol
(Hirobriz Breezhaler) does not contain PGx but does contain information
regarding the drug’s pharmacodynamics as a beta2-adrenoceptor (ADRB2)
agonist and pharmacokinetics involving UGT1A1, CYP3A4, and ABCB1.
The PMDA package insert for indacaterol (Onbrez) states that individuals
with low UGT1A1 expression have increased steady-state area under the
concentration-time curve (AUC) and maximum plasma concentration (Cmax)
compared to those among individuals with wild-type UGT1A1 expression.
Following repeated inhalation of indacaterol in subjects with a variant,
low-activity UGT1A1 genotypes, the steady-state Cmax and AUC were both
1.2-fold higher than those related to the wild-type genotype
(non-Japanese data).
The FDA-approved drug label for indacaterol (ARCAPTA NEOHALER) states
that the steady-state AUC and Cmax of indacaterol were 1.2-fold higher
in patients with the (TA)7/(TA)7 (*28/*28) genotype than in the patients
with the (TA)6/(TA)6 (*1/*1) genotype, suggesting no relevant effect of
the UGT1A1 genotype on indacaterol exposure.
The information is actionable for voriconazole labels approved by other
agencies. The EMA-approved label states that it does not contain PGx; it
contains warning information regarding the co-administration of drugs
that are substrates, inhibitors, or activators of CYP3A4, CYP2C9, or
CYP2C19 due to drug-drug interactions. The actionable information for
the same drug states that CYP2C19 poor metabolizers have, on average,
four-fold higher voriconazole exposure than do normal metabolizers. In
contrast, intermediate metabolizers have two-fold higher exposure than
do normal metabolizers. The PMDA-approved label notes that voriconazole
is metabolized by CYP2C19 (as well as CYP2C9 and CYP3A4) and provides
tables showing the difference in pharmacokinetic metrics between
extensive, intermediate, and poor metabolizers in adults and children.
Ninety-three TMMDA-approved drug labels have information about
cytochrome P 450 enzymes. Of these, the labels of 41 (44.09%), 31
(33.33%), and 1 (1.08%) drug contain informative information,
actionable information, and state testing recommended, respectively.
Twenty (21.51%) labels contained information on drug-drug interactions
and concomitant use with enzyme inducers or inhibitors. However, we did
not classify these as informative labels, although some of the
EMA-approved labels were similar to informative labels. For five drugs,
the original drug labels had information similar to that in the
corresponding labels approved by other agencies; however, this
similarity was lacking among the labels for the generic versions of
these drugs.