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Clinical Trial
. 2015 Feb;79(2):286-97.
doi: 10.1111/bcp.12509.

Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis

David Ternant  1 , Emilie Ducourau, Piéra Fuzibet, Céline Vignault, Hervé Watier, Thierry Lequerré, Xavier Le Loët, Olivier Vittecoq, Philippe Goupille, Denis Mulleman, Gilles Paintaud
Affiliations
Clinical Trial

Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis

David Ternant et al. Br J Clin Pharmacol. 2015 Feb.

Abstract

Aims: 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.

Trial registration: ClinicalTrials.gov NCT00234234.

Keywords: adalimumab; pharmacodynamics; pharmacokinetic-pharmacodynamic modelling; pharmacokinetics; rheumatoid arthritis.

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Figures

Figure 1
Figure 1
Pharmacokinetic and pharmacokinetic–pharmacodynamic (PK–PD) models. Adalimumab pharmacokinetics was described using a one-compartment model with first-order absorption and elimination rates. The relationship between adalimumab concentrations and C-reactive protein (CRP) levels was described using an indirect model with inhibition of CRP input. The relationship between adalimumab concentrations and the disease activity score in 28 joints (DAS28) was described using a direct Emax inhibitory model. Abbreviations: CL, clearance; Cp, model-predicted adalimumab concentrations; CRP, serum C-reactive protein concentrations; kin, zero-order production rate constant; ka, first-order absorption rate constant; kout, first-order elimination rate constant; C50, adalimumab concentration leading to a 50% decrease of kin; DAS0, DAS28 at baseline, IC50, adalimumab concentration leading to a 50% decrease of DAS0; VD, volume of distribution
Figure 2
Figure 2
Observed values of adalimumab concentrations, CRP concentrations and DAS28 measurements vs. population model-predicted values (PRED) and individual predicted values (IPRED). DV, dependent value
Figure 3
Figure 3
Distribution of population (WRES) and individual weighted residuals (IWRES) vs. individual predictions, and of NPDE for adalimumab concentrations, CRP concentrations and DAS28 measurements
Figure 4
Figure 4
Apparent clearance (CL/F) vs. sex and bodyweight (above) and random effect for apparent clearance (ETA_CL/F) vs. sex and bodyweight (below)
Figure 5
Figure 5
Observed (filled circles) and model-predicted adalimumab concentrations (continuous lines), observed (open diamonds) and model-predicted CRP concentrations (dotted lines), observed (open squares) and model predicted DAS28 measurements (dashed lines) vs. time in four representative patients
Figure 6
Figure 6
Simulations of three adalimumab dosing regimens using typical pharmacokinetic and PK–PD parameters: no loading dose (40 mg every other week); 80 mg loading dose (80 mg, then 40 mg every other week); and 160 mg loading dose (160 mg, then 40 mg every other week). Using a 160 mg loading dose, adalimumab concentrations after the loading dose are superior to steady-state concentrations, and maximal effect is reached between the first and the second injections. —, no loading dose; —, 80 mg loading dose; —, 160 mg loading dose
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