Pharmacokinetics of Novel Migraine Preventives Evaluated for Drug-Drug Interactions

Shivang Joshi, MD, MPH, RPh

The consideration of drug-drug interactions (DDI) is vital when treating patients with migraine, and findings from a recent study suggest that developing migraine-specific, evidence-based preventive treatments may reduce the risk of DDIs, as well as associated adverse events (AEs) in patients with comorbidities. 

Investigators found that most DDIs occurred through alterations in cytochrome (CYP) P450 isoenzyme activity, also the isoenzyme where most preventive therapies for migraine are metabolized. This can then be complicated by genetic polymorphism for metabolic enzymes, and shifts in drug metabolism may also be tied to ingestion of grapefruit juice and smoking status.

“Physicians should be aware of elimination pathways of drugs used for migraine prevention and possible competitive metabolic mechanisms to optimize patient care. While there are many distinct pathways and mechanisms in which DDIs can occur, most occur through alterations in CYP450 isoenzyme activity,” lead author Shivang Joshi, MD, MPH, RPh, associate professor of clinical pharmacy, University at Buffalo School of Pharmacy, and neurologist/headache specialist, DENT Neurological Institute, et al wrote. “The combination of 2 drugs that are substrates of, inhibit, or induce the same CYP450 isoenzyme can alter the pharmacokinetics of one or both medications, resulting in altered plasma concentrations and potential toxicity.”

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While prevention strategies are recommended for patients who experience frequent migraine attacks, considering comorbidities and how they are treated, whether with polytherapy or monotherapy, should be taken into consideration. As therapeutic monoclonal antibodies are not metabolized via CYP enzymes, developing preventive monoclonal antibody treatments, such as the recent class additions to the care model, can reduce the risk of DDIs and associated AEs when compared to therapies that have multiple avenues for treatment and multiple conditions to address. 

Investigators performed the literature search to find studies of the most effective and most often used pharmacologic classes of migraine preventives, including beta-blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the calcitonin gene-related peptide (CGRP) pathway. Classes were then evaluated to identify pharmacokinetic properties and potential DDIs with medications that patients may take for comorbid conditions. 

Mainly metabolized by CYP24A, gepants are susceptible to DDIs with other drugs that share the same pathway, namely rapamil, rifampin, and ketoconazole for ubrogepant (Ubrelvy; AbbVie) and itroconazole and rifampin for rimegepant (Nurtec ODT; Biohaven). Concomitant administration of P-glycoprotein and breast cancer-resistance protein (BCRP) inhibitors, such as verapamil, itraconazole, and novobiocin, can increase exposure to gepants, as both ubrogepant and rimegepant are substrates of P-glycoprotein and BCRP. No DDIs were found when taking ubrogepant, rimegepant, or atogepant at the same time as oral contraceptives containing progestin and ethinyl estradiol. 

Unlike gepants, monoclonal antibodies are not metabolized by CYP450, and as such, drug-monoclonal antibody interactions are unlikely. The interaction of erenumab (Aimovig; Amgen/Novartis) and ethinyl estradiol/norgestrel oral contraceptives was studied, finding no clinically relevant DDIs. There was no available information on DDIs for monoclonal antibody use with gepants. 

Preventive therapies such as the beta-blocker propranolol was found to have no pharmacodynamic effect with acute therapy in the form of triptans (rizatriptain, sumatriptan, zolmitriptan); however, peripheral vasoconstrictive AEs were reported when treated with ergolines (dihydroergotamine, ergotamine). Monamine oxidase inhibitors were found to have no known effect when interacting with triptans. Nifedipine, a calcium channel blocker, was found to have an antagonistic effect through ergot-mediated vasospasm. 

“When treating patients with migraine and comorbid conditions using polytherapy, the pharmacokinetic and pharmacodynamic properties of each drug must be considered,” Joshi et al said. “Changes in binding kinetics or rate of elimination with the introduction of additional medications may require dose adjustments and careful clinical monitoring.”

REFERENCE

Joshi S, Tepper SJ, Lucas S, Rasmussen S, Nelson R. A narrative review of the importance of pharmacokinetics and drug-drug interactions of preventive therapies in migraine management. Headache. 2021;61(6):838-853. doi:10.1111/head.14135