Towards an individualised target concentration of adalimumab in rheumatoid arthritis

Ducourau, Émilie; Ternant, David; Lequerré, Thierry; Fuzibet, Piéra; Loët, Xavier Le; Watier, Hervé; Goupille, Philippe; Paintaud, Gilles; Vittecoq, Olivier; Mulleman, Denis

doi:10.1136/annrheumdis-2013-204971

Cited by 25 publications

(22 citation statements)

References 6 publications

(6 reference statements)

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“…As a consequence, patients with high disease activity present a lower exposure to anti-TNF-a mAbs. Therefore, RA patients would need higher mAb doses according to disease activity [96], with an increase in doses as soon as underexposure is evidenced [67]. More pharmacokinetic-pharmacodynamic studies are needed to propose rational dosing strategies for anti-TNF-a drugs.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Pharmacokinetic-pharmacodynamic Modelingmentioning

confidence: 99%

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

et al. 2015

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Monoclonal antibodies (mAbs) are increasingly used to treat rheumatoid arthritis (RA). At present, anti-tumor necrosis factor-α drugs (infliximab, adalimumab, certolizumab pegol, and golimumab), rituximab, and tocilizumab are approved for RA treatment. This review focuses on the pharmacokinetics and pharmacodynamics of mAbs approved in RA. Being large proteins, mAbs exhibit complex pharmacokinetic and pharmacodynamic properties. In particular, owing to the interactions of mAbs with their antigenic targets, the pharmacokinetics of mAbs depends on target turnover and exhibits non-specific (linear) and target-mediated (often nonlinear) clearances. Their volume of distribution is low (3-4 L) and their elimination half-life usually ranges from 2 to 3 weeks. The inter-individual pharmacokinetic variability of mAbs is usually large and is partly explained by differences in antigenic burden or by anti-drug antibodies, which accelerate mAb elimination. The inter-individual variability of clinical response is large and influenced by the pharmacokinetics. The analysis of mAbs concentration-effect relationship relies more and more often on pharmacokinetic-pharmacodynamic modeling; these models being suitable for dosing optimization. Even if adverse effects of mAbs used in RA are well known, the relationship between mAb concentration and adverse effects is poorly documented, especially for anti-tumor necrosis factor-α mAbs. Overall, RA patients treated with mAbs should benefit from individualized dosing strategies. Because of the complexity of their pharmacokinetics and mechanisms of action, the current dosing strategy of mAbs is not based on sound knowledge. New studies are needed to assess individual dosing regimen, adjusted notably to disease activity.

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Section: Discussionmentioning

confidence: 99%

Section: Pharmacokinetic-pharmacodynamic Modelingmentioning

confidence: 99%

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

et al. 2015

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“…Such a model was preferred to an indirect response model, which is not adapted to the description of a disease activity score because it requires the estimation a DAS28 'input' and a DAS28 'output', parameters that would be difficult to interpret. We previously described the relationship between adalimumab concentration and DAS28 using a direct inhibition Emax model but without pharmacokinetic modelling [35].…”

Section: Figurementioning

confidence: 99%

Pharmacokinetics and concentration–effect relationship of adalimumab in rheumatoid arthritis

Ternant

Ducourau

Fuzibet

et al. 2015

Brit J Clinical Pharma

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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.

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“…Data in IBD show remarkable similarity with other groups studying immunogenicity to IFX and ADM in other indications including rheumatology and dermatology [28,45,46] . Taking into account some important differences, including dosing, differences in concomitant IMM and potential differences in the immune characteristics of each indication, we believe that this work and other evidence can be extrapolated for the use of IFX, ADM and probably golimumab across all indications including rheumatology and dermatology.…”

Section: Limitations and Future Perspectivesmentioning

confidence: 56%

“…We speculate that including objective markers to measure the disease burden (ideally TNF-α load) as well as individual differences in clearance may improve models. In addition, better and objective parameters to measure early disease improvement should be incorporated in the model to predict, for example, mucosal healing [46][47][48][49][50][51][52][53][54][55] .…”

Section: Limitations and Future Perspectivesmentioning

confidence: 99%

Is There a Role for Therapeutic Drug Monitoring of Anti-TNF Monoclonal Antibodies in Inflammatory Bowel Disease

Baert¹

2015

Dig Dis

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In recent years it has become clear that therapeutic drug monitoring can be an important tool to optimize outcome and costs of anti TNF treatment including the subcutaneous and fully human monoclonal antibodies. There is a clear dose response curve between early serum concentrations of all monoclonal antibodies and response both short term and long term. The wide variations in early serum concentrations are insufficiently explained by classic pharmacokinetic factors. Low early concentrations can lead to anti-drug antibody formation and ensuing loss of response. Therapeutic drug monitoring allows to rationalize the current practice of dose optimization and the use of concomitant immunomodulator treatment. However more prospective studies are needed before strong recommendations can enter treatment guidelines.

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Towards an individualised target concentration of adalimumab in rheumatoid arthritis

Cited by 25 publications

References 6 publications

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

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

Pharmacokinetics and concentration–effect relationship of adalimumab in rheumatoid arthritis

Is There a Role for Therapeutic Drug Monitoring of Anti-TNF Monoclonal Antibodies in Inflammatory Bowel Disease

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