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.