David Ternant (1), Piera Fuzibet (2), Emilie Ducourau (2), Olivier Vittecoq (3), Thierry Lequerre (3), Philippe Goupille (1), Denis Mulleman (1), Gilles Paintaud (1)
(1) CNRS UMR 7292 GICC, (2) Department of Rheumatology, Tours, France, (3) Department of Rheumatology, Rouen, France.
Objectives: Adalimumab, an anti-TNF-α monoclonal antibody, is effective in active rheumatoid arthritis (RA). Subcutaneous injections of adalimumab lead to highly variable concentrations between patients and this pharmacokinetic (PK) variability partly explains the variability of clinical effect. However, adalimumab PK after subcutaneous injection has never been reported. The goal of this study is to build a simplified PK model for therapeutic drug monitoring (TDM) of adalimumab in CD patients and to describe the concentration-effect relationship of adalimumab in these patients using PK-PD modeling.
Methods: Adalimumab PK data were taken from a multicentric observational study. Adalimumab 40 mg was administered subcutaneously every other week. Trough adalimumab concentrations, CRP levels and RA disease activity score (DAS28) were measured at inclusion visit, then at weeks 6, 12, 24 and 52. Adalimumab PK was decribed using a one compartment model with first-order absorption and elimination rates. The relationship between adalimumab concentrations and CRP levels was described using using an indirect response model with inhibition of CRP input, whereas the relationship between adalimumab concentrations and DAS28 was described using a direct inhibitory model. A population approach was used and models were run simultaneously. Sex, age and body weight were tested as covariates on each pharmacokinetic and PK-PD parameter.
Results: Thirty patients were included, and 131 adalimumab trough concentrations, CRP levels and DAS28 measurements were available. The following PK and PK-PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (Vd/F) = 12.4 L (75%), apparent clearance (CL/F) = 0.31 L/day (17%), first-order absorption constant (ka) = 0.41 day-1, zero-order CRP input rate (kin) = 129 mg/L/day (47%), first-order CRP output rate (kout) = 8.3 day-1 and adalimumab concentration leading to 50% decrease of kin (C50) = 5.7 mg/L (102%), initial DAS28 (DAS0) = 5.5 mg/L (11%) and adalimumab concentration leading to 50% decrease of DAS0 (IC50) = 11.8 mg/L (66%). Apparent clearance was higher for increasing body weight and for men.
Conclusions: This is the first study describing the pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis. This model allows therapeutic drug monitoring of adalimumab in RA patients.
Reference: PAGE 22 (2013) Abstr 2960 [www.page-meeting.org/?abstract=2960]
Poster: Other Drug/Disease Modelling