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Towards an individualised target concentration of adalimumab in rheumatoid arthritis
  1. Emilie Ducourau1,2,
  2. David Ternant1,3,
  3. Thierry Lequerré4,5,
  4. Piéra Fuzibet1,2,
  5. Xavier Le Loët4,5,
  6. Hervé Watier1,6,
  7. Philippe Goupille1,2,
  8. Gilles Paintaud1,3,
  9. Olivier Vittecoq4,5,
  10. Denis Mulleman1,2
  1. 1Université François-Rabelais de Tours, CNRS, UMR 7292, Tours, France
  2. 2Service de Rhumatologie, CHRU de Tours, Tours, France
  3. 3Laboratoire de Pharmacologie-Toxicologie, CHRU de Tours, Tours, France
  4. 4Université de Rouen, INSERM U905 & CIC/CRB0204, Rouen, France
  5. 5Service de Rhumatologie, CHRU de Rouen, Rouen, France
  6. 6Laboratoire d'Immunologie, CHRU de Tours, Tours, France
  1. Correspondence to Professor Denis Mulleman, Service de Rhumatologie, CHRU de Tours, 37044, Tours Cedex 9, France; mulleman{at} ED and DT contributed equally.

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Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA), but the response is highly variable between patients. Good responders have significantly higher adalimumab serum concentrations than non-responders.1 In a recent issue of the Annals, Pouw et al2 have proposed a therapeutic cut-off concentration for adalimumab that is predictive of clinical response at a population level but, as for other TNF-α antagonists, no individualised target concentration has been defined to adjust the dose in RA.3

In a post hoc analysis we measured adalimumab concentrations in 127 samples from 30 patients with RA who received 40 mg adalimumab subcutaneously every other week.4 Concomitantly to blood sampling, disease activity score in 28 joints (DAS28) was recorded at baseline and at 6 weeks, 12 weeks, 24 weeks and 52 weeks after treatment initiation. Then, we studied the relationship between adalimumab concentration and DAS28 with a direct Emax inhibition pharmacokinetic-pharmacodynamic model, using Monolix V.3.1 (INRIA, Saclay, France). Emax models are often used to describe the concentration-response relationship, where the ‘quantity’ of response is monotonically related to drug concentration.5 With such a model, the relationship reaches an asymptote for high adalimumab concentrations when DAS28 reaches its minimal value. Estimated baseline DAS28 and adalimumab IC50, that is, adalimumab concentration leading to 50% decrease of baseline DAS28, were 5.7 (coefficient of variation=10%) and 11.8 mg/L (coefficient of variation=75%), respectively. Therefore, for a patient with a median baseline DAS28=5.7, with an adalimumab concentration of 11.8 mg/L, the baseline DAS28 would be decreased twofold (figure 1). The adalimumab target concentration necessary to achieve …

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