Pharmacokinetics interactions of monoclonal antibodies

Ferri, Nicola; Bellosta, Stefano; Baldessin, Ludovico; Boccia, Donatella; Racagni, G.; Corsini, Alberto

doi:10.1016/j.phrs.2016.07.015

Cited by 83 publications

(84 citation statements)

References 63 publications

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“…Drug interactions with mAbs were reviewed elsewhere [156] and this part deals with drug interactions related to antigen mass (figure 3). 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] .…”

Section: Influence Of Concomitant Treatmentmentioning

confidence: 99%

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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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Section: Influence Of Concomitant Treatmentmentioning

confidence: 99%

“…[38,53,76,156] An evolocumab study using a TMDD model showed that PCSK9 levels were higher in patients treated with statins. [38] This increase in PCSK9 levels may lead to higher target-mediated clearance of anti-PCSK9 mAbs.…”

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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“…Indeed, evolocumab clearance is increased by about 20%, partially due to the statin-driven upregulation of PCSK9. Similarly, alirocumab exposure was reduced by about 40%, 15%, and 35% when administered with statins, ezetimibe, and fenofibrate, respectively (121). However, these drug-drug interactions are not to be rated as clinically meaningful and do not require A c c e p t e d M a n u s c r i p t dose adjustment.…”

Section: Proprotein Convertase Subtilisin/kexin 9 (Pcsk9) Antagonistsmentioning

confidence: 99%

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

et al. 2018

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Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

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“…Treatment algorithms for CRS are currently empirical. These algorithms include dexamethasone and an anti‐IL6 receptor antibody, tocilizumab, both of which can influence the activity of drug‐metabolizing enzymes and transporters and may therefore lead to drug–drug interactions . Thus, CAR T‐cell therapy has several issues which may be solved with collaborative efforts including clinical pharmacologists and pharmacometricians.…”

Section: Types Of Immunotherapymentioning

confidence: 99%

Rapid Advances in Immunotherapy to Treat Cancer

McCune

2018

Clin Pharma and Therapeutics

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Immunotherapy is now the fourth pillar of cancer therapy, with surgery, radiation, and traditional chemotherapy being the remaining pillars. Over the past decade, enthusiasm for immunotherapy has increased because of, in part, data showing that it consistently improves overall survival in select patients with historically refractory cancers. This issue covers various aspects of immunotherapy ranging from use of 1) chimeric antigen receptor (CAR) T cells to treat patients with B-cell acute lymphoblastic leukemia; 2) population pharmacokinetic/dynamic modeling to develop new immune checkpoint inhibitors; and 3) simulations of existing population pharmacokinetic models of immunotherapy to minimize waste without compromising exposure and efficacy.

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Pharmacokinetics interactions of monoclonal antibodies

Cited by 83 publications

References 63 publications

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

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

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Rapid Advances in Immunotherapy to Treat Cancer

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