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A narrative review of the importance of pharmacokinetics and drug–drug interactions of preventive therapies in migraine management

Abstract Objective To review the pharmacokinetics of major classes of migraine preventives and the clinical implications of drug–drug interactions (DDIs) with the use of these therapies in migraine management. Background Preventive treatments for migraine are recommended for a large proportion of patients with frequent migraine attacks. These patients often exhibit a number of comorbidities, which may lead to the introduction of multiple concomitant therapies. Potential DDIs must be considered when using polytherapy to avoid increased risk of adverse events (AEs) or inadequate treatment of comorbid conditions. Methods A literature search was performed to identify pharmacokinetic properties and potential DDIs of beta‐blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the calcitonin gene‐related peptide pathway with medications that may be used for comorbid conditions. Results Most DDIs occur through alterations in cytochrome P450 isoenzyme activity and may be complicated by genetic polymorphism for metabolic enzymes. Additionally, drug metabolism may be altered by grapefruit juice ingestion and smoking. The use of migraine preventive therapies may exacerbate symptoms of comorbid conditions or increase the risk of AEs associated with comorbid conditions as a result of DDIs. Conclusions DDIs are important to consider in patients with migraine who use multiple medications. The development of migraine‐specific evidence‐based preventive treatments allows for tailored clinical management that reduces the risk of DDIs and associated AEs in patients with comorbidities.

(DDIs) that can cause decreased effectiveness or ineffectiveness of prescribed drugs or adverse drug reactions, particularly when the prescribed drug may be an inducer or inhibitor of metabolic pathways of other drugs being taken. 5 To avoid increased risk of AEs or inadequate treatment of comorbid conditions when using polytherapy, DDIs should be considered when developing therapeutic regimens for the treatment of migraine. 6 A risk of DDIs within migraine treatment exists even in the absence of comorbid conditions because patients using migraine preventive treatment may also require acute migraine medication for breakthrough headaches. 7 Many DDIs are the result of coadministration of multiple drugs that undergo oxidative metabolism by the cytochrome P450 (CYP) enzymes, particularly the CYP3A4, CYP2D6, CYP1A2, and CYP2C isoenzymes. 8 Clinically significant drug interactions can be predicted by the type of isoenzyme involved in metabolism. Thus, an understanding of the pharmacokinetic properties of migraine preventives is central to identifying potential interactions with drugs used for treatment of comorbid conditions. With the recent US Food and Drug Administration (FDA) approval of a new class of migraine preventive medications, the monoclonal antibody-based therapies, a review of the pharmacokinetic properties of migraine preventives and their potential drug interactions is timely. Here, we review the most frequently used pharmacologic classes of migraine preventives with established or probable efficacy in migraine prevention, including beta-blockers, antiepileptic drugs, antidepressants, calcium channel blockers, and monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway. In the interim, rimegepant has been approved for migraine prevention. Finally, we discuss the clinical implications of DDIs with the use of these therapies in migraine management.

ME THODS
A literature search of the PubMed database was performed to identify articles related to pharmacokinetic properties of migraine preventive therapies including beta-blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the CGRP pathway. Articles related to the DDIs between these migraine preventive therapies and medications potentially used for comorbid conditions were also sought from the PubMed database. Other articles and data sources (e.g., prescribing information) not identified through the PubMed search were added as considered appropriate by the authors to ensure a comprehensive narrative review.

PHARMACOKINE TIC PROPERTIE S OF MIG R AINE PRE VENTIVE S Absorption and distribution
Beta-blockers Beta-blockers are commonly used to treat hypertension, cardiac arrhythmia, angina pectoris, and acute anxiety during public speaking and also show efficacy in migraine prevention. Propranolol, timolol, and metoprolol are classified as level A drugs (established as "effective" for migraine prevention), and nadolol and atenolol are classified as level B ("probably effective" for migraine prevention). 9 Only propranolol and timolol are approved by the FDA for migraine prevention. 10,11 Propranolol, timolol, and nadolol have nonselective binding and have affinity for β-1 and β-2 receptors, whereas metoprolol and atenolol are β-1 selective. Beta-receptors are normally stimulated by catecholamines, which have effects on the central nervous system, respiratory system, sympathetic ganglia, the heart, peripheral arteries, and the kidney. Beta-blockers are competitors of catecholamines because of their similar structure. 12 Overall, beta-blockers display variable pharmacokinetic properties. After absorption from the gastrointestinal tract, betablockers reach peak plasma concentration in 1-3 h. Propranolol is extensively protein-bound (93%) compared with timolol (10%), metoprolol (12%), nadolol (25%), and atenolol (3%). 13 This difference in protein-binding properties results in a higher propensity for propranolol to effectively displace other protein-bound drugs compared with other beta-blockers. In the plasma, beta-blockers bind albumin and α 1 -acid glycoprotein. The bioavailabilities of propranolol, timolol, metoprolol, nadolol, and atenolol are 30%, 50%-75%, 50%, 20%-30%, and 50%, respectively. 13 Propranolol has a lower bioavailability owing to a high first-pass elimination effect. 14 Beta-blockers have a large volume of distribution, ranging from 0.7 to 5.6 L/kg, which can be indicative of physicochemical properties (i.e., lipophilicity or hydrophilicity), can affect the duration of β-receptor blockade, as well as affect tissue concentration through extravascular penetration and diffusion through biologic barriers, such as the blood-brain barrier. 13 More specifically, the large distribution volume of beta-blockers is indicative of their lipophilic nature, which allows them to penetrate tissues more readily and have longer duration of action compared with molecules with a lower distribution volume, depending on their target.
Beta-blockers can be found in brain tissue, despite potentially low cerebrospinal fluid concentrations, indicating that beta-blockers cross the blood-brain barrier. 15 Atenolol, metoprolol, and propranolol are found in very low concentrations in breast milk. Nadolol is secreted to a greater extent, and is therefore contraindicated for use during lactation. 16 Antiepileptic drugs Divalproex sodium (valproic acid/sodium valproate) is an antiepileptic drug that has FDA approval for migraine prevention and level A evidence of efficacy. 9 Divalproex sodium is a teratogen and should not be used during or in anticipation of pregnancy. 17 It is found in breast milk at low concentrations. 16 Divalproex sodium is also used to treat manic episodes related to bipolar disorder. 18 Divalproex sodium is an antagonist of voltage-dependent Na + channels and reduces excitatory transmission by increasing brain gamma-aminobutyric acid (GABA) concentrations. 19 Divalproex sodium dissociates to valproate in the gastrointestinal tract. In the plasma, protein binding is dependent on concentration and ranges from 10% to 18.5%. There are three formulations for divalproex sodium, namely immediate release, extended release, and delayed release. 18,20,21 The bioavailability of the extended-release formulation is 90%, and peak plasma concentration is reached in 4-17 h. 21 The volume of distribution for total valproate is relatively low at 11 Topiramate is another antiepileptic that is approved for migraine prevention with level A evidence of efficacy. 9,19 Like divalproex, topiramate is a teratogen and should be avoided during pregnancy. 22 Topiramate is also found in breast milk at significant concentrations. 16 Topiramate has multiple targets, such as voltage-activated Na + channels, high-voltage-activated Ca 2+ channels, GABA A receptor, AMPA/kainate receptor, and carbonic anhydrase, while it also increases GABA concentrations in the brain. 23,24 It is available in immediate-and extended-release forms, 25,26 has high bioavailability (>80%), and reaches peak plasma concentrations 3.5 h after a 400mg dose. 27,28 Topiramate has a large volume of distribution (0.6-0.8 L/kg) and low plasma protein binding and is unlikely to displace protein-bound drugs. 28 Topiramate is found in cerebrospinal fluid, at concentrations that correlate with plasma levels, and is assumed to cross the blood-brain barrier via nonsaturable carriers. 29 Antidepressants Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors also called selective serotonin-norepinephrine reuptake inhibitors (SSNRIs) are two classes of antidepressants used for migraine prevention. TCAs and SSNRIs are thought to prevent migraine by inhibiting serotonin and norepinephrine reuptake and maintaining serotonin levels. Amitriptyline, a TCA with level B evidence of efficacy in migraine prevention, 9 is absorbed following oral administration and reaches peak plasma concentration in 4-8 h. 30 The bioavailability of amitriptyline is 32%-62%. 31 Amitriptyline has a large volume of distribution and is widely bound to tissue and plasma proteins. 32 Nortriptyline, a metabolite of amitriptyline, inhibits norepinephrine more potently than serotonin 33,34 and can be used as a migraine preventive if amitriptyline is not tolerated. 35 Venlafaxine, an SSNRI with level B evidence of efficacy, is absorbed through the gastrointestinal tract following oral administration with a peak plasma concentration reached 2 h after administration in healthy patients. 9,36 Similar to amitriptyline, venlafaxine has a large volume of distribution; however, venlafaxine has low plasma protein binding and extensive tissue binding. 36 Finally, amitriptyline shows low excretion levels in breast milk. 16 Neither amitriptyline nor venlafaxine is FDA approved for migraine prevention.

Calcium channel blockers
Calcium channel blockers are commonly used antihypertensive drugs that act by blocking calcium flow through calcium channels.
Several calcium channel blockers are considered effective for migraine prevention, including verapamil and amlodipine, although no calcium channel blockers are currently FDA approved for migraine prevention. 37,38 Verapamil is rapidly absorbed following oral administration, with mean peak plasma concentration reached in 2 h. 39 The bioavailability of orally administered verapamil is only 10%-20%, due to extensive first-pass hepatic elimination. 39 However, a sustained-release verapamil formulation has been found to have a relative bioavailability of almost 98%. 39 Verapamil is highly protein-bound (90%). 39 Very low levels of verapamil have been reported in breast milk. 16 Amlodipine can be administered intravenously or orally. 40 It is 97% protein-bound and has an oral bioavailability of 52%-88%. 40

Gepants
Gepants are a class of CGRP receptor antagonists that are being developed for migraine treatment and prevention. 41 Generally, CGRP receptor antagonists do not cross the blood-brain barrier and are not found in brain tissue. 42 Rimegepant and ubrogepant are approved by the FDA for the acute treatment of migraine with or without aura in adults. 43,44 Although no FDA-approved gepants are indicated for migraine prevention, 43,44 rimegepant is currently under study as a dual-action acute and preventive medication for migraine. 41 Furthermore, atogepant is a new gepant being developed exclusively for migraine prevention, which recently showed promising efficacy and safety results in a phase 2b/3 trial. 45 Ubrogepant is administered orally, reaches peak plasma concentrations at approximately 1.5 h, and is highly protein-bound (87%). 43 Rimegepant is taken orally and reaches its maximum plasma concentration at 1.5 h. 44 The bioavailability of orally administered rimegepant is approximately 64%. 44 Protein binding is approximately 96%. 44

Monoclonal antibody therapies
Monoclonal antibody-based therapies targeting the CGRP pathway are an emerging class of migraine preventive therapies. FDA approval was first granted to erenumab in 2018, followed by fremanezumab and galcanezumab in the same year, and eptinezumab in 2020. These therapies target the CGRP receptor (erenumab) or ligand (galcanezumab, fremanezumab, eptinezumab).
Therapeutic monoclonal antibodies are administered parenterally via intravenous (eptinezumab), or subcutaneous injection (erenumab, galcanezumab, and fremanezumab), due to their large size and hydrophilicity. [46][47][48][49][50] Administration via the subcutaneous route results in lower concentrations compared with intravenous administration due to absorption via the lymphatic system. 51 Absorption through the lymphatic system results in a longer time to reach peak plasma concentration at 2-8 days after administration. 51 The bioavailability of monoclonal antibodies administered subcutaneously ranges from 50% to 100%. More specifically, it is 82% for erenumab 50,52 and 66% for fremanezumab. 53 Due to their size and polarity, monoclonal antibodies are transported into tissues primarily by convective transport. 51 Determining the volume of distribution is more complex for monoclonal antibodies compared with small-molecule drugs because elimination occurs at tissue sites that are not in rapid equilibrium with plasma. 51 High-affinity binding and target-mediated elimination contribute to underestimation of the volume of distribution determined by noncompartmental analysis. The volume of distribution reported for the anti-CGRP monoclonal antibodies discussed here ranges from 3.7 to 7.3 L. [47][48][49][50] Anti-CGRP antibodies are large molecules and do not readily cross the blood-brain barrier. 54

Beta-blockers
Most beta-blockers are eliminated by hepatic metabolism or renal excretion of the unmetabolized drug (Table 1). In general, lipophilic beta-blockers (i.e., propranolol) are eliminated mostly by metabolism, and hydrophilic beta-blockers (i.e., atenolol and nadolol) are not metabolized and primarily excreted in urine as unchanged drug. Propranolol is metabolized through glucuronidation, ring hydroxylation, and side chain oxidation by the CYP1A2, CYP2D6, and CYP2C19 isoenzymes before excretion in urine. 11,55 Timolol and metoprolol are primarily metabolized by the CYP2D6 isoenzyme. 56,57 Nadolol has a longer half-life compared with the other beta-blockers used for migraine prevention (14-24 h vs. 3-9 h). 13

Antiepileptic drugs
Divalproex sodium is primarily eliminated through hepatic metabolism via glucuronidation (30%-50%), beta-oxidation (>40%), and CYP oxidation, and only a minor fraction is excreted by the kidneys (<3%). 19,21 CYP metabolism accounts for a minor fraction of the total metabolism of divalproex sodium 19 and is mediated by CYP2C9, CYP2A6, and CYP2B6. 58 The average half-life of divalproex sodium is 12 h (range, 8-20 h). 19 Topiramate is excreted predominantly unmetabolized by the kidneys and displays linear elimination kinetics. 28 Approximately 20% of oral topiramate is metabolized in the liver by hydroxylation, hydrolysis, and glucuronidation, and its half-life is approximately 21 h (31 h for the extended-release preparation). 19,28 Although its metabolism does not occur through CYP pathways, topiramate is a weak inhibitor of CYP2C19 and a weak inducer of CYP3A4. 19 Antidepressants TCAs are metabolized mainly by CYP450 isoenzymes (CYP1A2, CYP2C19, CYP3A4, and CYP2D6) and excreted in urine. Amitriptyline is metabolized by CYP2C19 to nortriptyline, which is further metabolized to 10-hydroxynortriptyline and then to 10-hydroxy amitriptyline by CYP2D6. 59 The half-life of amitriptyline is 10-28 h (16-80 h for its active metabolite nortriptyline), and one third to one half of amitriptyline is excreted within 24 h. 30 Venlafaxine is metabolized in the liver to the active metabolite O-demethylvenlafaxine and two minor metabolites by CYP2D6. 60 Clearance of venlafaxine is primarily renal, and the elimination halflife is approximately 4 h for venlafaxine and approximately 10 h for O-demethylvenlafaxine. 60 Calcium channel blockers Verapamil is mainly metabolized by the liver, primarily via the Ndealkylation and O-demethylation pathways. 39 The dealkylated products, norverapamil and desalkylverapamil, are metabolized to R-and S-verapamil by CYP3A4 and CYP3A5. [61][62][63] The elimination half-life for verapamil is 2.7-4.8 h. 39 Amlodipine is cleared by the liver via dehydrogenation of its dihydropyridine moiety to a pyridine derivative. 64 It has been suggested that CYP3A4 plays a key role in the metabolic clearance of amlodipine. 64 Amlodipine has a slow elimination half-life of approx-

Gepants
Ubrogepant is mainly metabolized in the liver by CYP3A4 and P-glycoprotein, resulting in two glucuronide conjugate metabolites. 43,65 The half-life of ubrogepant is approximately 5-7 h, and it is cleared primarily via the biliary/fecal route. 43 Rimegepant is also primarily metabolized in the liver by CYP3A4 and to a lesser extent by CYP2C9, without any major metabolites in the plasma. 44 The elimination half-life of rimegepant is approximately   (Table 2). 46

General metabolism considerations
The metabolism of drugs for migraine prevention raises important considerations. As mentioned previously, most preventive therapies for migraine are metabolized via CYP450 isoenzymes. Grapefruit juice can affect drug metabolism by mechanism-based inhibition of CYP450, particularly the CYP3A4 isoenzyme. 68 This interaction may significantly prolong clearance of migraine therapeutics. 68 The same interaction occurs with substrates of P-glycoprotein, which is also inhibited by grapefruit juice. 68 Thus, patients should be aware of the effects of grapefruit juice on migraine preventive therapies and avoid consumption. Note: ↑: PK effect that leads to a reported increase in exposure in the product's prescribing information (statistical or clinical significance not necessarily reported or implied). ↓: PK effect that leads to a reported decrease in exposure in the product's prescribing information (statistical or clinical significance not necessarily reported or implied).
b Clinically significant change reported.
c The PK profile of the total active moiety (i.e., risperidone plus 9-hydroxyrisperidone) was not significantly changed.

TA B L E 1-Continued
Cigarette smoking can also affect drug metabolism by CYP1A1, CYP1A2, and possibly CYP2E1, likely via polycyclic aromatic hydrocarbons found in tobacco smoke. 69 Additionally, nicotine is metabolized in the liver by CYP2A6 and has differential effects on several CYP isoenzymes in the brain. 69 Carbon monoxide also inhibits CYP enzymes in vitro in a dose-dependent manner. 69 Smoking status should be assessed when deciding on migraine preventive treatments, and a smoking cessation strategy should be considered.

Genetic variations and polymorphisms in different ethnic popu-
lations should also be considered when assessing drug metabolism, although it is accepted that in this regard race is an imprecise term and can reflect heterogeneous populations. 70 Most genes encoding CYP450 isoenzymes are highly polymorphic, with certain variants being able to alter the rate of drug metabolism in vivo. 71 Besides CYP450, some of the most common metabolism-related polymorphisms can be found in the P-glycoprotein (ABCB1 variant) and breast cancer-resistance protein (BCRP) genes (ABCG2 variant). 72 Additionally, P-glycoprotein expression is reduced by specific single nucleotide polymorphisms that are more prevalent in Asian and Caucasian populations. 73

Antiepileptic drugs
Divalproex sodium inhibits CYP2C9 and can decrease the clearance of drugs metabolized by CYP2C9. 77 Clearance of divalproex sodium is increased by enzyme-inducing medications, including rifampin, ritonavir, carbamazepine, lamotrigine, phenobarbital, and phenytoin, and serum concentration is increased by aspirin, fluoxetine, felbamate, isoniazide, and chlorpromazine. 19 Topiramate is unlikely to interact with highly protein-bound drugs and does not appear to alter the metabolism of most drugs.

However, it is an inducer of CYP3A4 and inhibitor of CYP2C19
and may alter the metabolism of drugs that are substrates of these enzymes (e.g., amitriptyline, cilostazol, verapamil). Topiramate displaces valproic acid from its plasma protein-binding site; however, this interaction may not be clinically significant.  Antibody-antibody interactions are also unlikely since clearance of immunoglobulin G is dependent on saturation of FcRn, but saturation is not likely to occur at typical therapeutic doses of monoclonal antibody. 87 No DDI information is available for mAb use with gepants.

MIG R AINE PRE VENTIVE THER APY DRUG-DIS E A S E CONS IDER ATIONS
When assessing preventive therapies for migraine, it is important to consider their interaction with drugs used to treat other conditions.
For example, the use of beta-blockers has been associated with an increased risk of cardiovascular events and a higher incidence of severe hypoglycemia among patients with diabetes mellitus. 89 Furthermore, nonselective beta-blockers, such as nadolol or propranolol, may lead to a higher risk of severe symptom exacerbation among patients with chronic obstructive pulmonary disease. 90 Although a large meta-analysis did not find evidence to support an increased risk of depressive symptoms in patients receiving beta-blockers, some clinicians still remain concerned about this possibility. 91 There have also been reports of depression in elderly patients receiving lipophilic beta-blockers, which is an important consideration given the high comorbidity of migraine with depression. 92,93 When using antiepileptic drugs for migraine, it is important to consider the patient's history with hypersensitivity to similar drugs, as some antiepileptic agents lead to high prevalence of rashes. 94 In the case of calcium channel blockers, there are some known The elimination pathway of a migraine preventive drug can affect patients in other ways as well. For example, topiramate has been shown to cause type 2 renal tubular acidosis, normal anion gap metabolic acidosis, and kidney stone formation. Therefore, physicians should observe for these side effects and advise patients to be vigilant about adequate hydration. 109

CON CLUS ION
Preventive treatments for migraine are recommended for a large proportion of patients with frequent migraine attacks.
These patients often exhibit a number of comorbidities, which TA B L E 3 PD effect resulting from known DDIs between preventive therapies and acute migraine medications