Adalimumab

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Adalimumab Drug Information

Pharmacodynamics

Pivotal Studies - Crohns

Adverse Effects

Pharmacokinetics

Therapeutic Drug Monitoring

Adalimumab -Pharmacodynamics

Adalimumab is a TNF-α inhibitor that binds specifically to tumor necrosis factor-alpha, neutralizing its biological function and modulating TNF-induced or regulated inflammatory responses.

Key Factors Affecting PK

Body weight: Higher weight associated with increased clearance
Anti-drug antibodies: Can increase clearance
Albumin levels: Lower levels may increase clearance
Age and gender: Minor effects
Concomitant methotrexate: Reduces immunogenicity and clearance

Steady State

Achieved in approximately 3 months with standard dosing
Minimal accumulation with bi-weekly dosing
Trough concentrations vary based on indication and dosing regimen

Therapeutic Drug Monitoring

Target trough concentrations vary by indication
Generally aim for >5 μg/mL in most autoimmune conditions
Higher targets may be needed for some indications

Acute Phase Response: Decreases in:

C-reactive protein
ESR
Serum amyloid A
Fibrinogen
Complement activation

CELLULAR EFFECTS:

Immune Cell Response:

Decreased T-cell activation
Reduced B-cell proliferation
Neutrophil migration inhibition
Monocyte deactivation
Decreased dendritic cell function

TIME COURSE:

Early Effects:

TNF-α neutralization: hours
Acute phase reduction: days
Clinical improvement: weeks

Sustained Effects:

Progressive inflammation reduction
Tissue repair: months
Disease modification: years

BIOMARKER CHANGES:

Inflammatory Markers:

Rapid CRP reduction
ESR normalization
Cytokine level changes
Metalloproteinase reduction

Disease-Specific Markers:

Calprotectin (IBD)

RESISTANCE MECHANISMS:

Immunogenicity:

Anti-drug antibody formation
Neutralizing antibodies
Altered clearance
Reduced efficacy

Alternate Pathways:

TNF-independent inflammation
Compensatory mechanisms
Disease evolution
Tissue-specific factors

Adalimumab Pharmacokinetics

Adalimumab exhibits linear pharmacokinetics with a terminal half-life of approximately 2 weeks and reaches steady-state serum concentrations after 3 months of therapy when administered subcutaneously every other week.

Absorption

Subcutaneous bioavailability: ~64%
Time to peak concentration (Tmax): 5-6 days
Absorption is relatively slow and steady from the injection site

Distribution

Volume of distribution (Vd): 4.7-6.0 L
Limited distribution to extravascular spaces
Primarily remains in the vascular system
Minimal crossing of placental barrier

Elimination

Half-life: approximately 14 days (range 10-20 days)
Clearance rate: 11-15 mL/hour
No single predominant elimination pathway identified
Undergoes proteolytic degradation to amino acids
No significant renal or hepatic elimination

Key Factors Affecting PK

Body weight: Higher weight associated with increased clearance
Anti-drug antibodies: Can increase clearance
Albumin levels: Lower levels may increase clearance
Age and gender: Minor effects
Concomitant methotrexate: Reduces immunogenicity and clearance

Steady State

Achieved in approximately 3 months with standard dosing
Minimal accumulation with bi-weekly dosing
Trough concentrations vary based on indication and dosing regimen

Therapeutic Drug Monitoring

Target trough concentrations vary by indication
Generally aim for >5 μg/mL in most autoimmune conditions
Higher targets may be needed for some indications

Adalimumab -Pivotal Studies : UC

Adalimumab demonstrated efficacy in ulcerative colitis in ULTRA 1 and ULTRA 2 trials, showing significant improvement in clinical remission compared to placebo at week 8 and maintained through week 52.

ULTRA 1 Trial:

Design: Randomized, double-blind, placebo-controlled
Population: 576 patients (390 adalimumab, 186 placebo)
Inclusion: Adult UC patients with Mayo score 6-12, endoscopic subscore ≥2
Treatment arms:
- 160/80mg induction (160mg week 0, 80mg week 2, then 40mg week 4,6)
- 80/40mg induction
- Placebo
Primary endpoint: Clinical remission at week 8 (Mayo score ≤2, no subscore >1)
Results:
- Week 8 remission: 18.5% (160/80mg) vs 9.2% (placebo) (p=0.031)
- Clinical response: 54.6% (160/80mg) vs 44.6% (placebo) (p=0.047)
- Mucosal healing: 46.9% (160/80mg) vs 41.5% (placebo) (p=0.34)

ULTRA 2 Trial:

Design: Randomized, double-blind, placebo-controlled
Population: 494 patients (248 adalimumab, 246 placebo)
Treatment: 160/80mg induction, then 40mg EOW
Stratification by prior anti-TNF use (~40% experienced)
Co-primary endpoints: Clinical remission at weeks 8 and 52
Results:
- Week 8 remission: 16.5% vs 9.3% (p=0.019)
- Week 52 remission: 17.3% vs 8.5% (p=0.004)
- TNF-naive subgroup performed better:
  - Week 8: 21.3% vs 11% (adalimumab vs placebo)
  - Week 52: 22% vs 12.4%

ULTRA 3 Extension:

Design: Open-label extension study
Duration: Up to 4 years
Population: Patients completing ULTRA 1 or 2
Treatment: Adalimumab 40mg EOW or weekly
Results:
- Remission at year 4: 24.7%
- Mucosal healing at year 4: 27.7%
- Steroid-free remission: 20.1%
- Better outcomes in TNF-naive patients

SERENA Trial (2023):

Design: Randomized, double-blind
Population: Moderate-to-severe UC
Treatment arms:
- Standard induction (160/80mg)
- Higher dose induction (160mg at weeks 0,1,2,3)
Primary endpoint: Clinical remission at week 8
Results:
- Improved early response with higher dosing
- Better mucosal healing rates
- Similar safety profile

Safety Profile Across Studies:

Most common adverse events:
- Infections (nasopharyngitis, upper respiratory)
- Injection site reactions
- Headache
Serious adverse events comparable to placebo
No new safety signals in long-term follow-up

Adalimumab - Pivotal Studies : CD

Adalimumab demonstrated efficacy in Crohn's disease in the CLASSIC I, CHARM, and EXTEND trials, showing significant induction and maintenance of clinical remission compared to placebo.

CROHN'S DISEASE PIVOTAL STUDIES:

CLASSIC-I (Induction Trial) Design:

Phase III, randomized, double-blind, placebo-controlled
299 TNF-naïve moderate-severe CD patients
4-week study
Arms: placebo vs adalimumab (40/20mg, 80/40mg, or 160/80mg) at weeks 0/2

Primary Results:

Remission rates week 4 (CDAI <150):
- Placebo: 12%
- 160/80mg: 36% (p=0.001)
- 80/40mg: 24%
- 40/20mg: 18%
Established 160/80mg as optimal induction dose

CHARM (Key Maintenance Trial) Design:

Phase III, 56-week maintenance study
854 CD patients
Open-label induction (80/40mg)
Week 4 responders randomized to:
- Placebo
- 40mg EOW
- 40mg weekly

Key Results:

Remission rates at week 56:
- Placebo: 12%
- 40mg EOW: 36% (p<0.001)
- 40mg weekly: 41% (p<0.001)
Additional findings:
- Fistula healing improved
- Steroid-free remission achieved
- Sustained response through 56 weeks

Key Learnings Across Studies:

Dosing

CD optimal induction: 160/80mg
UC optimal induction: 160/80mg
Maintenance: 40mg EOW

Efficacy Predictors:

TNF-naïve status
Early clinical response
Baseline disease severity
Concomitant medications

Safety Profile:

Consistent with TNF class
No new safety signals
Similar across indications
Acceptable long-term profile

Clinical Impact:

Established efficacy in both CD and UC
Demonstrated maintenance benefit
Supported multiple indications
Defined optimal dosing regimens

Adalimumab - Monitoring

Adalimumab therapy requires monitoring for infections, injection site reactions, tuberculosis reactivation, liver function abnormalities, and therapeutic drug levels to ensure safety and efficacy.

Target Concentrations:

Induction phase: > 12 μg/mL
Maintenance phase:
- Most guidelines suggest: 5-12 μg/mL
- Optimal therapeutic window: 7.5-12 μg/mL
- Minimum trough for mucosal healing: >7.5 μg/mL

When to Check Levels:

Proactive monitoring:
- During induction (week 4)
- Early maintenance (week 8-12)
- Every 6-12 months if stable
- After major changes (weight, disease activity)
Reactive monitoring:
- Primary non-response
- Secondary loss of response
- Persistent disease activity

Before considering switch/discontinuation

Anti-Drug Antibodies (ADA):

Clinically relevant threshold: >8-10 AU/mL
Impact factors:
- Immunogenicity rate: 10-20%
- Lower with concomitant immunomodulators
- Higher with drug holidays/inconsistent dosing

Clinical Algorithm:

Low levels (<5 μg/mL):
- Without ADA: Dose intensification
- With low ADA: Consider adding immunomodulator
- With high ADA: Switch drug class
Therapeutic levels (5-12 μg/mL):
- With symptoms: Consider alternate mechanism
- Without symptoms: Continue current dosing
High levels (>12 μg/mL):
- With symptoms: Consider alternate mechanism
- Without symptoms: Consider dose de-escalation

Dose Optimization Strategies:

Dose intensification options:
- Increase to 40mg weekly
- Double dose (80mg) every other week
Factors affecting drug levels:
- Body weight
- Albumin levels
- Disease severity
- Inflammatory burden
- Concomitant medications

Laboratory:

FBC every 3-6 months
LFTs every 3-6 months
TB screening annually
CRP/ESR as needed
Lipid panel periodically

Clinical:

Signs/symptoms of infection
Skin examination
Neurological symptoms
Cardiac status
Overall disease activity

MONITORING REQUIREMENTS:

Pre-treatment Screening:
Essential Tests:
Tuberculosis screening:
Quantiferon Gold
Chest X-ray
Hepatitis B serology
Full Blood Count
Liver function tests
Baseline inflammatory markers
Additional Considerations:
HIV testing
Pregnancy test if applicable
Vaccination status review
Cancer screening as appropriate

Adalimumab - Drug Interactions

Concurrent use of adalimumab with live vaccines, other biologics, or immunosuppressants may increase infection risk, while methotrexate coadministration may decrease antibody formation against adalimumab.

Biological DMARDs & TNF Blockers (High Risk)

Absolute contraindications with concurrent use:
- Other TNF inhibitors (etanercept, infliximab, certolizumab, golimumab)
- IL-1 inhibitors (anakinra)
- IL-12/23 inhibitors (ustekinumab)
- IL-17 inhibitors (secukinumab)
- JAK inhibitors (tofacitinib, baricitinib)
Risks:
- Serious infections, Neutropenia
- Increased malignancy risk
- Additive immunosuppression

Traditional DMARDs (Requires Monitoring)

Methotrexate:
- Common combination therapy
- May increase adalimumab blood levels
- Monitor liver function closely
- Increased risk of hepatotoxicity
- Regular CBC monitoring needed
Sulfasalazine:
- Generally safe combination
- Monitor for blood dyscrasias
- Watch for liver function changes
Leflunomide:
- Monitor liver function
- Increased risk of immunosuppression
- Regular blood count monitoring

Immunosuppressants

Corticosteroids:
- Monitor for increased infection risk
- May mask infection symptoms
- Consider tapering steroids when possible
Cyclosporine/Tacrolimus:
- High risk of opportunistic infections
- Monitor renal function
- Check drug levels regularly

Live Vaccines (Contraindicated) Specific examples:

BCG vaccine
Measles-mumps-rubella (MMR)
Oral polio vaccine
Yellow fever vaccine
Varicella vaccine
Live influenza vaccine
Rotavirus vaccine
Smallpox vaccine Timing considerations:
Wait minimum 3 months after last adalimumab dose
Update vaccinations before starting therapy when possible

Antibiotics

May need earlier initiation due to masked infection signs
Monitor efficacy closely
Common combinations:
- Broad-spectrum antibiotics for serious infections
- Prophylactic antibiotics in high-risk cases

Hepatotoxic Medications Monitor closely with:

Acetaminophen
NSAIDs
Isoniazid
Methotrexate
Regular liver function monitoring needed

Specific Drug Classes Requiring Monitoring

A. Antihypertensives:

Beta-blockers: may mask infection symptoms
ACE inhibitors: monitor for neutropenia

B. Diabetes Medications:

Monitor glucose more frequently
May need dose adjustments

C. Anticoagulants:

Warfarin: monitor INR more frequently
DOACs: watch for bleeding risk
Consider dose adjustments

Risk Factors Affecting Interactions

Age > 65
Renal impairment
Hepatic dysfunction and Diabetes
Previous serious infections
Chronic lung disease

Adalimumab - Adverse Effects

Adalimumab may cause injection site reactions, serious infections, reactivation of tuberculosis, demyelinating disorders, heart failure exacerbation, lupus-like syndrome, and increased risk of certain malignancies.

SERIOUS ADVERSE EFFECTS:

Infections:

Serious infections including:
- Tuberculosis (new/reactivation)
- Pneumonia
- Sepsis
- Invasive fungal infections
- Opportunistic infections
- Listeriosis
- Legionellosis

Malignancies:

Lymphoma (including hepatosplenic T-cell)
Non-melanoma skin cancer
Melanoma
Leukemia
Higher risk in children/adolescents

Neurologic:

Demyelinating disorders
Multiple sclerosis
Optic neuritis
Guillain-Barré syndrome
Peripheral neuropathy

Cardiovascular:

New/worsening heart failure
Arrhythmias
Worsening of existing cardiac conditions

COMMON ADVERSE EFFECTS:

Administration-related:

Injection site reactions
- Pain
- Erythema
- Itching
- Hemorrhage
- Irritation

General:

Upper respiratory infections
Headache
Rash
Nausea
Fatigue
Back pain
Arthralgias

Surgery:

Hold medication pre-surgery
Monitor wound healing
Infection surveillance
Timing of restart

Pregnancy:

Pregnancy testing
Pregnancy registry enrollment
Breastfeeding considerations
Infant vaccination planning

PRACTICAL RECOMMENDATIONS:

Infection Prevention:

Avoid live vaccines
Annual influenza vaccination
Pneumococcal vaccination
Good hygiene practices

Cancer Screening:

Regular skin examinations
Age-appropriate screening
Prompt evaluation of symptoms
Risk factor modification

Laboratory Monitoring Schedule: Months 1-3:

Monthly FBC, LFTs
CRP/ESR as needed
Symptom assessment

Months 4-12:

Every 3 months FBC, LFTs
Regular clinical assessment
Disease activity measures

After Year 1:

Every 3-6 months routine labs
Annual TB screening
Regular clinical assessment

Adalimumab - Use in Pregnancy

Adalimumab crosses the placenta in the third trimester but is considered relatively low-risk during pregnancy, with limited data suggesting no increased risk of adverse pregnancy outcomes.

Mechanism & Transfer

Placental transfer occurs via FcRn receptor-mediated transport
Transfer increases exponentially after week 20
By term, fetal levels can exceed maternal levels
Half-life in infants can be 2-3 times longer than in adults

Safety Evidence:

A. Large Registries Data:

OTIS/MotherToBaby Registry
PIANO Registry
European pregnancy registries
TREAT Registry
CRADLE study

B. Key Findings:

No increased major malformation rates (comparable to general population ~2-3%)
No pattern of specific birth defects
Pregnancy outcomes similar to general population:
Miscarriage rates
Preterm birth rates
Birth weight distributions
APGAR scores

Disease-Specific Management:

Active disease carries higher risks than medication
Increased risks with active disease:
Preterm birth
Low birth weight
Pregnancy loss
Consider continuing through pregnancy if needed for disease control
Monitor disease activity with non-invasive markers

Timing Considerations:

A. Pre-conception:

No need to stop before conception
Ensure disease control before pregnancy
Consider vaccination status

B. During Pregnancy: First Trimester:

Safe to continue if needed
Limited placental transfer

Second Trimester:

Increasing placental transfer
Monitor disease activity

Third Trimester:

Consider stopping at 32-34 weeks if:
Disease is well-controlled
Risk of flare is acceptable

Continue through pregnancy if:

Active disease
High risk of flare
Previous pregnancy complications

Laboratory Monitoring:

A. Mother:

Regular disease activity markers
Liver function tests
Complete blood count
CRP/ESR as needed

B. Therapeutic Drug Monitoring:

Consider checking levels if concerned about disease activity
May help guide timing of discontinuation

Breastfeeding:

Minimal transfer into breast milk
IgG antibodies poorly absorbed orally
Benefits likely outweigh theoretical risks
Compatible with breastfeeding per ACR/EULAR guideline

Long-term Follow-up:

No evidence of developmental delays
Normal immune responses after 12 months
Regular pediatric care recommended
Monitor growth and development

Adalimumab : References

Pivotal Clinical Trials & Efficacy

Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology. 2006;130(2):323-333.
Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007;132(1):52-65.
Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn's disease: results of the CLASSIC II trial. Gut. 2007;56(9):1232-1239.
Rutgeerts P, Van Assche G, Sandborn WJ, et al. Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial. Gastroenterology. 2012;142(5):1102-1111.
Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142(2):257-265.
Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60(6):780-787.]

Comparative Effectiveness & Positioning

Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn's disease. Aliment Pharmacol Ther. 2018;48(4):394-409.
Singh S, Andersen NN, Andersson M, et al. Comparison of infliximab and adalimumab in biologic-naive patients with ulcerative colitis: a nationwide Danish cohort study. Clin Gastroenterol Hepatol. 2017;15(8):1218-1225.
Targownik LE, Benchimol EI, Witt J, et al. The effect of initiation of anti-TNF therapy on the subsequent direct health care costs of inflammatory bowel disease. Inflamm Bowel Dis. 2019;25(10):1718-1728.

Long-term Outcomes & Real-world Evidence

Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. 2018;390(10114):2779-2789.
Ma C, Huang V, Fedorak DK, et al. Adalimumab dose escalation is effective for managing secondary loss of response in Crohn's disease. Aliment Pharmacol Ther. 2014;40(9):1044-1055.
D'Haens G, Reinisch W, Colombel JF, et al. Five-year safety data from PYRAMID registry: adalimumab in 5057 patients with Crohn's disease. J Crohns Colitis. 2020;14(12):1695-1706.
Panaccione R, Colombel JF, Sandborn WJ, et al. Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE. Aliment Pharmacol Ther. 2013;38(10):1236-1247.

Pharmacokinetics & Therapeutic Drug Monitoring

Mazor Y, Almog R, Kopylov U, et al. Adalimumab drug and antibody levels as predictors of clinical and laboratory response in patients with Crohn's disease. Aliment Pharmacol Ther. 2014;40(6):620-628.
Papamichael K, Juncadella A, Wong D, et al. Proactive therapeutic drug monitoring of adalimumab is associated with better long-term outcomes compared with standard of care in patients with inflammatory bowel disease. J Crohns Colitis. 2019;13(8):976-981.
Vande Casteele N, Herfarth H, Katz J, et al. American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel disease. Gastroenterology. 2017;153(3):835-857.

Pregnancy & Special Populations

Mahadevan U, Robinson C, Bernasko N, et al. Inflammatory bowel disease in pregnancy clinical care pathway: a report from the American Gastroenterological Association IBD Parenthood Project Working Group. Gastroenterology. 2019;156(5):1508-1524.
Julsgaard M, Christensen LA, Gibson PR, et al. Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection. Gastroenterology. 2016;151(1):110-119.
Kanis SL, de Lima-Karagiannis A, van der Ent C, et al. Anti-TNF levels in cord blood at birth are associated with anti-TNF type. J Crohns Colitis. 2018;12(8):939-947.

Biosimilars

Cohen SB, Alonso-Ruiz A, Klimiuk PA, et al. Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis. Ann Rheum Dis. 2018;77(6):914-921.
Ye BD, Pesegova M, Alexeeva O, et al. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study. Lancet. 2019;393(10182):1699-1707.
Armuzzi A, Bouhnik Y, Keir M, et al. Long-term safety of adalimumab in immune-mediated disease: an international multicohort study. Inflamm Bowel Dis. 2022;28(8):1232-1242.