Multiple-variable dose regimen for treating TNFa-related disorders
Multiple-variable dose methods for treating TNFα-related disorders, including Crohn's disease and psoriasis, comprising administering TNFα inhibitors, including TNFα antibodies, are described. Multiple-variable dose methods include administration of a TNF-inhibitor in an induction or loading phase followed by administration of the agent in a maintenance or treatment phase, wherein the TNF-inhibitor is administered in a higher dosage during the induction phase.
1 - 60 . (canceled)
61 . A method of treating Crohn's disease in a subject comprising administering to the subject a TNFα inhibitor such that a mean serum TNFα inhibitor trough level of about 12 μg/mL is achieved.
62 . The method of claim 61 , wherein the TNFα inhibitor is a human anti-TNFα antibody or antigen-binding portion thereof.
63 . The method of claim 62 , wherein the human anti-TNFα antibody or antigen-binding portion thereof, is adalimumab.
64 . The method of claim 63 , wherein the mean serum trough level of about 12 μg/mL is achieved by administration of a loading dose of adalimumab at week 0 followed by a second dose which comprises half the amount of the loading dose at week 2.
65 . The method of claim 63 , wherein the mean serum trough level of about 12 μg/mL is achieved at week 2.
66 . The method of claim 63 , wherein the mean serum trough level of about 12 μg/mL is achieved at week 4.
67 . An article of manufacture comprising a TNFα inhibitor and a package insert, wherein the package insert indicates that in patients with Crohn's disease a loading dose at week 0 followed by a second dose which is about 40-60% of the loading dose on week 2 achieves a mean serum TNFα inhibitor trough level of approximately 12 μg/mL at week 2 and week 4.
68 . The article of claim 67 , wherein the TNFα inhibitor is an anti-TNFα antibody, or an antigen-binding portion thereof.
69 . The article of claim 68 , wherein the anti-TNFα antibody, or an antigen-binding portion thereof, is human.
70 . The article of claim 69 , wherein the human anti-TNFα antibody, or an antigen-binding portion thereof, dissociates from human TNFα with a K d of 1×10 −8 M or less and a K off rate constant of 1×10 −3 s −1 or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC 50 of 1×10 −7 M or less.
71 . The article of claim 68 , wherein the human anti-TNFα antibody, or an antigen-binding portion thereof, comprises a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3, or modified from SEQ ID NO: 3 by a single alanine substitution at position 1, 4, 5, 7 or 8, and comprises a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 4, or modified from SEQ ID NO: 4 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11.
72 . The article of claim 68 , wherein the human anti-TNFα antibody, or an antigen-binding portion thereof, is adalimumab.
73 . The article of any one of claims 67 - 72 , wherein the loading dose is about 160 mg.
74 . The article of any one of claims 67 - 72 , wherein the second dose is about 80 mg.
75 . An article of manufacture comprising adalimumab and a package insert, wherein the package insert indicates that in patients with Crohn's disease a loading dose of 160 mg adalimumab at week 0 followed by 80 mg adalimumab on week 2 achieves a mean serum adalimumab trough level of approximately 12 μg/mL at week 2 and week 4.