Aripiprazole and CYP2D6

 Hannah Starcher, BSBA Pharmaceutical and Healthcare Business Candidate, Elise Smith, Pharm.D. Candidate; Austin Hopkins, Pharm.D. Candidate; Robyn Staebler, Pharm.D. Candidate, Jose Tamayo, Pharm.D. Candidate.

Aripiprazole (Abilify ®) is a medication used to treat depression, schizophrenia, bipolar disorder, and autism-associated irritability. It targets both the serotonin and dopamine receptors in the brain, acting as either an enhancer when levels are too low or as an inhibitor when levels are too high. Aripiprazole is typically prescribed in combination with other antidepressants. Development or increases in suicidal ideation and actions may occur as a result of taking aripiprazole. Other possible adverse reactions include Neuroleptic Malignant Syndrome (characterized by muscle rigidity, fever, unstable blood pressure, and agitation), high blood sugar, orthostatic hypertension (a drop in blood pressure when standing up), weight gain, changes in cholesterol levels, and seizures.

CYP2D6 is a metabolic enzyme thought to be responsible for the breakdown of aripiprazole. CYP2D6 is also thought to be responsible for the metabolism of around 25% of common prescription medications. Individuals’ variations of the CYP2D6 gene will determine their responsiveness to aripiprazole.

Individuals can be grouped into three different categories based on the number of normally functioning CYP2D6 alleles they possess. An individual usually has two allelic copies for the gene, of which each can be either inactive, decreased-activity, or fully active. Individuals who possess two inactive copies of the allele, also referred to as poor metabolizers, should be given a maximum of 10 mg/day, or about 67% of the normal recommended maximum dose. Patients who carry two decreased-activity, one active and one inactive, or one decreased-activity and one inactive allele are classified as intermediate metabolizers, but no dose adjustment is recommended. Individuals with a duplication of active alleles are ultra-rapid metabolizers, who also currently have no recommended change in dose.

James, a South African male, was prescribed aripiprazole in addition to other medications in order to better treat his depression. He was informed during counseling with the doctor that if he has a certain genotype of the CYP2D6 enzyme, then he may have decreased function of the enzyme which means he could experience increased side effects due to high levels of the drug. James is told that the risk is higher in patients of South African descent, but after counseling he decides not to have the genetic test done to. One month later, James reports to his doctor that he has been suffering from dizziness and fatigue after beginning his new treatment with aripiprazole. A genetic test is used which shows that James has the poor metabolizing genotype of the CYP2D6 enzyme. The doctor must now decrease James’s dose by 30-40% in order to avoid abnormally high serum concentrations of aripiprazole.

In the months following this case, the same doctor is overseeing treatment of a Swiss male named John, who requires a new therapy for his bipolar disorder. John is told about the potential of having a decreased functioning form of the CYP2D6 enzyme during counseling on the new treatment. John agrees to the genetic test to identify his form of the CYP2D6 enzyme. The test shows that John is a poor metabolizer for the CYP2D6 enzyme. Similar to the case with James, the doctor lowers the normal dose of aripiprazole by 30-40% in order to avoid any continuity of symptoms or increase in occurrence of side effects.

CYP2D6 genetic testing does not completely rule out the risks of taking aripiprazole, nor does it guarantee the medication will work for you. Genetic testing is a guide to personalize the treatment of patients, maximizing benefit and minimizing harm.

The links below provide access to important articles and information relative to aripiprazole. The links are to external websites and will be checked regularly for consistency.

• Aripiprazole Prescribing Information
• Aripiprazole Pharmacogenomic Dosing Guidelines
• Pharmacogenomics Knowledge Base: Aripiprazole

Abilify [Internet]. Rockville (MD): Otsuka America Pharmaceutical Inc.; c2015 [cited 2015 Nov 30]. Available from: https://abilify.com.

Azuma, Junichi, Tomoko Hasunuma, Masanori Kubo, Masaya Miyatake, Toshiko Koue, Koushi Higashi, Tsutomu Fujiwara, Sachiko Kitahara, Tamiki Katano, and Sumiko Hara. The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine. Eur J Clin Pharmacol. 2011;68(1):29-37.

Bernard, S., K. Neville, A. Nguyen, and D. Flockhart. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. The Oncologist. 2006;11(2):126-35.

Clinical Pharmacology [Internet]. Amsterdam (Netherlands): Elsevier c2017. Aripiprazole; [cited 20 Dec 2015]. Available from: http://clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=2729&sec=monindi&t=0

Hendset, Magnhild, Monica Hermann, Hilde Lunde, Helge Refsum, and Espen Molden. Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole. Eur J Clin Pharmacol. 2007;63(12):1147-51.

Lisbeth, Patteet, Haufroid Vincent, Maudens Kristof, Sabbe Bernard, Morrens Manuel, and Neels Hugo. Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol. Eur J Clin Pharmacol. 2016;72(2):175-84.

Swen JJ, Nijenhuis M, de Boer A, et al. Pharmacogenetics: from bench to byte—an update of guidelines. Clin Pharmacol Ther. 2011 May;89(5):662-73.