Migraine, Medicine

Migraine Relief on the Horizon?

I compare two different drugs to treat migraine relief

General Introduction

Migraine is an 11 billion dollar problem and is also, in fact, the most prominent form of neurological disability (Hawkins, 2008; Vos, et al., 2017). Migraines are characterized by unilateral headaches that can persist up to 72 hours after onset (Yuan, Lauritsen, Kaiser, & Silberstein, 2017). These pulsing sensations also come with increased sensitivity to light and sound (“The International Classification of Headache Disorders, 3rd edition (beta version)”, 2013). Two major conditions of the neurological disorder are episodic (classified as 1–14 migraine days per month) and chronic migraine (excess of 15 migraine days per month) (Edvinsson, Haanes, Warfvinge, & Krause, 2018).

Considering the large economic costs of the neurological condition and its effects on quotidian life, it’s imperative to develop methods of alleviating migraine severity and/or preventing migraine onset. Recent migraine prevention and treatment efforts have gotten more traction with respect to monoclonal antibodies that selectively act on ligands/receptors involved in the migraine induction pathway (Edvinsson, Haanes, Warfvinge, & Krause, 2018). Monoclonal antibodies are a promising venue for migraine treatment and are specifically being produced for the purpose of addressing migraines. Monoclonal antibodies are antibodies that are derived from a singular cell line. The drug of interest that will be explored in upcoming sections is a fully humanized monoclonal antibody. This is significant because a fully humanized antibody is synthesized primarily using human protein in order to prevent or reduce the likelihood of immune system rejection of the antibody (Shapiro & Fazio, 2017).

Administration Routes

AJOVY administration route is solely subcutaneous. It doesn’t cross the blood-brain barrier. The method of administration specifically is through subcutaneous injection in the abdomen, thigh, or upper arm (Teva Pharmaceuticals, 2018). Studies have been done where the drug was administered intravenously in male and female rats, there was an inhibitory sequencing of neuronal activity merely hours after administration rather than the typical expected duration of days. A mechanism has yet to be determined, but one proposed mechanism is that the CGRP-mAB complex may indirectly act to inhibit peripheral target neurons (Melo-Carillo, et. al., 2017).

Drug Action & Drug Effects

After AJOVY is injected, the drug gets distributed in several tissues, including the spleen, kidneys, lungs and heart. The drug acts as an antagonist by tightly binding to the ligand implicated in the pathway for inducing migraine. This ligand, Calcitonin gene-related peptide (CGRP), once bound to the humanized monoclonal antibody AJOVY, can’t activate CGRP co-receptors, specifically, receptor activity-modifying protein 1 (RAMP1) and calcitonin receptor-like receptor (CLR). The drug effects are thus, as such the prevention of vasodilation of cerebral and dural blood vessels. A downstream effect is that cAMP release is dose-dependently inibited by AJOVY (Shou, 2017).

Neurotransmitter/Hormonal Systems (that the drug acts on)

CGRP is a neuropeptide that is 37-amino acids in length and can primarily be found cell bodies of ventral and dorsal root neurons (Bigal, et. al., 2015). On the other hand, the AJOVY monoclonal antibodies are significantly larger (150 kilo-Daltons) and thus when bound to CGRP has an even lower likelihood of penetrating the blood brain barrier (Bigal, Walter, & Rapoport, 2013).

As part of the body’s hormonal system, CGRP has a role in the cardiovascular system. Specifically, it’s responsible for vasodilation and it’s been shown to induce migraine effects after injection. CGRP release can be triggered by capsaicin (found in chili peppers) and elevate its presence in the body (Jansen-Olesen, Mortensen, & Edvinsson, 1996). It’s location is contained mostly to the trigeminal system, in cranial vessel nerves that emerge from the anterior cranium (Goadsby & Edvinsson, 1994).

Receptors/Mechanism Involved in Main and Side Effects

There are two isoforms of calcitonin gene-related peptide (CGRP) that exist in the body — alpha and beta-CGRP. Alpha-CGRP and beta-CGRP are found in various parts of the body, including but not limited to the GI tract, vascular system, immune cells, and nervous system. The sensory nervous system has greater concentrations of alpha isoform whereas the enteric plexus and pituitary has a greater concentration of the beta isoform (Muddhrry, et al., 1988; Schütz, Mauer, Salmon, Changeux, & Zimmer, 2004).

Aδ nociceptor activation was inhibited due to AJOVY administration, whereas unmyelinated C nociceptors were unaffected. This is likely due to the exclusive presence of calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in the myelinated Aδ nociceptive fibers (Melo-Carrillo, et al., 2017). This could have implications on the drug effects noted by AJOVY injection. As we’ll see how these receptors in particular have been studied with regards to the CGRP ligand.

Specificity of Drug Action

While we’ve discussed the calcitonin gene-related peptide (CGRP) as it is AJOVY’s target, the CGRP receptor has some structural features worth noting. It is composed of three distinct subunits, alluded to before, receptor activity-modifying protein 1 (RAMP1), receptor component protein (RCP) and calcitonin-like receptor (CLR). The calcitonin receptor and RAMP1 receptors compose the AMY1 receptor which is bound by the CGRP. The receptor is G-protein coupled, which allows for the variable modularity in activation. For example, while CGRP has a high affinity for the AMY1 co-receptor, it has a lower affinity for CLR-based adrenomedullin receptors (Cieślak, Czarnecka, Roszek, & Komoszyński, 2015). AJOVY is a highly specific antibody that targets the neuropeptide CGRP; therefore, its logical to assume that it doesn’t bind to drug depots. No research has shown existence of drug depot binding (Teva Pharmaceuticals, 2018).

Metabolism and any effects that it may have on tolerance

It has been generally observed that medications existing to prevent migraines from occurring become less efficacious over time. There hasn’t been any noted instances of tolerance from AJOVY as a monoclonal antibody over time. The closest analogue to the drug in question is Botox, which has been shown to remain consistently efficacious (Russo, 2015). Enzymes break down AJOVY through proteolysis, and the byproducts are cleared from the body at a rate of 0.141 L/day (Teva Pharmaceuticals, 2018).

No doseage adjustments are required for patient populations based on factors including race, age, weight and sex and there haven’t been any noted problems in patients with renal/hepatic weakening. However, this is also due to the fact that there aren’t any studies published yet on how patients in the aforementioned populations would process the drug compared to other existing medications. There doesn’t appear to be any drug interactions between the antibody and cytochrome P450 enzymes because they don’t metabolize it. There were studies done with different acute treatment medications being administered and despite their presence, there wasn’t a noted effect on AJOVY exposure (Teva Pharmaceuticals, 2018).

Comparison Drug — Imitrex

Imitrex is another established drug that has purported use as migraine relief medication. If the drug is taken orally, it will be subject to first pass metabolism by the liver and will also have more variable concentration than other administration routes like subcutaneous injections (Derry, Derry, & Moore, 2014). Imitrex doesn’t easily cross the blood-brain barrier (Tfelt-Hansen, 2009). Imitrex operates by serving as an agonist for the serotonin receptors; specifically, 5-HT1B and 5-HT1D. This form of Imitrex is an acute treatment for migraine in adults (GSK Group of Companies, 2017). The drug thus, is acting on the serotonergic system; specifically on the trigeminal neurons. This is because the activation of the aforementioned serotonin receptors results in the inhibition of calcitonin gene-related peptide (CGRP) release. These receptors are thus located presynaptically. The mediation of the CGRP release has a similar drug effect of alleviating migraines by lowering the levels of CGRP circulating the body (Goadsby & Edvinsson, 1994).

While there haven’t been complete studies as to the effect of hepatic/renal impairment on the circulation of the monoclonal antibodies, Imitrex tablets are contraindicated in these patient populations (GSK Group of Companies, 2017). Overdosing is another possible outcome of excess imitrex administration. Animals exhibited severe adverse effects such as paralysis and convulsions after overdose. Patient populations who are undergoing pregnancy may want to hold off on Imitrex adminstration as it has been shown to result in fetal injury in animal models (GSK Group of Companies, 2017).

Evaluation of Imitrex in light of AJOVY availability

As we can see, while both AJOVY and Imitrex seek to achieve the same mollifying effect on migraine in individuals, they are different in many ways. However, once again, a key point to consider is that there is still much to be observed regarding aversive effects that may arise due to the chronic administration of the drug. Imitrex appears to have more risks associated with it in certain patient populations whereas AJOVY, while emerging appears safer, quicker acting, and requires fewer administrations per month relative to Imitrex tablets (Teva Pharmaceuticals, 2018).

Supplemental Thoughts

There are a few issues that still need to be addressed with regards to the migraine relief drug AJOVY. Platelet aggregation is kept in check via cAMP activity through the presence of the CGRP ligand. It’s been proposed that perhaps, CGRP inhibition would result in the increase in clot formation events that could thus harm the patient. Another thing to note would be that a small percentage of the monoclonal antibodies still make their way into the central nervous system and it is unknown if this small amount is a significant enough factor to be considered in the mechanism of action (Maassenvandenbrink, Meijer, Villalón, & Ferrari, 2016; Deen, et al., 2017). Another thing worth noting is that there may be sex differences in response. The intravenous administration of AJOVY in male and female rats is significant partly because its one of the first to investigate both sexes response to the CGRP monoclonal antibody (Melo-Carillo, et. al., 2017). On the other hand, the follow-up study investigating the myelinated and unmyelinated nociceptors response to the AJOVY administration utilized only male rats. As a result, the data collected may have been different had females been included. More work needs to be done on evaluating the chronic effects of AJOVY and better elucidation of the mechanism of action is required in order to understand potential adverse effects in specific patient populations. However, existing research has shown the monoclonal antibody to be more efficacious and safe than some of its peers in the migraine medication field (Melo-Carillo, et. al., 2017).

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