Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated concentrations of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased concentrations of TNF are also found in psoriasis plaques. In Ps, treatment with ABRILADA may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown.
Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1–2 × 10-10M).
After treatment with adalimumab, a decrease in concentrations of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP concentrations was also observed in patients with Crohn's disease, ulcerative colitis, and hidradenitis suppurativa. Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.
The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following administration of a single intravenous dose (adalimumab products are not approved for intravenous use). Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab mean serum trough concentrations at steady state increased approximately proportionally with dose in RA patients. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics.
Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable with that in patients treated with 40 mg every week.
Absorption
The average absolute bioavailability of adalimumab following a single 40 mg subcutaneous dose was 64%. The mean time to reach the maximum concentration was 5.5 days (131 ± 56 hours) and the maximum serum concentration was 4.7 ± 1.6 mcg/mL in healthy subjects following a single 40 mg subcutaneous administration of adalimumab.
Distribution
The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients.
Elimination
The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients.
Patient Population
Rheumatoid Arthritis and Ankylosing Spondylitis: In patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations were approximately 5 mcg/mL and 8 to 9 mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum. The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.
Psoriatic Arthritis: In patients receiving 40 mg every other week, adalimumab mean steady-state trough concentrations were 6 to 10 mcg/mL and 8.5 to 12 mcg/mL, without and with MTX concomitant treatment, respectively.
Plaque Psoriasis: Adalimumab mean steady-state trough concentration was approximately 5 to 6 mcg/mL during adalimumab 40 mg every other week treatment.
Adult Uveitis: Adalimumab mean steady concentration was approximately 8 to 10 mcg/mL during adalimumab 40 mg every other week treatment.
Adult Hidradenitis Suppurativa: Adalimumab trough concentrations were approximately 7 to 8 mcg/mL at Week 2 and Week 4, respectively, after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations at Week 12 through Week 36 were approximately 7 to 11 mcg/mL during adalimumab 40 mg every week treatment.
Adult Crohn's Disease: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were 7 mcg/mL at Week 24 and Week 56 during adalimumab 40 mg every other week treatment.
Adult Ulcerative Colitis: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were approximately 8 mcg/mL and 15 mcg/mL at Week 52 after receiving a dose of adalimumab 40 mg every other week and 40 mg every week, respectively.
Anti-Drug Antibody Effects on Pharmacokinetics
Rheumatoid Arthritis: A trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies was identified.
Hidradenitis Suppurativa: In subjects with moderate to severe HS, antibodies to adalimumab were associated with reduced serum adalimumab concentrations. In general, the extent of reduction in serum adalimumab concentrations is greater with increasing titers of antibodies to adalimumab.
Specific Populations
Geriatric Patients: A lower clearance with increasing age was observed in patients with RA aged 40 to >75 years.
Pediatric Patients:
Juvenile Idiopathic Arthritis:
Pediatric Crohn's Disease: Adalimumab mean ± SD concentrations were 15.7 ± 6.5 mcg/mL at Week 4 following 160 mg at Week 0 and 80 mg at Week 2, and 10.5 ± 6.0 mcg/mL at Week 52 following 40 mg every other week dosing in patients weighing ≥40 kg. Adalimumab mean ± SD concentrations were 10.6 ± 6.1 mcg/mL at Week 4 following dosing 80 mg at Week 0 and 40 mg at Week 2, and 6.9 ± 3.6 mcg/mL at Week 52 following 20 mg every other week dosing in patients weighing <40 kg.
Male and Female Patients: No gender-related pharmacokinetic differences were observed after correction for a patient's body weight. Healthy subjects and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.
Drug Interaction Studies:
Methotrexate: MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA [see Drug Interactions (7.1)].
Adalimumab products bind specifically to TNF-alpha and block its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab products also lyse surface TNF expressing cells in vitro in the presence of complement. Adalimumab products do not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated concentrations of TNF are found in the synovial fluid of patients with RA, JIA, PsA, and AS and play an important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased concentrations of TNF are also found in psoriasis plaques. In Ps, treatment with ABRILADA may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism(s) by which adalimumab products exert their clinical effects is unknown.
Adalimumab products also modulate biological responses that are induced or regulated by TNF, including changes in the concentrations of adhesion molecules responsible for leukocyte migration (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1–2 × 10-10M).
After treatment with adalimumab, a decrease in concentrations of acute phase reactants of inflammation (C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A decrease in CRP concentrations was also observed in patients with Crohn's disease, ulcerative colitis, and hidradenitis suppurativa. Serum concentrations of matrix metalloproteinases (MMP-1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after adalimumab administration.
The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10 mg/kg following administration of a single intravenous dose (adalimumab products are not approved for intravenous use). Following 20, 40, and 80 mg every other week and every week subcutaneous administration, adalimumab mean serum trough concentrations at steady state increased approximately proportionally with dose in RA patients. The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. Healthy subjects and patients with RA displayed similar adalimumab pharmacokinetics.
Adalimumab exposure in patients treated with 80 mg every other week is estimated to be comparable with that in patients treated with 40 mg every week.
Absorption
The average absolute bioavailability of adalimumab following a single 40 mg subcutaneous dose was 64%. The mean time to reach the maximum concentration was 5.5 days (131 ± 56 hours) and the maximum serum concentration was 4.7 ± 1.6 mcg/mL in healthy subjects following a single 40 mg subcutaneous administration of adalimumab.
Distribution
The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients.
Elimination
The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients.
Patient Population
Rheumatoid Arthritis and Ankylosing Spondylitis: In patients receiving 40 mg adalimumab every other week, adalimumab mean steady-state trough concentrations were approximately 5 mcg/mL and 8 to 9 mcg/mL, without and with MTX concomitant treatment, respectively. Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum. The pharmacokinetics of adalimumab in patients with AS were similar to those in patients with RA.
Psoriatic Arthritis: In patients receiving 40 mg every other week, adalimumab mean steady-state trough concentrations were 6 to 10 mcg/mL and 8.5 to 12 mcg/mL, without and with MTX concomitant treatment, respectively.
Plaque Psoriasis: Adalimumab mean steady-state trough concentration was approximately 5 to 6 mcg/mL during adalimumab 40 mg every other week treatment.
Adult Uveitis: Adalimumab mean steady concentration was approximately 8 to 10 mcg/mL during adalimumab 40 mg every other week treatment.
Adult Hidradenitis Suppurativa: Adalimumab trough concentrations were approximately 7 to 8 mcg/mL at Week 2 and Week 4, respectively, after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations at Week 12 through Week 36 were approximately 7 to 11 mcg/mL during adalimumab 40 mg every week treatment.
Adult Crohn's Disease: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were 7 mcg/mL at Week 24 and Week 56 during adalimumab 40 mg every other week treatment.
Adult Ulcerative Colitis: Adalimumab mean trough concentrations were approximately 12 mcg/mL at Week 2 and Week 4 after receiving 160 mg on Week 0 followed by 80 mg on Week 2. Mean steady-state trough concentrations were approximately 8 mcg/mL and 15 mcg/mL at Week 52 after receiving a dose of adalimumab 40 mg every other week and 40 mg every week, respectively.
Anti-Drug Antibody Effects on Pharmacokinetics
Rheumatoid Arthritis: A trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies was identified.
Hidradenitis Suppurativa: In subjects with moderate to severe HS, antibodies to adalimumab were associated with reduced serum adalimumab concentrations. In general, the extent of reduction in serum adalimumab concentrations is greater with increasing titers of antibodies to adalimumab.
Specific Populations
Geriatric Patients: A lower clearance with increasing age was observed in patients with RA aged 40 to >75 years.
Pediatric Patients:
Juvenile Idiopathic Arthritis:
Pediatric Crohn's Disease: Adalimumab mean ± SD concentrations were 15.7 ± 6.5 mcg/mL at Week 4 following 160 mg at Week 0 and 80 mg at Week 2, and 10.5 ± 6.0 mcg/mL at Week 52 following 40 mg every other week dosing in patients weighing ≥40 kg. Adalimumab mean ± SD concentrations were 10.6 ± 6.1 mcg/mL at Week 4 following dosing 80 mg at Week 0 and 40 mg at Week 2, and 6.9 ± 3.6 mcg/mL at Week 52 following 20 mg every other week dosing in patients weighing <40 kg.
Male and Female Patients: No gender-related pharmacokinetic differences were observed after correction for a patient's body weight. Healthy subjects and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.
Drug Interaction Studies:
Methotrexate: MTX reduced adalimumab apparent clearance after single and multiple dosing by 29% and 44% respectively, in patients with RA [see Drug Interactions (7.1)].
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