In our cohort, a wide range of the minimum effective (range 20 to 320 mg) and maximum tolerable (range 20 to 480 mg) doses were reported in patients with migraine. The one patient that used verapamil 20 mg reported marked reduction in headache frequency and severity and was unable to tolerate a higher dose due to lightheadedness, nausea, heart racing, and insomnia. For the six pharmacogenomic phenotypes currently available in EMR reports, most patients that used verapamil for migraine prevention were CYP1A2 rapid metabolizers, CYP2B6 intermediate metabolizers, and CYP3A4 normal metabolizers. There was a wide variety of CYP2C9, CYP2D6, and CYP3A5 phenotypes.
Overall, the distribution of different alleles of the CYP enzymes in our cohort is consistent with the American population data reported in the literature. In a meta-analysis (16), Zhou et al reported the haplotype frequencies of 176 alleles distributed over the 12 major CYP genes known to be the most impactful on drug metabolism. The authors gathered and analyzed whole genome and exome sequencing data from 56 945 unrelated individuals from five major populations- Africans, admixed Americans, East Asians, Europeans, and South Asians. The allele frequencies of the leading alleles in our cohort, CYP1A2*1F, CYP2B6*1, CYP2C9*1, CYP2D6*1, CYP3A4*1, and CYP3A5*3 are similar to the frequencies reported from the analysis of the admixed American population as listed in Table 2 (ref. 16).
Although this pilot study did not identify any statistical significance, we cannot exclude the effect of pharmacogenomic phenotypes on the effective and tolerable doses of verapamil. We aimed to use existing pharmacogenomic reports in the EMR. However, as pharmacogenomic testing is not routinely used in headache care, this study was limited by the small sample size. Given the wide range of verapamil used for cluster headache, initially we also investigated the cluster headache population. However, within identified patients that had a pharmacogenomic report, we found only one patient that was really using verapamil for the prevention of cluster headache yet without documented therapeutic response. Therefore, our current report focused on migraine. Predicting the adequate doses of verapamil in patients with cluster headache would still be a future research direction, given verapamil is a first-line medication for the prevention of cluster headache. Additionally, as pharmacogenomic testing is more frequently implemented for depression treatment, exploring the association between pharmacogenomic phenotypes and the therapeutic doses of antidepressants commonly used for migraine prevention, including amitriptyline, nortriptyline, and venlafaxine, might potentially yield to larger study sample sizes, though determining the therapeutic or tolerated doses used for migraine as opposed to depression could potentially be complex in some cases. Of note, CYP2D6 is listed in U.S. Food & Drug Administration label as an actionable pharmacogenomic biomarker for these three medications as the systemic concentrations can be altered by certain phenotypes of CYP2D6 and may require dose adjustment (17–19). For example, using tricyclic antidepressants such as amitriptyline or nortriptyline in CYP2D6 ultrarapid metabolizers may lead to suboptimal therapeutic response in treating depression since there might be increased metabolism of the tricyclic antidepressants to less-active compounds. If such use cannot be avoided, individuals may need to target a higher dose to reach an adequate therapeutic response. On the contrary, for CYP2D6 poor metabolizers, a 50% dose reduction should be considered to avoid side effects caused by higher-than-normal plasma concentration of active drugs if the use of tricyclic antidepressants is necessary (20). For venlafaxine, the prediction of therapeutic response and the occurrence of side effects by individual CYP2D6 metabolism activities is rather complex and no precise dose adjustment recommendation can be reached per current literature. CYP2D6 facilitates the metabolism of venlafaxine to active metabolite O-desmethylvenlafaxine, both are active antidepressants. It has been found that a high O-desmethylvenlafaxine/venlafaxine ratio is associated with better efficacy and less moderate to severe side effects (21). CYP2D6 ultrarapid metabolizer may increase the conversion from venlafaxine to O-desmethylvenlafaxine yet reduce the total sum of both venlafaxine and O-desmethylvenlafaxine. On the other hand, CYP2D6 intermediate or poor metabolizer may reduce the conversion from venlafaxine to O-desmethylvenlafaxine. It would be hard to predict the ratio change while adjust dose in altered metabolism between venlafaxine and O-desmethylvenlafaxine. A reduced efficacy and increased risk of side effects had been identified in CYP2D6 intermediate or poor metabolizers (22). Our cohort presents a variety of CYP2D6 phenotypes, 45.5% were normal, 27.3% were intermediate, 15.2% were intermediate-to-normal, and 12.1% were poor-to-intermediate metabolizers.
CYP3A4 is the most recognizable metabolic enzyme known to affect verapamil concentrations. CYP3A4 inhibitors such as erythromycin and ritonavir can increase verapamil concentration whereas CYP3A4 inducers such as rifampin could potentially cause an opposite effect (23). In our cohort, most subjects are CYP3A4 normal metabolizers, making it difficult to further examine the impact of CYP3A4 on verapamil. Smoking has been shown to decrease verapamil concentration, potentially by increasing CYP1A2 activity (24). In theory, smokers would require a higher verapamil dose to achieve therapeutic response. Our study did not find such association, likely limited by the small sample size or the existence of other confounding enzymes that could be affected by smoking but not listed in the current report, such as CYP2E1 (25). Besides those enzymes currently in the EMR pharmacogenomic report, CYP2C8, CYP2C18 and P-gp can also affect the metabolism or transportation of verapamil and the association between the phenotypes of those enzymes and verapamil dosages could be further investigated. P-gp plays an important role in transporting verapamil out of the brain. This leads to the low verapamil concentration in the central nervous system despite that it can easily cross the blood-brain barrier as a lipophilic medication. It is possible that less active P-gp may increase the presence of verapamil in central nervous system and enhance its neurological effect as demonstrated by a study via P-gp inhibitor (26). Our previous study did not identify an association between P-gp variants in the efficacy of verapamil at a daily dose of 240 mg for migraine prevention (9), though whether P-gp phenotypes affect the therapeutic window of verapamil in responders could be further investigated.
In addition to the small sample size, other limitations of our study include recall bias of patients and the inability to account for all confounding factors that were not documented. Examining patients that already had an existing pharmacogenomic report could also create selection bias toward patients with certain pre-existing conditions. Initially we attempted to gather information on concurrent medications for this study; however, changes of the concurrent medications and the compliance of using those medications were not consistently provided or updated in the existed EMR records with each documented response to verapamil and so we were unable to include this information. As the use of certain medications could potentially affect the concentration of verapamil through affecting the CYP enzymes, future studies could consider including the effect of concurrent medications into the analysis. Regardless, our pilot study demonstrates a wide range of the minimum effective and maximum tolerable dosages of verapamil for migraine prevention in patients with a variety of pharmacogenomic phenotypes. Our study also highlights the importance of future prospective studies to investigate the effect of pharmacogenomic variants on the efficacy and safety of headache preventive medications, ultimately to facilitate individualized medicine in headache care.