Relevance of Monitoring Blood and Salivar Levels of Drugs Used in Rheumatic Autoimmune Diseases
Study Details
Study Description
Brief Summary
No drug treatment is completely free of risk and lack of response, adverse events and poor adherence may affect its effectiveness. Within this context, this project aims to evaluate the importance of monitoring blood levels and salivary drug used in rheumatic autoimmune diseases in the monitoring of adherence to therapy. In addition, this project intends to use the monitoring of drug levels, based on pharmacokinetic studies and pharmacokinetics/pharmacodynamics modeling, to broaden the understanding of the possible cellular, tissue and immunological mechanisms involved in efficacy and adverse effects of these drugs with the prospect of reducing the damage and maintain therapeutic efficacy. The high-performance liquid chromatography (HPLC) coupled to mass spectrometry, which will be used to evaluate hydroxychloroquine, thalidomide, glucocorticoids, is considered the gold standard technology to qualitative and quantitative analysis of drugs in blood and its comparison with the dosage in the saliva is an improvement in simplification of the process. For biological agents the focus will be on the understanding the loss of efficacy and the possible role of anti-TNF antibodies using ELISA capture methodology.This project will be divided into four sections with their respective sub-projects according to the medications that will be studied: hydroxychloroquine, thalidomide, biologic agents and glucocorticoids.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 4 |
Detailed Description
No drug treatment is completely free of risk and lack of response, adverse events and poor adherence may affect its effectiveness. There is also a large inter-individual variability in response to treatments with regard to efficacy and toxicity, and for many drugs, there is also a period of weeks to months to establish its efficacy. Within this context, this project aims to evaluate the importance of monitoring blood levels and salivary drug used in rheumatic autoimmune diseases in the monitoring of adherence to therapy. In addition, this project intends to use the monitoring of drug levels, based on pharmacokinetic studies and pharmacokinetics/pharmacodynamics modeling, to broaden the understanding of the possible cellular, tissue and immunological mechanisms involved in efficacy and adverse effects of these drugs with the prospect of reducing the damage and maintain therapeutic efficacy. The high-performance liquid chromatography (HPLC) coupled to mass spectrometry, which will be used to evaluate hydroxychloroquine, thalidomide, glucocorticoids, is considered the gold standard technology to qualitative and quantitative analysis of drugs in blood and its comparison with the dosage in the saliva is an improvement in simplification of the process. The implementation of this methodology dedicated to research in our center, with the necessary training of human resources, will enable the standardization and availability of this advanced technology to other muldisciplinary projects in various areas of science. For biological agents the focus will be on the understanding the loss of efficacy and the possible role of anti-TNF antibodies using ELISA capture methodology.This thematic project will be divided into four sections with their respective sub-projects according to the medications that will be studied: hydroxychloroquine, thalidomide, biologic agents and glucocorticoids.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Other: SLE/cutaneous lupus with thalidomide This subproject includes only one arm of lupus patients with active and refractory cutaneous disease and eligible for Thalidomide 100mg/day for 12 months. |
Drug: Thalidomide
Thalidomide 100 mg/day
Other Names:
|
Active Comparator: Inactive SLE with standard dose of HCQ This subproject includes one arm of lupus patients with inactive disease, in which will be maintained on standard dose of Hydroxychloroquine (400mg/day). |
Drug: standard dose of HCQ
Hydroxychloroquine 5.0 mg/kg/day
Other Names:
|
Active Comparator: Inactive SLE with reduced dose of HCQ This subproject includes one arm of lupus patients with inactive disease: in which the dose will be reduced to 400mg 3 times a week (Hydroxychloroquine reduced). |
Drug: Hydroxychloroquine reduced
Hydroxychloroquine 2.5 mg/kg/day
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Serum Levels of Thalidomide [12 months]
Serum levels of thalidomide by liquid chromatography and tandem mass spectrometry (HPLC-MS/MS)
- Serum Levels of Hydroxycloroquine [12 months]
Serum levels of hydroxycloroquine by LCMS
Eligibility Criteria
Criteria
Thalidomide subproject:
Inclusion Criteria:
-
SLE diagnosis according to 1997 ACR criteria
-
Active and refractory cutaneous lupus lesions
-
Male gender (using contraceptive barrier method) or confirmed infertility for female gender
-
Normal electroneuromyography at study entry
Exclusion Criteria:
-
Alcoholism
-
History of peripheral neuropathy
-
Previous history of thrombophilia or positive antiphospholipid antibodies
-
Renal and/or central nervous system and/or hematological activity
HCQ reduced subproject:
Inclusion Criteria:
-
SLE diagnosis according to 1997 ACR criteria
-
Use of hydroxychloroquine (5 to 6.5mg/kg/day) for ≥5 years
-
SLEDAI-2K <4
Exclusion Criteria:
-
Alcoholism
-
Renal dialysis
-
Concomitant infectious process
-
Acute and chronic liver diseases
-
Concomitant use of some drugs that interact with HCQ (cimetidine, antacids, digoxin, aminoglycosides, penicillamine, neostigmine, pyridostigmine)
-
Signs of Retinopathy
HCQ high subproject:
Inclusion Criteria:
-
SLE diagnosis according to 1997 ACR criteria
-
No use of hydroxychloroquine for ≥ 6 months
-
LES/LESJ in activity (SLEDAI≥6)
Exclusion Criteria:
-
Alcoholism
-
Renal dialysis
-
Concomitant infectious process
-
Acute and chronic liver diseases
-
Concomitant use of some drugs that interact with HCQ (cimetidine, antacids, digoxin, aminoglycosides, penicillamine, neostigmine, pyridostigmine)
-
Signs of Retinopathy
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Hospital das Clinicas da Faculdade de Medicina da USP | São Paulo | Brazil | 05403-000 |
Sponsors and Collaborators
- University of Sao Paulo General Hospital
- Fundação de Amparo à Pesquisa do Estado de São Paulo
Investigators
- Principal Investigator: Eloisa Bonfa, MD, PhD, University of Sao Paulo
Study Documents (Full-Text)
More Information
Publications
- Albrecht J, Taylor L, Berlin JA, Dulay S, Ang G, Fakharzadeh S, Kantor J, Kim E, Militello G, McGinnis K, Richardson S, Treat J, Vittorio C, Van Voorhees A, Werth VP. The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus. J Invest Dermatol. 2005 Nov;125(5):889-94.
- Bai N, Cui XY, Wang J, Sun CG, Mei HK, Liang BB, Cai Y, Song XJ, Gu JK, Wang R. Determination of thalidomide concentration in human plasma by liquid chromatography-tandem mass spectrometry. Exp Ther Med. 2013 Feb;5(2):626-630. Epub 2012 Nov 30.
- Bernstein HN. Ocular safety of hydroxychloroquine. Ann Ophthalmol. 1991 Aug;23(8):292-6. Review.
- Briani C, Zara G, Rondinone R, Della Libera S, Ermani M, Ruggero S, Ghirardello A, Zampieri S, Doria A. Thalidomide neurotoxicity: prospective study in patients with lupus erythematosus. Neurology. 2004 Jun 22;62(12):2288-90.
- Coelho A, Souto MI, Cardoso CR, Salgado DR, Schmal TR, Waddington Cruz M, de Souza Papi JA. Long-term thalidomide use in refractory cutaneous lesions of lupus erythematosus: a 65 series of Brazilian patients. Lupus. 2005;14(6):434-9.
- Costedoat-Chalumeau N, Amoura Z, Hulot JS, Hammoud HA, Aymard G, Cacoub P, Francès C, Wechsler B, Huong du LT, Ghillani P, Musset L, Lechat P, Piette JC. Low blood concentration of hydroxychloroquine is a marker for and predictor of disease exacerbations in patients with systemic lupus erythematosus. Arthritis Rheum. 2006 Oct;54(10):3284-90.
- Costedoat-Chalumeau N, Dunogué B, Morel N, Le Guern V, Guettrot-Imbert G. Hydroxychloroquine: a multifaceted treatment in lupus. Presse Med. 2014 Jun;43(6 Pt 2):e167-80. doi: 10.1016/j.lpm.2014.03.007. Epub 2014 May 19. Review.
- Costedoat-Chalumeau N, Pouchot J, Guettrot-Imbert G, Le Guern V, Leroux G, Marra D, Morel N, Piette JC. Adherence to treatment in systemic lupus erythematosus patients. Best Pract Res Clin Rheumatol. 2013 Jun;27(3):329-40. doi: 10.1016/j.berh.2013.07.001. Review.
- Cuadrado MJ, Karim Y, Sanna G, Smith E, Khamashta MA, Hughes GR. Thalidomide for the treatment of resistant cutaneous lupus: efficacy and safety of different therapeutic regimens. Am J Med. 2005 Mar;118(3):246-50.
- Francès C, Cosnes A, Duhaut P, Zahr N, Soutou B, Ingen-Housz-Oro S, Bessis D, Chevrant-Breton J, Cordel N, Lipsker D, Costedoat-Chalumeau N. Low blood concentration of hydroxychloroquine in patients with refractory cutaneous lupus erythematosus: a French multicenter prospective study. Arch Dermatol. 2012 Apr;148(4):479-84. doi: 10.1001/archdermatol.2011.2558.
- Giannini F, Volpi N, Rossi S, Passero S, Fimiani M, Cerase A. Thalidomide-induced neuropathy: a ganglionopathy? Neurology. 2003 Mar 11;60(5):877-8.
- Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol. 2002 Feb;29(2):288-91.
- Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725.
- Jallouli M, Galicier L, Zahr N, Aumaître O, Francès C, Le Guern V, Lioté F, Smail A, Limal N, Perard L, Desmurs-Clavel H, Le Thi Huong D, Asli B, Kahn JE, Pourrat J, Sailler L, Ackermann F, Papo T, Sacré K, Fain O, Stirnemann J, Cacoub P, Leroux G, Cohen-Bittan J, Sellam J, Mariette X, Blanchet B, Hulot JS, Amoura Z, Piette JC, Costedoat-Chalumeau N; Plaquenil Lupus Systemic Study Group. Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus. Arthritis Rheumatol. 2015 May;67(8):2176-84. doi: 10.1002/art.39194.
- Knop J, Bonsmann G, Happle R, Ludolph A, Matz DR, Mifsud EJ, Macher E. Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus. Br J Dermatol. 1983 Apr;108(4):461-6.
- Kyriakis KP, Kontochristopoulos GJ, Panteleos DN. Experience with low-dose thalidomide therapy in chronic discoid lupus erythematosus. Int J Dermatol. 2000 Mar;39(3):218-22.
- Michaelides M, Stover NB, Francis PJ, Weleber RG. Retinal toxicity associated with hydroxychloroquine and chloroquine: risk factors, screening, and progression despite cessation of therapy. Arch Ophthalmol. 2011 Jan;129(1):30-9. doi: 10.1001/archophthalmol.2010.321.
- Morita S, Takahashi T, Yoshida Y, Yokota N. Population Pharmacokinetics of Hydroxychloroquine in Japanese Patients With Cutaneous or Systemic Lupus Erythematosus. Ther Drug Monit. 2016 Apr;38(2):259-67. doi: 10.1097/FTD.0000000000000261.
- Tsakonas E, Joseph L, Esdaile JM, Choquette D, Senécal JL, Cividino A, Danoff D, Osterland CK, Yeadon C, Smith CD. A long-term study of hydroxychloroquine withdrawal on exacerbations in systemic lupus erythematosus. The Canadian Hydroxychloroquine Study Group. Lupus. 1998;7(2):80-5.
- HPLC-Rheumatic diseases
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Inactive SLE With Standard Dose of HCQ | Inactive SLE With Reduced Dose of HCQ | SLE/Cutaneous Lupus With Thalidomide |
---|---|---|---|
Arm/Group Description | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed full 2016-AAO dose of HCQ (4-5.5 mg/kg/day, real body weight). | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed reduced 2016-AAO dose of HCQ (2-3.0 mg/kg/day, real body weight) | Adult patients with CLE (biopsy proven)/SLE (American College of Rheumatology classification criteria, 1997) treated with thalidomide. Inclusion criteria: absence of pregnancy potential for females; agreement of male patients to use condoms throughout the treatment period with thalidomide and up to 30 days after its ending, even though they had already undergone vasectomy; active skin lesions; no response to previous use of HCQ, prednisone 20 mg/day, and immunosuppressants/dapsone or indication of thalidomide according to the attending physician; 5) agreement of recruited patients to participate in the study according to signed informed consent form, and agreement to thalidomide use according to signed responsibility term at starting treatment and at each renewal of the prescription; 6) a normal NCS; 7) normal serum vitamin B12 levels; 8) negative tests for hepatitis B/C and HIV; 9) negative antiphospholipid antibodies. Exclusion criteria: other associated autoimmune diseases, such as Sjogren's syndrome; previous or current alcoholism; diabetes mellitus; history of PN; previous use of thalidomide; previous or current use of leflunomide, TNF-alpha inhibitors, chemotherapy and other neurotoxic drugs; history of cancer or thrombosis; current renal or nervous system lupus activities, autoimmune haemolytic anaemia and/or thrombocytopenia <50,000/mm3; inability to understand the study. |
Period Title: Overall Study | |||
STARTED | 41 | 32 | 20 |
COMPLETED | 41 | 32 | 9 |
NOT COMPLETED | 0 | 0 | 11 |
Baseline Characteristics
Arm/Group Title | Inactive SLE With Standard Dose of HCQ | Inactive SLE With Reduced Dose of HCQ | SLE/Cutaneous Lupus With Thalidomide | Total |
---|---|---|---|---|
Arm/Group Description | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed full 2016-AAO dose of HCQ (4-5.5 mg/kg/day, real body weight). | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed reduced 2016-AAO dose of HCQ (2-3.0 mg/kg/day, real body weight). | This subproject includes only one arm of lupus patients with active and refractory cutaneous disease and eligible for Thalidomide 100mg/day for 12 months. | Total of all reporting groups |
Overall Participants | 41 | 32 | 20 | 93 |
Age (years) [Median (Standard Deviation) ] | ||||
Median (Standard Deviation) [years] |
37
(10.5)
|
37
(6.9)
|
44.8
(7.6)
|
37
(8.7)
|
Sex: Female, Male (Count of Participants) | ||||
Female |
39
95.1%
|
29
90.6%
|
17
85%
|
85
91.4%
|
Male |
2
4.9%
|
3
9.4%
|
3
15%
|
8
8.6%
|
Race/Ethnicity, Customized (Count of Participants) | ||||
Caucasian |
13
31.7%
|
6
18.8%
|
9
45%
|
28
30.1%
|
Non-Caucasian |
28
68.3%
|
26
81.3%
|
11
55%
|
65
69.9%
|
Drug blood levels (ng/mL) [Mean (Standard Deviation) ] | ||||
Mean (Standard Deviation) [ng/mL] |
1343.5
(521.5)
|
1404.9
(492.0)
|
1374.2
(506.8)
|
Outcome Measures
Title | Serum Levels of Thalidomide |
---|---|
Description | Serum levels of thalidomide by liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) |
Time Frame | 12 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | SLE/Cutaneous Lupus With Thalidomide |
---|---|
Arm/Group Description | Adult patients with CLE (biopsy proven)/SLE (American College of Rheumatology classification criteria, 1997) treated with thalidomide. |
Measure Participants | 20 |
Mean (Standard Deviation) [ng/mL] |
415.1
(326.0)
|
Title | Serum Levels of Hydroxycloroquine |
---|---|
Description | Serum levels of hydroxycloroquine by LCMS |
Time Frame | 12 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Inactive SLE With Standard Dose of HCQ | Inactive SLE With Reduced Dose of HCQ |
---|---|---|
Arm/Group Description | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed full 2016-AAO dose of HCQ (4-5.5 mg/kg/day, real body weight). | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed reduced 2016-AAO dose of HCQ (2-3.0 mg/kg/day, real body weight) |
Measure Participants | 41 | 32 |
Mean (Standard Deviation) [ng/mL] |
991.6
(576.3)
|
569.0
(533.4)
|
Adverse Events
Time Frame | 12 months | |||||
---|---|---|---|---|---|---|
Adverse Event Reporting Description | ||||||
Arm/Group Title | SLE/Cutaneous Lupus With Thalidomide | Inactive SLE With Standard Dose of HCQ | Inactive SLE With Reduced Dose of HCQ | |||
Arm/Group Description | SLE/cutaneous lupus with thalidomide arm (12 months). | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed full 2016-AAO dose of HCQ (4-5.5 mg/kg/day, real body weight). | Lupus nephritis patients on stable inactive disease for at least 6 months prescribed reduced 2016-AAO dose of HCQ (2-3.0 mg/kg/day, real body weight). | |||
All Cause Mortality |
||||||
SLE/Cutaneous Lupus With Thalidomide | Inactive SLE With Standard Dose of HCQ | Inactive SLE With Reduced Dose of HCQ | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/20 (0%) | 0/41 (0%) | 0/32 (0%) | |||
Serious Adverse Events |
||||||
SLE/Cutaneous Lupus With Thalidomide | Inactive SLE With Standard Dose of HCQ | Inactive SLE With Reduced Dose of HCQ | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/20 (0%) | 0/41 (0%) | 0/32 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
SLE/Cutaneous Lupus With Thalidomide | Inactive SLE With Standard Dose of HCQ | Inactive SLE With Reduced Dose of HCQ | ||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 12/20 (60%) | 0/41 (0%) | 0/32 (0%) | |||
Nervous system disorders | ||||||
Only sensory peripheral neuropathy | 12/20 (60%) | 12 | 0/41 (0%) | 0 | 0/32 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Prof Eloisa Bonfa |
---|---|
Organization | Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo |
Phone | 551130617490 |
eloisa.bonfa@hc.fm.usp.br |
- HPLC-Rheumatic diseases