Pharmacokinetics and concentration–effect relationship of adalimumab in rheumatoid arthritis

Abstract

AIMSThis study aimed at describing adalimumab pharmacokinetics (PK) and the concentration-effect relationship of adalimumab using pharmacokineticpharmacodynamic (PK-PD) modelling in patients with rheumatoid arthritis (RA). METHODSAdalimumab 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. RESULTSThirty 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; 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.

Clinical Pharmacokinetics and Pharmacodynamics of Monoclonal Antibodies Approved to Treat Rheumatoid Arthritis

“…The general idea would be to find the optimal scheme for each patient. This optimal scheme, frequently searched empirically, could be calculated using pharmacokinetic modeling and data from the literature, for infliximab [29] as well as for adalimumab [31,32,36], taking into account individual factors of pharmacokinetic variability. In addition, using these studies, Bayesian pharmacokinetic models may be developed to estimate individual pharmacokinetic parameters using only a few concentration values [118].…”

“…When BSA increases from 1.4 to 1.9 m 2 , rituximab central volume of distribution and clearance are increased by 25 and 35 %, respectively [30]. The clearance of adalimumab [36] and rituximab [30] is around 40 % higher in men than in women. The influence of BW or BSA justifies the adjustment of mAb doses to body size.…”

“…More specifically, two-compartment models were used to describe the pharmacokinetics of infliximab [29], rituximab [30], adalimumab [31,32], golimumab [33], and tocilizumab in RA [34,35]. The pharmacokinetics of most mAbs administered by the subcutaneous (SC) route was described using one-compartment models [16], as done for adalimumab in RA [36]. Nevertheless, some studies used twocompartment models to describe the pharmacokinetics of mAbs administered by the SC route, as golimumab [37], tocilizumab [38], and certolizumab pegol [39], but these studies benefited from combined IV and SC data.…”

“…The adalimumab concentration-effect relationship was described using a population approach and indirect models for CRP [94,95] or direct E max models for DAS28 [36]. In the latter study, a large inter-individual variability in patient sensitivity to adalimumab was observed: concentrations leading to 50 % decrease in CRP ''input'' (C 50 ) and in DAS28 (IC 50 ) were 3.6 and 11.0 mg/L, respectively, with inter-individual standard deviations of 88 and 71 %, respectively.…”

“…However, because of the long t of adalimumab, this target concentration is reached a long time (15-20 weeks) after treatment initiation. Simulations based on the pharmacokinetic-pharmacodynamic model showed that a 160-mg loading dose would allow steady-state concentrations and an optimal efficacy between the first and the second injections [36,96]. An indirect model was used to describe the relationship between tocilizumab concentrations and DAS28.…”