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Letters to the Editor

Phenoconversion of Cytochrome P450 2D6: The Need for Identifying the Intermediate Metabolizer Genotype

See reply by Preskorn and related article by Preskorn et al.

Phenoconversion of Cytochrome P450 2D6: The Need for Identifying the Intermediate Metabolizer Genotype

To the Editor: Preskorn and colleagues1 reported on an impressively large population-based study among 900 patients who recently started venlafaxine treatment and who were both genotyped and phenotyped for cytochrome P450 (CYP) 2D6 metabolism. Among these patients, 3.9% and 27.0%, respectively, were genotyped and phenotyped as a poor metabolizer. The investigators inferred that "personalized medicine solely based on genetics can be misleading."(p614) Although we agree with this statement, some issues could have been addressed more extensively to underscore the need for pharmacogenetics.

Firstly, certain comedication can cause a patient to switch from a genetically classified extensive metabolizer or intermediate metabolizer to a poor metabolizer phenotype.2 Dose adaptation guidelines based on CYP2D6 genotype concerning, for example, codeine or tricyclic antidepressants already emphasize the important influence of such comedication on interpretation of genotype data.3,4 Importantly, CYP-inhibiting comedication is even an experimental clinical option to obtain adequate therapeutic blood levels in ultrarapid metabolizers of CYP2D6.5

Secondly, the intermediate metabolizers were excluded from analyses of the effect of comedication on phenoconversion rates. This seems reasonable since their reference method for phenotyping (ratio of venlafaxine to O-desmethylvenlafaxine) was not able to distinguish between the poor metabolizer and intermediate metabolizer genotype.6 To this point, we looked at the definition of intermediate metabolizers according to Preskorn et al, because there is a lot of inconsistency in the literature about this definition.3 According to the last 2 columns of Table 2, Preskorn et al classified patients genotyped as *1*3, *1*4, *1*5, or *1*6 as extensive metabolizers. According to the definitions of the Dutch pharmacogenetics working group,7 but also by other groups,8 these patients (n = 222 of n = 740 patients classified as extensive metabolizers according to Preskorn et al) could be classified as intermediate metabolizers,7 or heterozygote extensive metabolizers.8 The lower activity of the CYP2D6 enzyme in the mentioned group of 222 patients is generally accepted.9-11 According to Table 2, the results of Preskorn et al seem to be in agreement with the lower activity of extensive metabolizers with a *3, *4, *5, or *6 mutation. Moreover, it seems that this group of intermediate metabolizer (heterozygote extensive metabolizer) patients in particular were phenotyped as poor metabolizers when comedication that influences CYP2D6 was used. We would therefore be interested in an analysis that excludes this group of intermediate metabolizers (heterozygote extensive metabolizers) or, even better, an analysis of all the intermediate metabolizer (heterozygote extensive metabolizers) genotyped patients as a different subgroup.

Finally, it would be very interesting to see how many of the 209 patients noted in Figure 1 who were genotyped as non-poor metabolizers and phenotyped as poor metabolizers have an intermediate metabolizer (including the heterozygote extensive metabolizer) genotype.

In conclusion, according to the limited information about the intermediate metabolizers displayed in Table 2, we would infer that genotyping is a powerful method of identifying intermediate metabolizers (heterozygote extensive metabolizers) who will be at risk for a poor metabolizer phenoconversion, especially if they use CYP2D6 inhibitors. Therefore, genotyping can be used as the starting point of personalized medicine together with therapeutic drug monitoring. Genotyping and therapeutic drug monitoring should not be seen separately but as a combined pharmacologic tool to predict the risk for unsatisfactory response in patients.

References

1. Preskorn SH, Kane CP, Lobello K, et al. Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine. J Clin Psychiatry. 2013;74(6):614-621. PubMed doi:10.4088/JCP.12m07807

2. Borges S, Desta Z, Jin Y, et al. Composite functional genetic and comedication CYP2D6 activity score in predicting tamoxifen drug exposure among breast cancer patients. J Clin Pharmacol. 2010;50(4):450-458. PubMed doi:10.1177/0091270009359182

3. Hicks JK, Swen JJ, Thorn CF, et al; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther. 2013;93(5):402-408. PubMed doi:10.1038/clpt.2013.2

4. Crews KR, Gaedigk A, Dunnenberger HM, et al; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype. Clin Pharmacol Ther. 2012;91(2):321-326. PubMed doi:10.1038/clpt.2011.287

5. van Hasselt FM, Coehorst Y, Wilffert B, et al. Influencing CYP enzymes to boost psychiatric treatment: a review on clinical evidence. Pharmacopsychiatry. 2013;46(2):43-46. PubMed

6. Nichols AI, Lobello K, Guico-Pabia CJ, et al. Venlafaxine metabolism as a marker of cytochrome P450 enzyme 2D6 metabolizer status. J Clin Psychopharmacol. 2009;29(4):383-386. PubMed doi:10.1097/JCP.0b013e3181acc4dd

7. Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte—an update of guidelines. Clin Pharmacol Ther. 2011;89(5):662-673. PubMed doi:10.1038/clpt.2011.34

8. Doki K, Homma M, Kuga K, et al. CYP2D6 genotype affects age-related decline in flecainide clearance: a population pharmacokinetic analysis. Pharmacogenet Genomics. 2012;22(11):777-783. PubMed doi:10.1097/FPC.0b013e3283588fe5 > 9. Dodgen TM, Hochfeld WE, Fickl H, et al. Introduction of the AmpliChip CYP450 Test to a South African cohort: a platform comparative prospective cohort study. BMC Med Genet. 2013;14(1):20. PubMed doi:10.1186/1471-2350-14-20

10. Gaedigk A, Simon SD, Pearce RE, et al. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83(2):234-242. PubMed doi:10.1038/sj.clpt.6100406

11. Laika B, Leucht S, Heres S, et al. Intermediate metabolizer: increased side effects in psychoactive drug therapy: the key to cost-effectiveness of pretreatment CYP2D6 screening? Pharmacogenomics J. 2009;9(6):395-403. PubMed doi:10.1038/tpj.2009.23

Elizabeth J. J. Berm, PharmD, MSc

e.j.j.berm@rug.nl

Arne J. Risselada, PhD

Hans Mulder, PhD

Eelko Hak, PhD

Bob Wilffert, PhD

Author affiliations: Department of Pharmacotherapy & Pharmaceutical Care (Drs Wilffert and Berm) and Department of PharmacoEpidemiology & PharmacoEconomics (Dr Hak), University Center for Pharmacy, University of Groningen, Groningen; and Clinical Pharmacy, Wilhelmina Hospital Assen, Assen (Drs Risselada and Mulder), the Netherlands.

Potential conflicts of interest: None reported.

Funding/support: None reported.

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