Willi Weber

Comparing efficacy of 10mg vs 20mg ARAVA in treatment of rheumatoid arthritis: A Population PK / PD Analysis

Willi Weber, Diether Rueppel, Heiner Speth

Aventis Pharma, Germany

PDF of poster

ARAVA is an isoxazole with immunosuppressive and anti-proliferate activity used for the treatment of rheumatoid arthritis. We investigated the relationship between ARAVA’s active metabolite concentration at steady state, and the clinical responder rate classified according to the ACR20 [1] criterion and the Paulus criterion [2]. The pharmacokinetic and pharmacodynamic data of a 10 mg and a 20 mg dose group are investigated and compared in the light of the

  1. Drop out rate,
  2. The onset of efficacy,
  3. The concentration effect relationship, and
  4. The fraction of patients obtaining the full therapeutic potential of ARAVA after at least 23 weeks of treatment

Methods: We used the NONMEM software [3] with the FO method and a one-compartment PK-model with first order input. In a 2nd step we used a naive logistic model with steady state concentration as a predictor of clinical outcome observed after at least 23 weeks of treatment.

Results: Our results are summarized as follows:

  • Drop out rate: In adult patients the rate of discontinuations was higher in the 10 mg group than in the 20 mg treatment group.
  • Onset of efficacy: A tendency for an earlier onset of the effect of the treatment was found in the 20 mg dose group when compared to the 10 mg dose group.
  • ACR20 criterion: Using a priori knowledge of the PK/PD relationship between CSS as predictor variable and ACR20 as dependent variable, the individual estimates of the probability of success were more than 88% of the maximal ACR20 effect at concentrations above 24 mg/L.
  • Paulus criterion: Using a priori knowledge of the PK/PD relationship between CSS as predictor variable and the Paulus criterion as dependent variable, the individual estimates of the probability of success were more than 88% of the maximal effect (Paulus criterion) at concentrations above 13 mg/L.

Conclusions:

  1. In the adults, the observed higher rate of discontinuations in the 10 mg group may be interpreted as lack of efficacy in a larger fraction of RA patients than in the 20mg treatment group.
  2. Using a loading dose of 100mg for the first 3 days followed by a 20 mg maintenance dose showed a trend of an earlier onset of efficacy than starting treatment with a single 100mg loading dose followed by 10 mg maintenance dose.
  3. When rheumatoid arthritis is diagnosed, early aggressive treatment using a 20 mg daily maintenance dose should be more effective in avoiding irreversible joint destruction than using a 10 mg dose.

References
[1] The American Rheumatism Association. Revised criteria for the classification of rheumatoid arthritis, Arthritis and Rheumatism 31, 1988
[2] H.E. Paulus, M.J. Egger, J.R. Ward, J.H. Williams. Cooperative Systematic Studies of Rheumatic Disease Group. Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. Arthritis and Rheumatism, 33: 477-484, 1990
[3] A.J. Boeckmann, S.L. Beal and L.B. Sheiner. NONMEM User Guide, Version V, Level 1.0. University of California, 1998

Reference: PAGE 13 (2004) Abstr 540 [www.page-meeting.org/?abstract=540]

Poster: poster