Glatiramer

Mechanism of Action

Glatiramer acetate is a 40 to 100 amino acid polymer composed primarily of 4 amino acids: L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, in a molar ratio of 4.2 to 3.4 to 1.4 to 1.0, respectively. The premise behind the drug's mechanism of action lies in the construct that patients with multiple sclerosis have antibodies directed against myelin basic protein (MBP), a component of the myelin sheaths of neurons within the central nervous system. Glatiramer acetate's chemical construct allows the drug to mimic MBP and thus serve as a decoy for the antibodies in these patients, decreasing the inflammatory response. Otherwise, the inflammatory response allows for the vulnerability of the blood-brain barrier to demyelination and axonal injury.[1]

The postulates from multiple clinical studies are that glatiramer acetate shifts the immune response from a pro-inflammatory state comprised of Th1 T-cells to regulatory, non-inflammatory Th2 T-cells. The introduction of the polymer allows it to bind to major histone compatibility (MHC) complex class II molecules on MBP-specific antigen-presenting cells, preventing MBP from stimulating these cells. Instead of the usual pro-inflammatory cytokine release, such as IL-2 and IL-12, anti-inflammatory cytokines, such as IL-1, IL-4, and IL-10, are the cytokines dispersed.[5]

While glatiramer acetate cannot penetrate the blood-brain barrier, the drug's ability to induce the peripheral Th2 cells and their subsequent crossing of the blood barrier reduces further inflammation within the CNS. This mechanism has been dubbed "bystander suppression."

In the preclinical trials thus far, researchers have noted that glatiramer acetate induces a neuroprotective or neuro-regenerative effect. The drug increases neurotrophic factors like brain-derived neurotrophic factor (BDNF), which research has discovered is vital to neuronal and glial cell survival. There is also evidence suggesting glatiramer's ability to induce remyelination and enhance neurogenesis.[5][6] In a study of T-cell lines obtained from glatiramer acetate-treated multiple sclerosis patients, reactive T-cells were found to secrete BDNF.[7][8]

Pharmacokinetics

Absorption: Radiolabeling techniques have evaluated the pharmacokinetics of glatiramer in animal studies. Maximum serum radioactivity is observed after 2 to 4 hours. Glatriamer is quickly absorbed after subcutaneous injection, with 10% remaining at the injection site after 1 hour.[9]

Distribution: Animal models suggest that glatiramer archives are distributed in the stomach and thyroid.

Metabolism: Hydrolysis is responsible for the metabolism of glatiramer to small peptides and amino acids.[10]

Elimination: The degradation of glatiramer primarily occurs in the subcutaneous tissue.[11]

Administration

Available Dosage Forms

Glatiramer acetate is administered by subcutaneous injection.

• Sites approved for injection include arms, abdomen, hips, and thighs
• Glatiramer acetate comes in 2 dosing schedules: 20 mg per mL per day or 40 mg per mL 3 times per week, with doses given at least 48 hours apart
• Glatiramer acetate 20 mg/mL and 40 mg/mL are not interchangeable
• It is recommended to rotate injection sites to minimize the occurrence of lipoatrophy
• Do not administer intravenously or intramuscularly
• It is recommended to allow the solution to warm to room temperature before administration

Adult Dosing

Glatiramer is indicated to treat relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults. The dosage for glatiramer acetate is 20 mg SQ once daily or 40 mg SQ 3 times a week (eg, Mon, Wed, Fri) administered at least 48 hours apart.

Given the positive results in reducing relapse rates by implementing glatiramer acetate therapy in multiple sclerosis patients, curiosity emerged regarding the effects of using the drug at a higher dosage. In 2007, researchers performed a phase II clinical trial comparing a high dosage of 40 mg glatiramer acetate to the standard dosage of 20 mg, encompassing 38 RRMS patients over 9 months. The efficacy assessment was the number of gadolinium-enhancing lesions on MRI. Results showed increased efficacy in the patients on the higher dosage of glatiramer acetate 40 mg as they demonstrated 2.26 lesions on MRI compared to 3.62 lesions seen on MRI in those patients on a standard dosage of 20 mg. In addition, safety profiles were comparable between the 2 groups.

The results prompted a phase III, randomized, double-blind, parallel-group trial that embodied over 1155 patients in over 136 sites across 20 different countries to compare daily administration of SQ 40 mg versus 20 mg glatiramer acetate in 1 year. The relapse rate assessed primary outcome efficacy in the first year, while MRI findings determined secondary outcome efficacy. At the end of 1 year, no statistically significant difference was found between the 2 groups; The standard 20 mg group had a 0.28 mean relapse rate, and the higher-dosed 40 mg group had a 0.27 mean relapse rate. The mean number of new T2 lesions and percentage of brain volume changes were similar between the 2 groups.[12]

In 2013, Khan et al performed a phase III, randomized, double-blind study trial including over 1404 patients with RRMS in over 142 sites in 17 countries, compared a high dose of 40 mg glatiramer acetate 3 times per week to placebo over 1 year. This study revealed a 34% reduction in risk of confirmed relapses in those receiving treatment compared to those receiving placebo, 0.331 vs 0.501, p=0.0001.[13] The cumulative number of gadolinium-enhancing lesions was statistically significantly less than the placebo, with p less than 0.0001. In 2014, glatiramer acetate 40 mg/mL 3 times a week was approved for RRMS by the FDA.

Specific Patient Population

Hepatic impairment: There is no information provided/studied on dose adjustments by the manufacturer.

Renal impairment: There is no information provided/studied on dose adjustments by the manufacturer.

Pregnancy considerations: The American Academy of Neurology (AAN) recommends against starting disease-modifying therapies for MS during pregnancy; an exception is females at high risk of MS activity. Therefore, patients should be instructed to immediately consult their healthcare provider if they are pregnant or plan to become pregnant while using glatiramer. Glatiramer is considered an FDA Pregnancy Category B medicine.

Breastfeeding considerations: Glatiramer is undetectable in most women and appears in only low concentration for up to 3 hours in others. Additionally, maternal use of glatiramer does not cause adverse effects in breastfed infants. Absorption by the infant is estimated to be minimal (<3%). Most experts consider glatiramer safe and a preferred disease-modifying agent for managing multiple sclerosis during lactation. For additional safety, breastfeeding could be withheld for 1 to 3 hours after a dose to prevent infant exposure.[14]

Pediatric patients: The safety and efficacy of glatiramer acetate have not been confirmed in patients younger than 18 years. However, glatiramer has been used off-label for pediatric-onset multiple sclerosis (POMS).[15]

Older patients: Glatiramer acetate has not been studied in older patients. According to a recent study, glatiramer can increase the risk of falls in older adults. However, other comorbidities and polypharmacy contributing to the increased risk of falls should be considered.[16]

Adverse Effects

The most commonly reported adverse effect of glatiramer acetate is injection site reaction, which manifests as a lump at the subcutaneous injection site. Approximately 10% of patients will report fever, chills, and aches. In addition, many patients have a transient immediate postinjection reaction of flushing, shortness of breath, and palpitations, which self-resolve within 30 minutes.[17]

Less than 1% of patients will develop lipoatrophy, a visible dent at the injection site due to local necrosis of adipose tissue.  

Serious but rare side effects to various organ systems, including cardiovascular, gastrointestinal, hematopoietic, lymphatic, musculoskeletal, nervous, and urogenital systems, have been noted, as has Jessner lymphocytic infiltrate, a cutaneous condition characterized by a persistent papule or plaque eruption.

Nicolau syndrome has been reported due to chronic glatiramer acetate treatment. Nicolau syndrome presents with pain, erythema, and discoloration at the injection site. The condition is characterized by ischemic necrosis of the skin and deeper tissue.[18][19]

Drug-Drug Interactions

Interactions between glatiramer and other drugs have not been studied or included in product labeling.[20] Vaccine responses are decreased to varying degrees in patients treated with glatiramer acetate.[21]

Contraindications

Contraindications

• Known hypersensitivity to glatiramer acetate or mannitol
• Not approved for use for patients younger than 18

Warnings and Precautions

• Anaphylactoid reactions and anaphylaxis have been reported.[22]
• Chest pain may precipitate as an immediate post-injection reaction and is usually transient pain, resolving in a few minutes. Episodes typically begin more than 1 month after starting treatment.
• Hepatic toxicity (cases of hepatitis and liver failure) has been reported, so advise the patient to watch for the signs/symptoms of liver dysfunction and consider discontinuing glatiramer if warranted.
• Glatiramer administration might interfere with the patient’s immune function. Therefore, AAN recommends screening for infections, including latent tuberculosis and hepatitis, before initiating immunosuppressive/immunomodulating (ISIM) in a population with a high risk of infections. A specialist should treat patients who test positive for latent infections.
• AAN recommends against administering live-attenuated vaccines in patients with MS who receive ISIM treatment. The recommendation is to delay the vaccination of people with MS who are experiencing a relapse.[23]
• Recent FDA safety alert: All autoinjectors are incompatible with FDA-approved glatiramer acetate. Counsel the patient that using an autoinjector that is not compatible may increase the hazard of medication errors, like missing a dose or administration of a partial dose.

Monitoring

A critical issue emerging regarding immunomodulating drugs like glatiramer is the generation of antibodies to the drugs themselves. While some studies have had conflicting results, researchers conducted a sera analysis study of 217 patients who participated in several glatiramer acetate trials' treatment and placebo arms. The subjects were tested for antibodies to glatiramer acetate via the ELISA method. IgG antibodies, mainly IgG1, were found in the patients who received active treatment. The titers increased to a peak concentration within 3 months of initiating treatment but slowly tapered off. The patients with higher antibody titers seem more likely to be relapse-free.[6]

Toxicity

There is no available information on glatiramer acetate overdoses. In severe hepatotoxicity, glatiramer should be discontinued. Corticosteroid treatment should be considered in severe and persistent liver injury.[10]

Enhancing Healthcare Team Outcomes

Glatiramer acetate is an immunomodulating medication for treating relapsing-remitting multiple sclerosis and a clinically isolated syndrome. Diagnosing relapsing and remitting multiple sclerosis may be challenging; it remains clear that few drugs, including glatiramer acetate, are proven to decrease exacerbations and may even offer neuroprotection.

Implementing an interprofessional approach with coordination with clinicians, neurologists, pharmacists, and other healthcare professionals is essential to have this medication approved and accessible to patients. Patient education is also crucial, explaining how the drug works and the expected clinical treatment course with likely outcomes. Nurses will be responsible for monitoring therapy as it progresses, noting adverse events, and answering patient questions while alerting the prescriber of any concerns. The prescriber should consult with a pharmacist, verifying dosing, interactions, and other pearls to make therapy more successful. If any interprofessional team member notes a change in patient status, adverse event, or interaction, they should be empowered to communicate this to the prescribing clinician so shared decision-making can lead to corrective action.

Glatiramer therapy is best when the administration and follow-up are through an interprofessional healthcare team that includes all healthcare providers working collaboratively to monitor treatment and ensure optimal patient therapeutic outcomes.