Kristen Reynolds, PhD
On July 13, 2015 the FDA approved a new medication for the treatment of schizophrenia and for augmentation of antidepressant therapy in major depressive disorder in adults. Rexulti® (brexpiprazole, Otsuka Pharmaceutical) is an atypical antipsychotic hailed as Otsuka’s successor of Abilify® (aripiprazole), the top selling drug of 2013 whose patent expired in October of 2014.
Brexpiprazole, similar to aripiprazole, is dependent on hepatic CYP2D6 and CYP3A4 for clearance. Approximately 7-10% of the general population possesses an inherited form of the CYP2D6 gene that results in decreased clearance. Individuals with these genetic differences are called Poor Metabolizers (PMs) and are at risk of adverse drug reactions due to higher-than-normal drug exposure at standard doses.
The prescribing information for brexpiprazole indicates that patients who are known genetic CYP2D6 PMs, or those with decreased CYP2D6 clearance due to co-administration with a CYP2D6 inhibitor, should be administered only half of the standard brexpiprazole dosage. Additionally, because brexpiprazole is also dependent on CYP3A4 for clearance, patients who take known CYP3A4 inhibitors (such as ketoconazole or clarithromycin) at the same time as brexpiprazole may need to decrease the usual dose by half. In patients who are known CYP2D6 PMs and who are taking CYP3A4 inhibitors, the recommendation is to administer only one-quarter of the usual dose, thus representing a 75% dose reduction strategy based on both drug-gene and drug-drug interactions.
Additional dose adjustments are indicated in patients taking strong CYP3A4 inducers, with a recommendation to double to usual dose over 1-2 weeks. A similar dose increase has not been established for patients who are known CYP2D6 Ultra-rapid Metabolizers (UMs). In general, CYP2D6 UMs may be at risk of therapeutic failure due to faster-than-normal drug elimination. CYP2D6 UMs are typically a smaller fraction of the population (2-3%, depending on ethnicity), so post-market surveillance and case reports will be necessary to determine whether additional dose adjustments for this sub-population would be warranted.
The PGXL PRIMER™ personalized medicine program already incorporates all the relevant genetic and drug-related information necessary to identify the optimal patient targets for this new medication.