Semi-mechanistic Population Pharmacokinetic Model of Multivalent Trastuzumab Emtansine in Patients with Metastatic Breast Cancer

Chudasama, Vaishali L.; Stark, F. Schaedeli; Harrold, John M.; Tibbitts, Jay; Girish, Sandhya; Gupta, Manish; Frey, Nicolas; Mager, Donald E.

doi:10.1038/clpt.2012.153

Cited by 46 publications

(33 citation statements)

References 26 publications

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“…5), this validated method may be highly valuable for a better assessment of the PK behavior of the dosed antibody drug conjugate, especially for ADC with cleavable linker and non active naked antibody. Those actual results are in good agreement with those of semi-mechanistic population pharmacokinetic model-predicted concentrations of unconjugated trastuzumab, showing slow formation of naked Ab following deconjugation of T-DM1, in patients with metastatic breast cancer (Chudasama et al, 2012). The measure of the naked antibody should allow to better characterize the non active circulating entities that may compete on the target binding sites with the active ADC.…”

Section: Discussionsupporting

confidence: 75%

Validation of an immunoassay to selectively quantify the naked antibody of a new Antibody Drug Conjugate – SAR566658 – for pharmacokinetic interpretation improvement

Pascual

Verdier

Malette

et al. 2013

Journal of Immunological Methods

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Section: Discussionsupporting

confidence: 75%

Validation of an immunoassay to selectively quantify the naked antibody of a new Antibody Drug Conjugate – SAR566658 – for pharmacokinetic interpretation improvement

Pascual

Verdier

Malette

et al. 2013

Journal of Immunological Methods

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“…Additionally, the presence of multiple ADC species that potentially could be generated in an in vivo setting, as a result of partial deconjugation of the payload, will need to be considered when these approaches are employed for evaluation of target capacity (39). This point is a critical consideration as different ADC species, with varying degrees of drug loading, may potentially have different biodistribution, elimination, and efficacy profiles under in vivo conditions (47)(48)(49).…”

Section: Determination Of In Vivo Target Capacitymentioning

confidence: 99%

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection

Sadekar

Figueroa²,

Tabrizi³

2015

AAPS J

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Abstract. Antibody drug conjugates (ADCs) are a multi-component modality comprising of an antibody targeting a cell-specific antigen, a potent drug/payload, and a linker that can be processed within cellular compartments to release payload upon internalization. Numerous ADCs are being evaluated in both research and clinical settings within the academic and pharmaceutical industry due to their ability to selectively deliver potent payloads. Hence, there is a clear need to incorporate quantitative approaches during early stages of drug development for effective modality design and target selection. In this review, we describe a quantitative approach and framework for evaluation of the interplay between drug-and systems-dependent properties (i.e., target expression, density, localization, turnover, and affinity) in order to deliver a sufficient amount of a potent payload into the relevant target cells. As discussed, theoretical approaches with particular considerations given to various key properties for the target and modality suggest that delivery of the payload into particular effect cells to be more sensitive to antigen concentrations for targets with slow turnover rates as compared to those with faster internalization rates. Further assessments also suggest that increasing doses beyond the threshold of the target capacity (a function of target internalization and expression) may not impact the maximum amount of payload delivered to the intended effect cells. This article will explore the important application of quantitative sciences in selection of the target and design of ADC modalities.

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“…This approximation is frequently made to describe the pharmacokinetics of mAbs in case of nonlinear shape of terminal elimination and has been used for 23 therapeutic antibodies in 28 studies (table 1). In the 18 studies where "full" Michaelis-Menten model is used [56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72] , VM and KM values are highly variable between studies, VM and KM ranges being 0.008-26.4 mg/day and 0.02-33.9 mg/L, respectively. However, the Michaelis-Menten term has been used in simplified forms.…”

Section: Michaelis-menten Modelmentioning

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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Semi-mechanistic Population Pharmacokinetic Model of Multivalent Trastuzumab Emtansine in Patients with Metastatic Breast Cancer

Cited by 46 publications

References 26 publications

Validation of an immunoassay to selectively quantify the naked antibody of a new Antibody Drug Conjugate – SAR566658 – for pharmacokinetic interpretation improvement

Validation of an immunoassay to selectively quantify the naked antibody of a new Antibody Drug Conjugate – SAR566658 – for pharmacokinetic interpretation improvement

Antibody Drug Conjugates: Application of Quantitative Pharmacology in Modality Design and Target Selection

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

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