Key findings towards optimising adalimumab treatment: the concentration–effect curve

Pouw, Mieke F.; Krieckaert, C.; Nurmohamed, Michael T.; Kleij, Desirée van der; Aarden, Lucien A.; Rispens, Theo; Wolbink, Gertjan

doi:10.1136/annrheumdis-2013-204172

Cited by 175 publications

(183 citation statements)

References 19 publications

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“…However, the pharmacokinetics of infliximab and adalimumab were found to be influenced by methotrexate co-medication, trough concentrations of both infliximab [65] and adalimumab [55] being higher in the presence of methotrexate. Methotrexate was associated with a 30 % decrease in infliximab clearance and an increase in t from 9.3 to 13.3 days [29].…”

Section: Influence Of Co-medicationsmentioning

confidence: 90%

“…2). Of note, methotrexate co-treatment did not influence infliximab pharmacokinetics in ankylosing spondylitis patients, probably because antigen burden is lower in this disease than in RA [55]. No sound data reported an influence of other disease-modifying anti-rheumatic drugs (such as azathioprine or prednisolone) on mAbs pharmacokinetics [66].…”

Section: Influence Of Co-medicationsmentioning

confidence: 97%

“…Methotrexate was associated with a 30 % decrease in infliximab clearance and an increase in t from 9.3 to 13.3 days [29]. Median adalimumab trough concentrations were 4.1 and 7.4 mg/L without and with methotrexate, respectively [55]. Methotrexate, acting as an , which, when they are present, accelerate mAb elimination [67,72].…”

Section: Influence Of Co-medicationsmentioning

confidence: 98%

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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: Influence Of Co-medicationsmentioning

confidence: 90%

Section: Influence Of Co-medicationsmentioning

confidence: 97%

Section: Influence Of Co-medicationsmentioning

confidence: 98%

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

et al. 2015

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“…The concentrations of anti-TNF biopharmaceuticals (infliximab, adalimumab) were shown to increase when methotrexate, an inhibitor of dihydrofolate reductase, is co-administered notably in RA patients [157] . Pharmacokinetic modelling studies of infliximab showed that immunomodulator (such as methotrexate) co-treatment is associated with lower infliximab clearance [105,111] , independently from CRP levels.…”

Section: Influence Of Concomitant Treatmentmentioning

confidence: 99%

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

et al. 2018

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Therapeutic antibodies are increasingly used to treat various diseases, including neoplasms and chronic inflammatory diseases. Antibodies exhibit complex pharmacokinetic properties, notably due to the influence of antigen mass, i.e. the amount of antigenic targets to which the monoclonal antibody binds specifically. This review focuses on the influence of antigen mass on the pharmacokinetics of therapeutic antibodies quantified by pharmacokinetic modelling in humans. Out of 159 pharmacokinetic studies, 85 reported an influence of antigen mass. This influence led to nonlinear elimination decay in 50 publications which was described using target-mediated drug disposition (TMDD) or derived models, as quasi-steady-state, irreversible binding and Michaelis-Menten models. In 35 publications, the pharmacokinetics was apparently linear and the influence of antigen mass was described as covariate of pharmacokinetic parameters. If some reported covariates, such as circulating antigen concentration or tumor size, are likely to be correlated to antigen mass, others, such as disease activity or disease type, may contain little information on the amount of antigenic targets. In some cases, antigen targets exist in different forms, notably in the circulation and expressed at cell surface. The influence of antigen mass should be soundly described during the early clinical phases of drug development. To maximize therapeutic efficacy, sufficient antibody doses should be administered to ensure the saturation of antigen targets by therapeutic antibody in all patients. If necessary, antigen mass should be taken into account in routine clinical practice. Key points-Current knowledge on the pharmacokinetics of monoclonal antibodies (mAbs) states that higher antigen amount was associated with mAb concentrations and higher mAb clearance. -Beacause of antigen mass, mAb pharmacokinetics may display nonlinear elimination shape. The influence of antigen mass on mAb pharmacokinetics is described using target-mediated drug disposition (TMDD) model, or approximations of this model. Antigen mass influence may be quantified using covariates. -Current mAb clinical development and use in clinical practice may be improved by optimization of dose, which should ensure the saturation of antigen targets in all patients.3

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“…Так, M. Pouw и соавт. [31] проанализиро-вали взаимосвязь эффективности АДА с уровнем препара-та в сыворотке у 221 пациента с РА. Авторами было проде-монстрировано, что клинический эффект АДА увеличива-ется при повышении концентрации препарата в сыворот-ке.…”

Section: Discussionunclassified

Efficacy of Adalimumab in Early Rheumatoid Arthritis in Relation to Its Serum Level and the Presence of Anti-Drug Antibody

Авдеева¹,

Александрова²,

Каратеев³

et al. 2014

rsp

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Key findings towards optimising adalimumab treatment: the concentration–effect curve

Abstract: Adalimumab trough levels in a range of 5-8 μg/mL are sufficient to reach adequate clinical response. These levels are influenced substantially by concomitant MTX use.

Cited by 175 publications

References 19 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

Influence of Antigen Mass on the Pharmacokinetics of Therapeutic Antibodies in Humans

Efficacy of Adalimumab in Early Rheumatoid Arthritis in Relation to Its Serum Level and the Presence of Anti-Drug Antibody

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