Population Pharmacokinetics of Belimumab Following Intravenous Administration in Patients With Systemic Lupus Erythematosus

Struemper, Herbert; Chen, Cecil; Cai, Wendy

doi:10.1002/jcph.104

Cited by 47 publications

(79 citation statements)

References 23 publications

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“…In this study, the authors noted that both renal and nonrenal clearance contributed to an enhanced total clearance of adalimumab. Similarly, for patients with systemic lupus erythematosus, who often have proteinuria, IgG clearance can be altered [97]. In this work, the authors found an association between increasing baseline proteinuria and increasing clearance, which they indicated may be clinically relevant with very high proteinuria levels.…”

Section: Patients With Renal Impairmentmentioning

confidence: 50%

Drug Development of Therapeutic Monoclonal Antibodies

Mould¹,

Meibohm

2016

BioDrugs

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Monoclonal antibodies (MAbs) have become a substantial part of many pharmaceutical company portfolios. However, the development process of MAbs for clinical use is quite different than for small-molecule drugs. MAb development programs require careful interdisciplinary evaluations to ensure the pharmacology of both the MAb and the target antigen are well-understood. Selection of appropriate preclinical species must be carefully considered and the potential development of anti-drug antibodies (ADA) during these early studies can limit the value and complicate the performance and possible duration of preclinical studies. In human studies, many of the typical pharmacology studies such as renal or hepatic impairment evaluations may not be needed but the pharmacokinetics and pharmacodynamics of these agents is complex, often necessitating more comprehensive evaluation of clinical data and more complex bioanalytical assays than might be used for small molecules. This paper outlines concerns and strategies for development of MAbs from the early in vitro assessments needed through preclinical and clinical development. This review focuses on how to develop, submit, and comply with regulatory requirements for MAb therapeutics.

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Section: Patients With Renal Impairmentmentioning

confidence: 50%

Drug Development of Therapeutic Monoclonal Antibodies

Mould¹,

Meibohm

2016

BioDrugs

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“…Peak mean serum concentrations of belimumab occurred approximately 5 days after dosing and declined monoexponentially in the present study. This is in contrast to the biexponential decline observed for intravenous administration of belimumab and other monoclonal antibodies 8, 11. This difference is likely because of slower absorption from the subcutaneous compartment compared with intravenous administration, which masks the faster distribution from central circulation to peripheral tissues 12…”

Section: Discussionmentioning

confidence: 88%

“…The concentration of belimumab in serum samples was determined using a validated target‐mediated capture sandwich electrochemiluminescence (ECL) assay 8. Serum samples were minimally diluted (1/400) with assay diluent prior to analysis.…”

Section: Methodsmentioning

confidence: 99%

Relative Bioavailability of a Single Dose of Belimumab Administered Subcutaneously by Prefilled Syringe or Autoinjector in Healthy Subjects

Struemper

Murtaugh

Gilbert

et al. 2015

Clinical Pharm in Drug Dev

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Intravenous belimumab is approved for the treatment of systemic lupus erythematosus; subcutaneous self‐administration would enable greater patient access. This study assessed relative bioavailability, tolerability, and safety of 1 subcutaneous dose of self‐administered belimumab by healthy subjects using a single‐use autoinjector or prefilled syringe. Subjects (randomized 1:1:1:1) self‐administered belimumab 200 mg subcutaneously (abdomen or thigh) by prefilled syringe or autoinjector. Pharmacokinetics, adverse events (AEs), injection‐site pain, and administration errors were recorded. Of 81 subjects, 5 experienced administration errors and were excluded from pharmacokinetic analyses. Mean serum belimumab concentration profiles were similar for both devices, with a weak trend toward higher concentrations for thigh injection compared with abdominal injections. Maximum observed serum concentration was slightly higher with the autoinjector (27.0 vs 25.3 µg/mL) and area under the concentration–time curve slightly lower (701 vs 735 day · μg/mL), compared with the prefilled syringe. Incidence of AEs was 51% (41 of 81 subjects; headache was most common), with no serious or severe AEs. Median injection‐site pain scores were low (0 after 1 hour). Device handling was reported as acceptable by ≥95% of autoinjector users and ≥90% of prefilled syringe users for each characteristic assessed. These results support the use of either device for belimumab subcutaneous administration.

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“…In some studies, the non-linear dose-concentration relationship, especially observed for low doses was described as an influence of dose on volume of distribution [82][83][84][85] or as a time-varying volume. [86] The increase in volume for low doses and/or low mAb concentrations was consistent with a capture of mAbs by antigen targets.…”

Section: Dose and Time Varying Pharmacokinetic Parametersmentioning

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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Population Pharmacokinetics of Belimumab Following Intravenous Administration in Patients With Systemic Lupus Erythematosus

Cited by 47 publications

References 23 publications

Drug Development of Therapeutic Monoclonal Antibodies

Drug Development of Therapeutic Monoclonal Antibodies

Relative Bioavailability of a Single Dose of Belimumab Administered Subcutaneously by Prefilled Syringe or Autoinjector in Healthy Subjects

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

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