Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis

AimsThis 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). MethodsAdalimumab PK and PK-PD data were obtained from a multicentric observational study. Adalimumab (40mg) 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. ResultsThirty patients treated for RA were analysed. The following pharmacokinetic and PK-PD parameters were estimated (interidividual coefficient of variation): apparent volume of distribution (V-d/F)=10.8l (92%); apparent clearance (CL/F)=0.32lday(-1) (17%); first-order absorption rate (k(a))=0.28 day(-1); CRP input (k(in))=22.0mgl(-1)day(-1) (65%); adalimumab concentration leading to a 50% decrease in k(in) (C-50)=3.6mgl(-1) (88%); baseline DAS28 (DAS(0))=5.5mgl(-1) (11%); and adalimumab concentration leading to 50% decrease of DAS(0) (IC50)=11.0mgl(-1) (71%). Simulations showed that a 160mg loading dose should reduce the time to reach efficacy in terms of both CRP and DAS28 after the first injection. ConclusionsThis is the first study to describe adalimumab pharmacokinetics and the concentration-effect relationship in RA. A 160mg loading dose may lead to an increased benefit from treatment in RA patients.