Pharmacogenomic testing for CYP2C19 and CYP2D6 in cyclic vomiting syndrome

Abstract

Background: Amitriptyline (AT) is recommended as first-line prophylactic therapy in patients with cyclic vomiting syndrome (CVS). However, significant side effects limit its use and dosing is based on trial and error. Though the Clinical Pharmacogenetic Implementation Consortium (CPIC) Guidelines recommend dosing for AT based on CY2D6 and CYP2C19 genotype profile, this is not followed in clinical practice. Methods: This pilot study determined CYP2C19 and CYP2D6 genotypes and ascertained its association with adverse drug reactions (ADRs), clinical response, and serum concentration of AT and nortriptyline in a well-characterized cohort of adults with CVS. Key Results: Of 46 subjects with CVS, age 33 ± 12 years, 61% female, 85% Caucasian, a third (33%) had normal CYP2C19 metabolizer status, while 4% were poor, and 43% were ultrarapid metabolizers. Most (61%) had normal CYP2D6 genotype while 9% were poor and 2% were ultra-rapid metabolizers. There was no statistically significant association between genotype and ADRs, clinical response or serum drug concentration. There was a trend towards significance between genotype and clinical response, with 64% of responders having normal CYP2D6 metabolism versus 36% of nonresponders (p = 0.06). ADRs were encountered in 46% of patients with 28% discontinuing the medication as a result. Conclusions and Inferences: A subset of patients with CVS have dysfunctional alleles of CYP2C19 and CYP2D6. Larger prospective studies to evaluate the clinical impact of pharmacogenomic testing in CVS are needed. This has the potential to optimize clinical management, predict ADRs and allow for personalized therapy.