title: Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis.
abstract: OBJECTIVE
  This study aimed at describing adalimumab pharmacokinetics (PK) and the concentration-effect relationship of adalimumab using pharmacokinetic-pharmacodynamic (PK-PD) modelling in patients with rheumatoid arthritis (RA).
  
  
  METHODS
  Adalimumab PK and PK-PD data were obtained from a multicentric observational study. Adalimumab (40 mg) was administered subcutaneously every other week, and its pharmacokinetics was described using a one-compartment model. The relationship between adalimumab concentration and C-reactive protein (CRP) concentration was described using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentration and disease activity score in 28 joints (DAS28) was described using a direct inhibition model. Dose regimens that included a loading dose of adalimumab were simulated.
  
  
  RESULTS
  Thirty patients treated for RA were analysed. The following pharmacokinetic and PK-PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd /F) = 10.8 l (92%); apparent clearance (CL/F) = 0.32 l day(-1) (17%); first-order absorption rate (ka ) = 0.28 day(-1) ; CRP input (kin ) = 22.0 mg l(-1)  day(-1) (65%); adalimumab concentration leading to a 50% decrease in kin (C50 ) = 3.6 mg l(-1) (88%); baseline DAS28 (DAS0 ) = 5.5 mg l(-1) (11%); and adalimumab concentration leading to 50% decrease of DAS0 (IC50 ) = 11.0 mg l(-1) (71%). Simulations showed that a 160 mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection.
  
  
  CONCLUSIONS
  This is the first study to describe adalimumab pharmacokinetics and the concentration-effect relationship in RA. A 160 mg loading dose may lead to an increased benefit from treatment in RA patients.
authors.affiliation: CNRS, UMR 7292, 'Genetics, Immunotherapy, Chemistry and Cancer', Université François Rabelais de Tours, Tours, France; Laboratoire de pharmacologie-toxicologie, CHRU de Tours, Tours, France.
authors.forename: David
authors.initials: D
authors.lastname: Ternant
authors.forename: Emilie
authors.initials: E
authors.lastname: Ducourau
authors.forename: Piéra
authors.initials: P
authors.lastname: Fuzibet
authors.forename: Céline
authors.initials: C
authors.lastname: Vignault
authors.forename: Hervé
authors.initials: H
authors.lastname: Watier
authors.forename: Thierry
authors.initials: T
authors.lastname: Lequerré
authors.forename: Xavier
authors.initials: X
authors.lastname: Le Loët
authors.forename: Olivier
authors.initials: O
authors.lastname: Vittecoq
authors.forename: Philippe
authors.initials: P
authors.lastname: Goupille
authors.forename: Denis
authors.initials: D
authors.lastname: Mulleman
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
mesh_terms: D000068879:Adalimumab; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002097:C-Reactive Protein / Q000378:metabolism; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D013997:Time Factors; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D002097:C-Reactive Protein; D000068879:Adalimumab
keywords: adalimumab; pharmacodynamics; pharmacokinetic-pharmacodynamic modelling; pharmacokinetics; rheumatoid arthritis