Prescribed Doses of CYP2D6-Metabolized Drugs and Hemodynamic Responses in Relation to CYP2D6 Genotype Among Older Patients Exposed to Polypharmacy

Overview

Journal Drugs Aging

Specialties Geriatrics
Pharmacology

Date 2020 Apr 30

PMID 32346827

Authors

Rita Romskaug

Torgeir Bruun Wyller

Jorund Straand

Hege Kersten

Espen Molden

Affiliations

Soon will be listed here.

Abstract

Background: Many drugs with dose-dependent effects on hemodynamic variables are metabolized by cytochrome P450 2D6 (CYP2D6). The aim of this study was to compare prescribed dosages and hemodynamic responses of such drugs in relation to pharmacogenetic variability in CYP2D6 metabolism among patients aged ≥ 70 years exposed to polypharmacy.

Materials And Methods: We included 173 patients with detailed information about drug use. The patients were retrospectively subjected to CYP2D6 genotyping, which comprised the most common variant alleles encoding reduced, absent, or increased CYP2D6 metabolism. In order to compare dosages across different CYP2D6-metabolized drugs, all prescribed daily doses were harmonized to the 'percent of a daily defined dose' (DDD). The mean harmonized DDD was compared between genotype-predicted normal metabolizers (NMs) and patients with reduced or absent CYP2D6 enzyme activity, defined as intermediate or poor metabolizers (IMs/PMs). Blood pressure, pulse, and patient proportions with orthostatism and bradycardia were also compared between genotype subgroups.

Results: The genotype-predicted phenotype subgroups comprised 79 NMs (45.7%), 75 IMs (43.4%), and 16 PMs (9.2%). There were no differences in dosing of CYP2D6 substrates between NMs and IMs/PMs (p = 0.76). A higher proportion of CYP2D6 IMs/PMs experienced orthostatism (p = 0.03), while there were no significant subgroup differences for the other hemodynamic variables.

Conclusion: In this real-life clinical setting of patients aged ≥ 70 years, dosing of CYP2D6 substrates were not adjusted according to genotype-predicted CYP2D6 metabolism. The increased occurrence of orthostatism in patients with reduced/absent CYP2D6 metabolism may indicate that individualized dosing based on genotype has the potential to prevent adverse effects in these vulnerable patients.

References

OBryant S, Waring S, Cullum C, Hall J, Lacritz L, Massman P . Staging dementia using Clinical Dementia Rating Scale Sum of Boxes scores: a Texas Alzheimer's research consortium study. Arch Neurol. 2008; 65(8):1091-5. PMC: 3409562. DOI: 10.1001/archneur.65.8.1091. View

Goryachkina K, Burbello A, Boldueva S, Babak S, Bergman U, Bertilsson L . CYP2D6 is a major determinant of metoprolol disposition and effects in hospitalized Russian patients treated for acute myocardial infarction. Eur J Clin Pharmacol. 2008; 64(12):1163-73. DOI: 10.1007/s00228-008-0525-3. View

Zineh I, Beitelshees A, Gaedigk A, Walker J, Pauly D, Eberst K . Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension. Clin Pharmacol Ther. 2004; 76(6):536-44. DOI: 10.1016/j.clpt.2004.08.020. View

Fux R, Morike K, Prohmer A, Delabar U, Schwab M, Schaeffeler E . Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study. Clin Pharmacol Ther. 2005; 78(4):378-87. DOI: 10.1016/j.clpt.2005.07.004. View

Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P . Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004; 351(27):2827-31. DOI: 10.1056/NEJMoa041888. View

Ingelman-Sundberg M . Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2004; 5(1):6-13. DOI: 10.1038/sj.tpj.6500285. View

Lotsch J, Rohrbacher M, Schmidt H, Doehring A, Brockmoller J, Geisslinger G . Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation?. Pain. 2009; 144(1-2):119-24. DOI: 10.1016/j.pain.2009.03.023. View

Haslemo T, Eliasson E, Jukic M, Ingelman-Sundberg M, Molden E . Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients. Br J Clin Pharmacol. 2018; 85(1):194-201. PMC: 6303206. DOI: 10.1111/bcp.13788. View

Cacabelos R, Cacabelos N, Carril J . The role of pharmacogenomics in adverse drug reactions. Expert Rev Clin Pharmacol. 2019; 12(5):407-442. DOI: 10.1080/17512433.2019.1597706. View

10.

Salvi F, Miller M, Grilli A, Giorgi R, Towers A, Morichi V . A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc. 2008; 56(10):1926-31. DOI: 10.1111/j.1532-5415.2008.01935.x. View

11.

Lymperopoulos A, McCrink K, Brill A . Impact of CYP2D6 Genetic Variation on the Response of the Cardiovascular Patient to Carvedilol and Metoprolol. Curr Drug Metab. 2015; 17(1):30-6. DOI: 10.2174/1389200217666151105125425. View

12.

Wu D, Li G, Deng M, Song W, Huang X, Guo X . Associations between ADRB1 and CYP2D6 gene polymorphisms and the response to β-blocker therapy in hypertension. J Int Med Res. 2015; 43(3):424-34. DOI: 10.1177/0300060514563151. View

13.

Sharp C, Gardiner S, Jensen B, Roberts R, Troughton R, Lainchbury J . CYP2D6 genotype and its relationship with metoprolol dose, concentrations and effect in patients with systolic heart failure. Pharmacogenomics J. 2009; 9(3):175-84. DOI: 10.1038/tpj.2009.9. View

14.

Hamadeh I, Langaee T, Dwivedi R, Garcia S, Burkley B, Skaar T . Impact of CYP2D6 polymorphisms on clinical efficacy and tolerability of metoprolol tartrate. Clin Pharmacol Ther. 2014; 96(2):175-81. PMC: 4111800. DOI: 10.1038/clpt.2014.62. View

15.

Lee S, Ki C, Hong K, Kim J . A case report of a poor metabolizer of CYP2D6 presented with unusual responses to nortriptyline medication. J Korean Med Sci. 2004; 19(5):750-2. PMC: 2816343. DOI: 10.3346/jkms.2004.19.5.750. View

16.

Bijl M, Visser L, Hofman A, Vulto A, van Gelder T, Stricker B . Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants. Br J Clin Pharmacol. 2007; 65(4):558-64. PMC: 2291379. DOI: 10.1111/j.1365-2125.2007.03052.x. View

17.

Li S, Lin H, Sun W, Wang Y, Ding Y, Zhao H . A meta-analysis of the effect of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamics of metoprolol . Int J Clin Pharmacol Ther. 2017; 55(6):483-492. DOI: 10.5414/CP202545. View

18.

Rendic S . Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002; 34(1-2):83-448. DOI: 10.1081/dmr-120001392. View

19.

Bijl M, Visser L, van Schaik R, Kors J, Witteman J, Hofman A . Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther. 2008; 85(1):45-50. DOI: 10.1038/clpt.2008.172. View

20.

Hughes C, Berg L, Danziger W, COBEN L, Martin R . A new clinical scale for the staging of dementia. Br J Psychiatry. 1982; 140:566-72. DOI: 10.1192/bjp.140.6.566. View