A Narrative Review of the Importance of Pharmacokinetics and Drug–Drug Interactions of Preventive Therapies in Migraine Management

Shivang Joshi MD, MPH, RPh; Stewart J. Tepper MD; Sylvia Lucas MD, PhD; Soeren Rasmussen MD; Rob Nelson PharmD, BCPS

Disclosures

Headache. 2021;61(6):838-853. 

In This Article

Pharmacokinetic Properties of Migraine Preventives

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, beta-blockers 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 α1-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 L/1.73 m2.[21]

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 Ca2+ channels, GABAA 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 400-mg 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.[46–50] 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.[47–50] Anti-CGRP antibodies are large molecules and do not readily cross the blood–brain barrier.[54]

Metabolism and Excretion

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 half-life 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 N-dealkylation and O-demethylation pathways.[39] The dealkylated products, norverapamil and desalkylverapamil, are metabolized to R- and S-verapamil by CYP3A4 and CYP3A5.[61–63] 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 approximately 34 h.[40]

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 11 h, and it is cleared mainly by the fecal and renal route.[44] Similarly, atogepant has an approximate half-life of 10 h.[45]

Monoclonal Antibody Therapies. Monoclonal antibodies are too large to be metabolized via renal or hepatic mechanisms and are metabolized and cleared via specific target-mediated clearance and nonspecific elimination by the reticuloendothelial system (RES), also known as the mononuclear phagocyte system (MPS).[66,67] These mechanisms occur in parallel and depend on antibody concentration. Clearance rates are high at low antibody concentrations and low at high antibody concentrations, as the antigen-dependent clearance pathway is saturated and clearance occurs through the RES/MPS.[66] Binding of therapeutic monoclonal antibodies to neonatal Fc receptors (FcRn) in the RES/MPS prevents clearance and contributes to the long half-life of monoclonal antibodies compared with small-molecule drugs.[66] The longer half-life of monoclonal antibodies allows for less frequent dosing, typically from 1 to 3 months (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.

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 populations 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]

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