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Text
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URL Address
<a href="http://doi.org/10.1002/art.10307" target="_blank" rel="noreferrer noopener">http://doi.org/10.1002/art.10307</a>
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Pages
1460-1469
Issue
6
Volume
46
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Title
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Hydroxychloroquine concentration-response relationships in patients with rheumatoid arthritis
Publisher
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Arthritis and Rheumatism
Date
A point or period of time associated with an event in the lifecycle of the resource
2002
2002-06
Subject
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drugs; efficacy; gold; low-dose methotrexate; ocular safety; pharmacokinetics; placebo; plasma; Rheumatology; serum concentrations; trial
Creator
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Munster T; Gibbs J P; Shen D; Baethge B A; Botstein G R; Caldwell J; Dietz F; Ettlinger R; Golden H E; Lindsley H; McLaughlin G E; Moreland L W; Roberts W N; Rooney T W; Rothschild B; Sack M; Sebba A I; Weisman M; Welch K E; Yocum D; Furst D E
Description
An account of the resource
Objective. A dose-response relationship for hydroxychloroquine (HCQ), in terms of the proportion of patients achieving the Paulus 20% criteria for improvement, had previously been observed in patients with rheumatoid arthritis (RA) receiving a 6-week loading regimen of 400, 800, or 1,200 mg HCQ daily. This present retrospective analysis was performed to investigate possible relationships between the blood HCQ and HCQ-metabolite concentrations and measures of efficacy and toxicity. In addition, we sought to ascertain whether further investigation of HCQ/HCQ-metabolite levels might lead to testing of one of these substances as a new antirheumatic drug. Methods. Patients with active RA (n = 212) began a 6-week, double-blind trial comparing 3 different doses of HCQ at 400, 800, or 1,200 mg/day, followed by 18 weeks of open-label HCQ treatment at 400 mg/day. Patients were repeatedly evaluated for treatment efficacy and toxicity. Blood samples were available from 123 patients for analysis of HCQ, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bisdesethylchloroquine (BDCQ) levels using high-performance liquid chromatography. Achievement of the modified Paulus 20% improvement criteria for response in RA was used as the primary efficacy parameter. Spontaneously reported adverse events were categorized and analyzed as toxicity outcome variables. The relationship between response (efficacy and toxicity) and drug levels was evaluated using logistic regression analysis. Results. The subset of patients with blood concentration data was equivalent to the larger study population in all demographic and outcome characteristics. The mean HCQ, DHCQ, and DCQ elimination half-lives were 123, 161, and 180 hours, respectively. There was a positive correlation between the Paulus 20% improvement criteria response and blood DHCQ concentrations during weeks 1-6 (P < 0.001). A potential relationship between ocular adverse events and BDCQ levels was found (P = 0.036). Logistic regression analysis of adverse events data showed that adverse gastrointestinal events were associated with higher HCQ levels (P = 0.001-0.021) during weeks 1, 2, and 3. Conclusion. There is a weak, but predictable, relationship between blood DHCQ concentrations and efficacy of treatment with HCQ. In addition, there is an association between gastrointestinal adverse events and elevated blood HCQ concentrations. Further investigation of these relationships is warranted to see if DHCQ may be introduced as a new antirheumatic drug.
Identifier
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<a href="http://doi.org/10.1002/art.10307" target="_blank" rel="noreferrer noopener">10.1002/art.10307</a>
Format
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Journal Article
2002
Arthritis and rheumatism
Baethge B A
Botstein G R
Caldwell J
Dietz F
Drugs
efficacy
Ettlinger R
Furst D E
Gibbs J P
gold
Golden H E
Journal Article
Lindsley H
low-dose methotrexate
McLaughlin G E
Moreland L W
Munster T
ocular safety
pharmacokinetics
placebo
Plasma
Rheumatology
Roberts W N
Rooney T W
Rothschild B
Sack M
Sebba A I
serum concentrations
Shen D
trial
Weisman M
Welch K E
Yocum D