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Biological treatment in Pediatrics patients.pptx

Biological treatment in Pediatrics patients

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Biological treatments in Pediatrics patients types, uses and safety considerations Prepared by: Yahya Nawzad Khalid SHO Clinical Pharmacy, KHCMS Supervised by: Dr. Azad A. Haleem Al. Mezori Professor of Pediatric & Pediatric Endocrinology
Introduction • Biological products “Biologics” :are a diverse category of products and are generally large, complex molecules. These products may be produced through biotechnology in a living system, such as a microorganism, plant cell, or animal cell, and are often more difficult to characterize than small molecule drugs. FDA • Small molecules (conventional) medications are typically chemically synthesized, smaller, and simpler in structure (90% of available drugs).
Biologics vs Biosimilars • Biosimilars: Are biologic medications that are highly similar to an existing, FDA-approved biologic (the reference product). • They are not identical to the reference product, but they have no clinically meaningful differences in terms of safety, purity, and potency. • They are generally more affordable than the original biologics • Relatively a similar concept as Brand vs Generic
The term “biologic” technically includes many commonly used medications like: • Insulins, Heparin, Albumin, • Erythropoietin (Epoetin alfa, Darbepoetin alfa) • Immunoglobulins (IVIG) • G-CSF (Filgrastim/Pegfilgrastim) • Recombinant hormones (Somatropin, FSH, HCG) • Vaccines • Blood products • Antivenoms
General classification of biologics 1. Monoclonal Antibodies (mAbs) eg. adalimumab, omalizumab 2. Fusion Proteins eg. etanercept, Abatacept 3. Cytokines and Growth Factors 4. Enzyme Replacement Therapies (ERT) eg. Imiglucerase, Alglucosidase alfa, Idursulfase, Taliglucerase alfa ( produced in genetically modified carrot cells) 5. Vaccines (live-attenuated, inactivated, mRNA, vector-based) 6. Gene and Cell Therapies eg CAR T-cell therapy (e.g., tisagenlecleucel) 7. Immunoglobulin Products e. IVIG 8. Hyperimmune globulins eg. Rabies, tetanus
Biological Treatments and Sites of Action Category Examples Site of Action / Target Clinical Uses Cytokine inhibitors Anti-TNF: infliximab, adalimumab, etanercept TNF-α (pro-inflammatory cytokine) in the extracellular space Rheumatoid arthritis, Crohn’s disease, psoriasis Interleukin inhibitors Anti-IL-6 (tocilizumab), Anti-IL-1 (anakinra), Anti-IL-17 (secukinumab), Anti-IL-12/23 (ustekinumab) Block specific interleukins or their receptors in the inflammatory cascade RA, psoriasis, IBD, ankylosing spondylitis B-cell targeted therapies Rituximab (anti-CD20) CD20 on B lymphocytes → depletion of B-cells Lymphomas, RA, multiple sclerosis T-cell co-stimulation modulators Abatacept (CTLA4-Ig) Blocks CD80/86 on APCs, preventing T-cell activation via CD28 RA, juvenile idiopathic arthritis Cell adhesion molecule inhibitors Natalizumab (anti-α4 integrin), vedolizumab Block integrins on leukocytes → prevent migration across endothelium MS, Crohn’s disease, ulcerative colitis Immune checkpoint inhibitors Anti-CTLA-4 (ipilimumab), Anti-PD- 1 (nivolumab), Anti-PD-L1 (atezolizumab) Block inhibitory receptors on T- cells to enhance anti-tumor immunity Various cancers Growth factor inhibitors Bevacizumab (anti-VEGF) Inhibits VEGF → reduces angiogenesis Cancers, macular degeneration Enzyme replacement therapies Laronidase, galsulfase, idursulfase Replace deficient lysosomal enzymes in specific cells/tissues Lysosomal storage diseases Complement inhibitors Eculizumab (anti-C5) Inhibits cleavage of C5 in complement cascade PNH, atypical HUS
Biological Treatments and Sites of Action Key Points About Sites of Action -Extracellular space → cytokine neutralization (e.g., anti-TNF, anti-IL drugs) - Cell surface → receptor blockade or depletion of immune cells (e.g., rituximab, abatacept) - Intracellular signaling pathways → less common for biologics (more for small molecules), but some antibody-drug conjugates deliver cytotoxic payloads inside cells - Tissue-specific targets → e.g., gut-selective integrin blockade in IBD
Types of monoclonal antibodies Type Description Examples Suffix Murine 100% mouse protein; highly immunogenic Not commonly used now -momab (e.g., Muromomab-CD3) Chimeric ~65–70% human, variable region from mouse Infliximab, Rituximab -ximab Humanized >90% human; only antigen-binding site (CDR) from mouse, less immunogenic Omalizumab, Palivizumab -zumab Fully Human 100% human protein; least immunogenic Adalimumab, Dupilumab -umab
Biologics in Pediatric Patients • In pediatric patients, biologics are used to treat a range of Autoimmune, Allergic, Autoinflammatory, and Oncologic conditions. Disease Category Examples Common Biologic Agents Used Rheumatologic Juvenile Idiopathic Arthritis (JIA) Etanercept, Adalimumab, Tocilizumab, Anakinra Gastrointestinal (IBD) Crohn’s disease, Ulcerative colitis Infliximab, Adalimumab, Vedolizumab, Ustekinumab Dermatologic Atopic dermatitis, Psoriasis Dupilumab, Secukinumab Allergic/Asthma Severe eosinophilic asthma, urticaria Omalizumab, Mepolizumab, Dupilumab Immunodeficiency/Autoinflammatory CAPS, HLH, FMF, CGD Anakinra, Canakinumab, Emapalumab, IFN-γ Hematologic/Oncologic Leukemia, Lymphoma, Hemophilia Rituximab, Blinatumomab, Emicizumab, CAR-T cells Neurologic Neuromyelitis optica, MS Eculizumab, Natalizumab
Types of Biologic Agents in Pediatrics Class Mechanism of Action Examples Anti-TNF agents Block tumor necrosis factor (TNF-α) Infliximab, Adalimumab IL-1 blockers Block interleukin-1 pathway Anakinra, Canakinumab IL-6 blockers Block interleukin-6 receptor Tocilizumab IL-4/13 blockers Inhibit Th2 cytokine signaling Dupilumab IL-12/23 or IL-17 inhibitors Target key psoriasis cytokines Ustekinumab, Secukinumab Anti-IgE Binds free IgE to prevent allergic reactions Omalizumab B-cell targeted Depletes or modulates B cells Rituximab Checkpoint inhibitors Immune modulation in pediatric oncology Nivolumab, Pembrolizumab CAR-T cells Engineered T-cells targeting cancer antigens Tisagenlecleucel
Safety and Monitoring - Increased risk of infections (e.g., TB, HSV, fungal) - Live vaccines generally contraindicated during biologic therapy - TB and hepatitis screening before initiation - Monitor growth, lab parameters, and infection signs - Possible adverse effects: injection site reactions, malignancy (rare)
Clinical pharmacy consideration • Dosing and Administration • Primarily weight or BSA based dosing • Routes: subcutaneous, intravenous; no oral forms • PK/PD Differences • Growth and developmental variability alters pharmacokinetics • Dosing adjustments required as patients grow. • TDM guides dose optimization to maximize efficacy and reduce immunogenicity.
Clinical pharmacy consideration • Immunogenicity • Higher in children due to: • Immature immune regulation • Variable exposure • Potential interruptions in therapy • Anti-drug antibodies (ADAs) can: • Reduce efficacy • Increase infusion/injection reactions • Concomitant immunomodulators (e.g., methotrexate) may reduce ADA formation.
Clinical pharmacy consideration Adherence and Counseling • Key in chronic pediatric diseases. • Educate child and caregiver on: • Purpose, dosing schedule, and storage • Signs of infection or hypersensitivity • Proper injection technique • Address fears (needle phobia), psychosocial impact, and family dynamics. • Consider medication adherence tools (reminder apps, calendar tracking).
Biologic Therapies used for asthma biologics should be considered in children with specific asthma phenotypes: • (1) omalizumab (anti-IgE) can be used in children ≥6 years old with severe allergic asthma • (2) mepolizumab (anti–IL-5) (≥6 years), dupilumab (anti–IL-5 Rα) • (≥6 years), and benralizumab (anti–IL-4 Rα) (≥12 years) can be used in children with severe eosinophilic asthma. • (3) tezepelumab (anti-TSLP) (≥12 years) can be used in children with severe asthma. • The FDA issued a black box warning regarding risk of anaphylaxis and need for patient monitoring with use of omalizumab
Biologic Therapies used for asthma Benefits of Biologics in Pediatric Asthma • Reduce exacerbations • Improve lung function (FEV1) • Decrease oral corticosteroid use • Improve quality of life • Better asthma control and symptom relief
Biologic Therapies used for asthma Monitoring • Evaluate for eosinophil counts, IgE levels, allergen sensitivity • Rule out parasitic infections before anti–IL-5 agents • Watch for injection-site reactions, hypersensitivity • Reassess response after 4–6 months of therapy • Live vaccines generally avoided during therapy
Biologics used in JIA
Biologics used in JIA TNFα Antagonists • Etanercept • Fusion protein: 2 TNF receptor monomers + Fc portion of IgG1 • Binds TNF-α and lymphotoxin-α (TNF-β) • Effective in ~75% of MTX-refractory polyarticular JIA after 3 months • Dosing: • 0.8 mg/kg SC weekly (max 50 mg) • Or 0.4 mg/kg SC twice weekly (max 25 mg/dose)
Biologics used in JIA TNFα Antagonists • Adalimumab • Fully human monoclonal antibody against TNF-α • Used alone or with MTX • Study data: lower disease flare rate vs placebo (43% vs 71%) • Dosing (SC every other week): • 10 mg (10–<15 kg), 20 mg (15–<30 kg), 40 mg (≥30 kg)
Biologics used in JIA TNFα Antagonists • Golimumab • Human monoclonal antibody against both soluble and transmembrane TNF • FDA-approved for polyarticular JIA • IV dosing: 80 mg/m² at weeks 0 & 4, then every 8 weeks • Also used (off-label) in psoriatic arthritis
Biologics used in JIA Infliximab • Chimeric mouse-human mAb • Off-label in JIA (did not meet JIA trial endpoints) • Approved for pediatric IBD • Also used in uveitis, Behçet syndrome, sarcoidosis Certolizumab Pegol • Pegylated humanized anti-TNF mAb • FDA-approved for RA, PsA, AS in adults • Currently under pediatric trials for JIA
Biologics used in JIA Modulator of T-Cell Activation • Abatacept • Selective T-cell costimulation inhibitor, Induces T-cell anergy, reducing inflammation • Uses Approved for moderate to severe polyarticular JIA in children ≥4 years
Biologics used in JIA • Intravenous (IV) Administration • Every other week for 3 doses (Weeks 0, 2, 4), then monthly • Weight-based dosing: • <75 kg: 10 mg/kg/dose • 75–100 kg: 750 mg/dose • 100 kg: 1,000 mg/dose • Max dose = 1,000 mg • Subcutaneous (SC) Administration (FDA approved since 2017) • Weekly SC injections • 50 mg (10–25 kg) • 87.5 mg (25–<50 kg) • 125 mg (≥50 kg)
Biologics used in JIA Anakinra • IL-1 receptor antagonist: IL-1α & IL-1β (Cytokine receptor blockade) • SC: 1–2 mg/kg daily • FDA: RA (adults), Pediatric use niche: Systemic JIA, CAPS Canakinumab • IL-1β monoclonal antibody • SC: Every 8 weeks (CAPS) | Every 4 weeks (sJIA) • FDA approved for CAPS and sJIA, EU approved for Gout
Biologics used in JIA B-Cell Depletion • Rituximab • Anti-CD20 chimeric mAb → depletes B cells (plasma cells spared) • FDA approved for: • GPA & MPA in children ≥2 years • Off-label: SLE (especially hematologic), RA • Adverse effects: infusion reactions, infections, cytopenias, HBV reactivation, rare PML
Biologics used in JIA Belimumab • Anti-BLyS human mAb → inhibits B-cell survival • FDA approved for SLE in children ≥5 years • Dosing: IV 10 mg/kg (every 2 weeks ×3, then every 4 weeks) • Side effects: infections, hypersensitivity, mood changes
Biologics used in JIA Tocilizumab • Anti–IL-6 receptor monoclonal antibody • Binds both soluble and membrane-bound IL-6 receptors • Uses Systemic JIA (sJIA) Polyarticular JIA • IV: Every 2 weeks (sJIA), every 4 weeks (polyarticular JIA) • SC: <30 kg: 162 mg every 3 weeks, ≥30 kg: 162 mg every 2 weeks • Aes: Elevated liver enzymes (transaminases) and Increased lipid levels
Biologics used in JIA Intravenous Immune Globulin (IVIG) • Contains pooled IgG antibodies from donors • Modulates immune response in autoimmune/inflammatory diseases • Kawasaki disease, Juvenile dermatomyositis, Lupus-associated thrombocytopenia, Polyarticular JIA (supportive evidence) • Dosing: 1-2g/kg given once monthly
Adverse Effects of TNF Inhibitors • Common AE: Injection site reactions, typically decreasing over time. • Infection Risk: Increased serious infections including sepsis, latent tuberculosis reactivation, and invasive fungal infections. Requires TB screening before starting therapy; treat latent TB prior to initiation. Avoid use in patients with chronic or recurrent infections. • Immune-Mediated Reactions: Lupus-like syndrome, leukocytoclastic vasculitis, interstitial lung disease, demyelinating syndromes, antibody formation, rashes, cytopenias, anaphylaxis, serum sickness. • Malignancy Risk: theoretically increased risk of malignancy, though long-term safety remains uncertain. • Overall: After over 10 years’ use, benefit/risk remains favorable but long-term TNF suppression safety is relatively unknown.
Biologic Therapies in Pediatric Crohn Disease infliximab • Chimeric anti-TNF-α mAb • Rapid onset; IV infusion at weeks 0, 2, 6 → then every 8 weeks • Benefits: Induces/maintains remission, heals fistulas, steroid sparing, promotes growth, prevents recurrence • Monitoring: Trough levels, TB screening before starting • Challenges: Variable response, antibody formation → infusion reactions, dose escalation often needed
Biologic Therapies in Pediatric Crohn Disease Adalimumab • Fully humanized mAb against TNF-α • Treatment of chronically active moderate to severe Crohn disease in adults and children. • Dosing: Loading dose then once every 2 weeks. (dose escalation might be needed) • SC administration
Biologic Therapies in Pediatric Crohn Disease Vedolizumab • humanized mAb that inhibits adhesion and migration of leukocytes into the GI tract • Dosing: IV infusion at weeks 0, 2, 6 → then every 8 weeks • Slower onset of action than infliximab and adalimumab therefore concomitant therapy might be needed until response is demonstrated. • Dose escalation every 4 weeks may be necessary in patients with loss of response (being studied)
Biological agents used in Psoriasis • TNF-α inhibitors such as Etanercept, infliximab and adalimumab • IL-12/23 inhibitor Ustekinumab • IL-17 inhibitors secukinumab and ixekizumab • IL-23 inhibitors may also have a role in the treatment of severe disease and are being studied in pediatric populations.
Gene therapy
Summary • Precise action on immune pathways (e.g., TNF-α, IL-4, IL-6) → better disease control, fewer systemic side effects and less potential for drug interactions • Can alter disease progression in chronic conditions like JIA, IBD, asthma • Reduces or eliminates long-term corticosteroid use and associated complications • Improved inflammation control promotes normal growth and nutritional recovery • Fewer flares, less pain, reduced school absence, and improved daily functioning • Many biologics work quickly and maintain long-term remission with proper dosing • Generally well tolerated in children when guided by appropriate screening and lab monitoring
Biological treatment in Pediatrics patients.pptx