Secukinumab

Mechanism of Action

Interleukin-17 is a proinflammatory cytokine released by T-helper-17 (Th17) cells. Under the action of interleukin-6 and transforming growth factor-ß, CD4 T cells differentiate into Th17 cells and induce the expression of interleukin-23 receptors (IL-23R) and IL-17. Apart from T-cells, mast cells and neutrophils also secrete IL-17.

Interleukin-17 encompasses a group of cytokines, IL-17A to IL-17F, with IL-17A being the key effector cytokine. Furthermore, IL-17A is 10-30 more potent than IL-17F displaying a greater affinity to the interleukin-17 receptor (IL-17R).

The efferent pathway from binding to IL7R involves the secretion of chemokines (CCL20, CXCL1m CXCL8) that augments the inflammatory response while activating the innate immune system. The known effects of IL-17 become amplified by other cytokines such as tumor necrosis factor-a.[7]

Another effect of IL-17 is seemingly contradictory, being a stimulator of cancer cell invasion while promoting T-cell mediated tumor rejection. The significance is unknown due to a lack of evidence confirming a carcinogenic or protective.[8]

The basic concept underlying the usage of biologics is to block the disease process at a very early stage, being more specific and reducing the side effects of therapy. The number of IL-17A-producing lymphocytes resulting in raised IL-17A concentrations is observed in psoriatic arthritis and ankylosing spondylitis. Treatment with secukinumab can potentially reduce IL-17A levels in psoriatic plaques. Secukinumab specifically targets IL-17A, thereby blocking its binding with IL-17R and the expression of cytokines. This blockade normalizes the inflammatory processes and thus combats epidermal hyperproliferation, T-cell infiltration, and excessive expression of pathogenic genes.[7]

Pharmacokinetics: Pharmacokinetics (PK) of secukinumab is similar in patients with ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and non-radiographic axial spondyloarthritis.

Absorption: Following a single subcutaneous dose of 150 mg or 300 mg in plaque psoriasis subjects, Cmax for secukinumab is approximately achieved after six days of administration. Steady-state concentrations of secukinumab are observed by week 24 following the 4-week dosing regimens. Bioavailability ranged from 55% to 77% following the subcutaneous dose of 150 mg (one-half the recommended dose) or 300 mg.

Distribution: The concentration of secukinumab in interstitial fluid in lesional and non-lesional skin of plaque psoriasis patients varied from 27% to 40% of those in serum at one and two weeks after a single subcutaneous dose of 300 mg. It is important to note that secukinumab clearance and volume of distribution increase as body weight increases.

Metabolism: The metabolism of secukinumab has not been well defined. However, as secukinumab is a human IgG1 monoclonal antibody, it is hypothesized to be degraded into small peptides and amino acids via catabolic pathways in the same manner as IgG. 

Excretion: In clinical trials, after intravenous and subcutaneous administration, the systemic clearance (CL) varied from 0.14 L/day to 0.22 L/day, and the mean half-life varied from 22 to 31 days in patients with plaque psoriasis. The study also pointed out that injections of secukinumab into the abdomen or thigh using different delivery systems resulted in similar pharmacokinetic parameters.[9]

Administration

Secukinumab comes formulated as lyophilized powder of 150 mg in a vial, prefilled syringe, or a sensory-ready pen that requires storage at a cool temperature (2 to 8 degrees C).[10]

Before administration, the pen or prefilled syringe must be kept aside for 20 to 30 mins until it reaches room temperature. Next, product reconstitution is performed with 10 ml sterile distilled water, followed by gentle stirring to dissolve the powder, and kept aside for 10 mins. Finally, the solution must be inspected to be free of residual particles or discoloration, and administration must follow promptly.

A specialist physician should administer secukinumab while performing routine disease monitoring. It is given subcutaneously at sites such as the upper arm, thigh, and abdomen while avoiding sites of previous injection or tender, bruised, inflamed, indurated, or lesional skin.

The drug's pharmacokinetic profile is such that it will attain peak concentrations after 5-6 days and a two-fold increase achieved after monthly dosing that becomes stable after 20 weeks. The average bioavailability is 73%, while the distribution is primarily peripheral, thereby increasing its specificity. The half-life is 27 days, with its elimination being dose and time-dependent.[7]  

Adult Dosing

• Plaque psoriasis: 300 mg subcutaneous injection at 0, 1, 2, 3, and 4 weeks is given, followed by 300 mg SC injection every four weeks.[11]

• Psoriatic arthritis: Two regimens may be followed, with or without the loading dose. With loading dose, 150 mg is given subcutaneously at weeks 0, 1, 2, 3, and 4: followed by a dose every four weeks. Without loading dose, 150 mg via subcutaneous route at intervals of 4 weeks. In case of suboptimal response, clinicians can consider a dosage of 300 mg every four weeks.[11]

• Ankylosing spondylitis: Two regimens may be followed, with and without a loading dose. With loading dose, 150 mg is given subcutaneously at weeks 0,1,2,3, and 4: followed by a dose every four weeks. Without loading dose, 150 mg via subcutaneous route at intervals of 4 weeks. In case of no response, up-dosing to 300 mg is an option.[11]

• Non-Radiographic Axial Spondyloarthritis: Administer secukinumab with or without a loading dosage by subcutaneous injection. A Loading dose regimen is 150 mg at weeks 0, 1, 2, 3, and 4 and every four weeks after that. Without loading dose, 150 mg via subcutaneous route at intervals of 4 weeks.[11]

• Enthesitis-Related Arthritis: The dose of secukinumab is based on body weight. Secukinumab is administered by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by a dose every four weeks. For patients weighing ≥ 15 kg and < 50 kg, the suggested dose is 75 mg. For patients weighing ≥ 50 kg, the suggested dose is 150 mg.[11]

Specific Patient Population

Patients with Hepatic Impairment: According to product labeling, no clinical trial of the effect of hepatic impairment on the pharmacokinetics of secukinumab has been conducted.

Patients with Renal Impairment: According to product labeling, no clinical trial of the effect of renal impairment on the pharmacokinetics of secukinumab has been conducted.

Pregnancy Considerations: According to product labeling, limited human data on secukinumab use in pregnant women is inadequate to inform a drug-associated risk of adverse developmental outcomes. However, preclinical embryo-fetal development studies observed no adverse outcomes after subcutaneous secukinumab administration during organ development at 30 times MRHD(maximum recommended human dose). In addition, another study found no potential safety signals regarding spontaneous abortions or congenital malformations. However, the limitations of this research were a large amount of missing outcome data and the relatively short exposure to secukinumab.[12] Hence, the developmental and health benefits of breastfeeding should be evaluated, along with the mother's clinical requirement for secukinumab and possible adverse effects on the breastfed child from secukinumab or the underlying maternal condition.

Breastfeeding Considerations: There is a lack of information concerning the clinical use of secukinumab during breastfeeding. As secukinumab has a high molecular weight and is a big protein molecule, the concentration in maternal milk is likely to be very low. Secukinumab is also probably partially destroyed in the infant's gastrointestinal tract. However, significant research is still needed. Hence, clinicians should be cautious while prescribing secukinumab during breastfeeding.[13]

Adverse Effects

The most common adverse drug reactions with secukinumab are nasopharyngitis, upper respiratory tract infection, and diarrhea(>1%). Other adverse effects have been reported.[1][4][14] These include:

• Inflammatory bowel disease and exacerbation of Crohns disease
• Urticaria and anaphylaxis
• Headache
• Pruritus
• Hypertension
• Arthralgia and back pain
• Cough
• Rhinorrhea
• Infections 
• Pyoderma
• Malignancies 
• Nonmelanoma skin cancer (basal cell carcinoma, squamous cell carcinoma)
• Melanoma
• Bladder cancer
• Thyroid cancer
• Neutropenia
• Injection site reactions[15]
• Mucocutaneous candidiasis[16]

Contraindications

The absolute contraindications for using biologics are the presence of active infections, more importantly, latent or active tuberculosis, hepatitis B, C, and HIV, and hypersensitivity to secukinumab or latex.[17]

Other contraindications include:

• PUVA sessions
• Premalignant conditions
• Demyelinating disease
• Optic neuritis
• Multiple sclerosis
• Children
• Pregnancy and lactation
• Congestive heart failure
• Fever
• Jaundice or marked liver enzyme elevations
• Inflammatory bowel disease
• Concurrent use of live vaccines with secukinumab[18]

Monitoring

Baseline Monitoring

• Complete blood count and hemogram
• Erythrocyte sedimentation rate or C-reactive protein
• Liver function test
• Renal function test and urinalysis
• Serum electrolytes
• Anti-nuclear and anti-dsDNA antibodies
• Screening for hepatitis and HIV infection
• Chest X-ray
• Tuberculin skin testing or Quantiferon Gold test
• Pregnancy test in females of childbearing age
• Serology for varicella-zoster and measles. (if clinically indicated)    

Ongoing Monitoring

Evaluation of response to treatment is measurable by respective assessment scores, i.e., Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) at three months initially and subsequently every six months. A complete blood count and hemogram should be repeated at three months and every six months. Liver function tests, renal function tests, serum electrolytes, and urinalysis evaluations should be monitored at three months and every six months.[17][19] Neutralizing anti-secukinumab antibodies are detected infrequently (<0.4% of patients), but they are not associated with loss of efficacy or treatment failure.[6]

Toxicity

The safety profile of secukinumab leaves it highly recommendable. Since secukinumab interferes with the normal immune process, it enhances the risk of infections, including staphylococcal and candidal; however, mild disease results and is not disseminated. Another possible toxic effect is the carcinogenic potential, with existing reports of malignancies such as non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma), melanoma, bladder cancer, and thyroid cancer.[1] 

According to product labeling, in clinical trials, doses of 30 mg/kg intravenously have been administered without toxicity. However, the patient should be monitored for any signs or symptoms of toxicity and adverse drug reactions in the event of overdosage. There is no antidote to secukinumab. Management is primarily supportive.

Enhancing Healthcare Team Outcomes

The common notion related to biologic therapy is the necessity for lifelong or long-term treatment, the failure of which can lead to incomplete resolution or recurrences. With secukinumab, relapses and recurrences are less frequent and can be preventable with a maintenance regime of fixed-interval dosing. Also, following patient education by an interprofessional team including clinicians (MDs, DOs, NPs, and PAs), specialists (e.g., a rheumatologist), nurses, and pharmacists, subsequent doses can be self-administered increasing patient compliance and adherence.[7] The pharmacist can verify all dosing, check for drug-drug interactions, and counsel the patient on adverse events and signs that would warrant contacting their clinician. Nurses can also provide counsel, monitor therapeutic progress and adverse events, and verify patient compliance. All interprofessional team members must monitor patient progress, document any concerns or status changes, and communicate promptly with the appropriate team members in the event therapeutic changes are in order. These examples show how an interprofessional team approach can optimize outcomes with secukinumab therapy. [Level 5]

Patients on active secukinumab therapy should avoid live vaccines and contact with infectious agents due to the markedly depressed immunity that can lead to infection. Furthermore, the administration of non-live vaccines is also discouraged due to the unlikelihood of mounting a desired immune response.[17] The likelihood of a history of latent or active tuberculosis with no confirmation of complete therapy or recent travel to a country with a high prevalence of tuberculosis may warrant a course of empiric anti-tubercular treatment.

A study identified that Continuing Professional Development (CPD) programs could facilitate interprofessional collaboration in managing chronic diseases such as psoriasis and psoriatic arthritis. Interprofessional collaboration between dermatologists, rheumatologists, and clinicians can improve patient outcomes through early diagnosis to prevent joint damage and alleviate long-term socioeconomic consequences in patients with psoriasis and psoriatic arthritis.[20]