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Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: serum concentrations predict response to treatment in patients with rheumatoid arthritis
  1. E N van Roon1,
  2. T L T A Jansen2,
  3. M A F J van de Laar3,
  4. M Janssen4,
  5. J P Yska1,
  6. R Keuper1,
  7. P M Houtman2,
  8. J R B J Brouwers5
  1. 1Department of Clinical Pharmacy and Clinical Pharmacology, Medisch Centrum Leeuwarden, Leeuwarden, Netherlands
  2. 2Department of Rheumatology, Medisch Centrum Leeuwarden
  3. 3Department of Rheumatology, Medisch Spectrum Twente and University of Twente, Enschede, Netherlands
  4. 4Department of Rheumatology, Rijnstate Hospital, Arnhem, Netherlands
  5. 5Groningen University Institute for Drug Exploration (GUIDE), Subdivision Pharmacotherapy and Pharmaceutical Care, Netherlands
  1. Correspondence to:
    Mr E N van Roon
    Department of Clinical Pharmacy and Pharmacology, Medical Centre Leeuwarden, PO Box 888, 8901 BR Leeuwarden, Netherlands; e.n.van.roonznb.nl

Abstract

Background: Leflunomide is the prodrug of the disease modifying antirheumatic metabolite A77 1726. More than 50% of patients withdraw from leflunomide treatment within one year, mainly because of adverse drug reactions. Therapeutic drug monitoring of A77 1726 may be useful in predicting the efficacy of leflunomide treatment.

Objective: To study the relation between A77 1726 steady state serum concentrations and disease activity using the 28 joint (DAS28) response.

Methods: Outpatients with rheumatoid arthritis on a stable leflunomide dose for >4 months were included. DAS28 score and adverse drug reactions were recorded. Blood samples were taken for determination of A77 1726 concentrations. The primary end point was the relation of serum A77 1726 concentrations with DAS28 response category

Results: Serum A77 1726 concentrations were determined in 52 patients. A receiver operating characteristic (ROC) curve showed an area under the curve (AUC) of 0.73 (95% confidence interval, 0.54 to 0.93) (p<0.05). The sensitivity exceeded 99% at concentrations below 16 mg/l. DAS28 values at the point of sampling showed no relation with A77 1726 concentrations (AUC of the ROC curve = 0.50 (0.33 to 0.67) (NS)).

Conclusions: A77 1726 steady state serum concentrations show a relation with DAS28 response. Determination of serum A77 1726 concentrations in patients with insufficient response to treatment may help when decisions have to be made about continuation of treatment or dose adjustment.

  • AUC, area under the curve
  • DAS28, 28 joint disease activity score
  • DHODH, dihydro-orotate dehydrogenase
  • DMARD, disease modifying antirheumatic drug
  • EULAR, European League Against Rheumatism
  • ROC, receiver operating characteristic
  • leflunomide
  • A77 1726
  • therapeutic drug monitoring
  • DAS28
  • rheumatoid arthritis
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