Use of pharmacogenetics, enzymatic phenotyping, and metabolite monitoring to guide treatment with azathioprine in patients with systemic lupus erythematosus.
OBJECTIVE
Individualized therapy based on genetic background and monitoring of metabolites can optimize drug safety and efficacy. Such an approach is available for azathioprine (AZA), the thiopurine antimetabolite. AZA exerts therapeutic effects when metabolized to the active thiopurine nucleotide, 6-thioguanine (6-TGN). In inflammatory bowel disease (IBD), 6-TGN levels in the target range of 235-400 pmol/8x10(8) red blood cells (RBC) are associated with a high likelihood of response. Our objective was to evaluate whether drug escalation based on metabolite levels improves efficacy and maintains safety in patients with systemic lupus erythematosus (SLE).


METHODS
We conducted a 6-month open-label dose-escalation clinical study of patients with active SLE treated with azathioprine dosed by body weight and metabolite levels. The primary endpoint was >or=50% improvement in any one parameter of disease activity, or 50% decrease in glucocorticoid dose.


RESULTS
Of 50 patients enrolled in the study, 21 achieved clinical responses, 13 of whom had 6-TGN<235 pmol/8 x10(8) RBC. Ten patients had no clinical response at 6 months, yet achieved either therapeutic IBD 6-TGN levels (>235, n=4) or received maximum AZA dose>or=3.5 mg/kg (n=6). In 19 patients the drug was discontinued prematurely due to side effects or SLE activity. For those patients in whom either liver function test or white blood cell count abnormalities were encountered, metabolites guided attribution to drug or disease activity.


CONCLUSIONS
Clinical responses in SLE can occur at levels of 6-TGN lower than the target range established for IBD. During followup, measurements of AZA metabolites may provide a rational approach to safety.
Askanase
Anca D
AD
Department of Medicine, Hospital for Joint Diseases, Division of Rheumatology, New York University School of Medicine, 560 First Avenue, TCH-407, New York, NY 10016, USA. ardinu@aol.com
Wallace
Daniel J
DJ
Weisman
Michael H
MH
Tseng
Chung-E
CE
Bernstein
Lana
L
Belmont
H Michael
HM
Seidman
Ernest
E
Ishimori
Mariko
M
Izmirly
Peter M
PM
Buyon
Jill P
JP
D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006579:Heterozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008780:Methyltransferases / Q000235:genetics; D008875:Middle Aged; D010349:Patient Compliance; D010597:Pharmacogenetics; D010641:Phenotype; D013866:Thioguanine / Q000097:blood; D055815:Young Adult
D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine