Methods for optimizing biological response modifier therapy using therapeutic drug monitoring of immunosuppressants
The invention provides methods for treating humans in need of combined immunosuppressant and biological response modifier therapy.
1 . A method for treating a human subject in need of combined immunosuppressant and biological response modifier (BRM) therapy, comprising
(a) determining a metabolite level of an immunosuppressant in a sample from a human subject receiving or to receive a BRM therapy in combination with the immunosuppressant;
(b) comparing the metabolite level in the sample to a threshold metabolite level below which the BRM leads to unacceptable immunogenicity; and
(c) administering to the human subject a subsequent dose of immunosuppressant and/or a dose of the BRM in an amount effective to treat the subject based upon comparing the metabolite level in the sample to the threshold metabolite level.
2 . The method of claim 1 , wherein the BRM therapy comprises administering an anti-tumor necrosis factor (TNF) antibody.
3 . The method of claim 1 wherein the BRM therapy comprises administering infliximab.
4 . The method of claim 3 , wherein the immunosuppressant is methotrexate (MTX).
5 . The method of claim 4 , wherein the metabolite is methotrexate polyglutamate MTXPG 3 .
6 . The method of claim 5 , wherein the sample is a red blood cell (RBC) sample.
7 . The method of claim 6 , wherein if the MTXPG 3 level is at or below 25 nmol/L RBC,
(i) increasing a subsequent dose of MTX or switching to an immunosuppressant other than MTX; and/or
(ii) decreasing a subsequent dose of infliximab.
8 . The method of claim 6 , wherein if the MTXPG 3 level is above 25 nmol/L RBC,
(i) maintaining or decreasing a subsequent dose of MTX; and/or
(ii) maintaining or increasing a subsequent dose of infliximab.
9 . The method of claim 7 wherein the subject has rheumatoid arthritis.
10 . The method of claim 8 wherein the subject has rheumatoid arthritis.
11 . A method for optimizing dosage of an immunosuppressant comprising
(a) determining a metabolite level of an immunosuppressant in a sample from a human subject receiving or to receive a BRM therapy in combination with the immunosuppressant;
(b) comparing the metabolite level in the sample to a threshold metabolite level below which the BRM therapy leads to unacceptable immunogenicity; and
(c) recommending adjustment or adjusting a subsequent dose of immunosuppressant and/or biological response modifier to be administered to the human subject based upon comparing the metabolite level in the sample to the threshold metabolite level.
12 . The method of claim 11 , wherein the immunosuppressant is MTX.
13 . The method of claim 12 , wherein the metabolite is MTXPG.
14 . The method of claim 11 , wherein the immunosuppressant is leflunomide.
15 . The method of claim 14 , wherein the metabolite is A77 1726.
16 . The method of claim 11 , wherein the immunosuppressant is azathiopurine.
17 . The method of claim 16 , wherein the metabolite is 6-thioguanine nucleotide or 6-methylmercaptopurine.
18 . The method of claim 12 , wherein the BRM therapy comprises administration of a therapeutic agent selected from the group consisting of infliximab, etanercept, adalimumab, golimumab, abatacept, rituximab, toclizumab, and ocrelizumab, natalizimab, belimumab.
19 . The method of claim 14 , wherein the BRM therapy comprises administration of a therapeutic agent selected from the group consisting of infliximab, etanercept, adalimumab, golimumab, abatacept, rituximab, toclizumab, and ocrelizumab, natalizimab, belimumab.
20 . The method of claim 16 , wherein the BRM therapy comprises administration of a therapeutic agent selected from the group consisting of infliximab, etanercept, adalimumab, golimumab, abatacept, rituximab, toclizumab, and ocrelizumab, natalizimab, belimumab.