Clinical Implications of Pathophysiological and Demographic Covariates on the Population Pharmacokinetics of Trastuzumab Emtansine, a HER2‐Targeted Antibody‐Drug Conjugate, in Patients With HER2‐Positive Metastatic Breast Cancer

Gupta, Manish; LoRusso, Patricia; Wang, Bei; Yi, Joo‐Hee; Burris, Howard A.; Beeram, Muralidhar; Modi, Shanu; Chu, Yu‐Waye; Agresta, Samuel V.; Klencke, Barbara; Joshi, Amita; Girish, Sandhya

doi:10.1177/0091270011403742

Cited by 61 publications

(53 citation statements)

References 22 publications

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“…This procedure reduces the extrahepatic intramolecular and intermolecular disulfides of DM1 formed in plasma, leading to overestimation of circulating free DM1 concentrations. The consistently low plasma concentrations reported in the clinic for DM1 have been proposed to be to the result of low systemic release of DM1 (thioether-linkage instability) in circulation, rapid elimination of DM1, and/or a high volume of distribution of DM1 (Girish et al, 2012;Gupta et al, 2012). In a similar fashion, early clinical studies with AVE9633, an AMC using cleavable disulfide-linked DM4, also show low levels of free DM4 in plasma with DM4 exhibiting a more rapid clearance than that of the parent molecule AVE9633 (Lapusan et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Characterization of the Drug-Drug Interaction Potential of Catabolites of Antibody-Maytansinoid Conjugates

et al. 2012

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ABSTRACT:The in vitro characterization of the inhibition potential of four representative maytansinoid species observed upon hepatic and/or tumor in vivo processing of antibody-maytansine conjugates (AMCs) with cleavable and noncleavable linkers is reported. We investigated the free maytansinoid species , respectively. Because of instability in plasma, further characterization of the DM1 and DM4 intramolecular and intermolecular disulfide conjugates observed in vivo is required before an accurate drug-drug interaction (DDI) prediction can be made. AMCs with noncleavable thioether-linked DM1 as the cytotoxic agent are predicted to have no potential for a DDI with any of the major human P450s studied.

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Section: Discussionmentioning

confidence: 99%

In Vitro Characterization of the Drug-Drug Interaction Potential of Catabolites of Antibody-Maytansinoid Conjugates

et al. 2012

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“…However, apparent linear pharmacokinetics does not necessarily imply an actual saturation of antigenic target by mAb, notably in the "extreme" case where antibody is in stoichiometric default compared to antigen (with only phases (i) and (iv) of the four TMDD phases [26] figure 2). Indeed, apparent linear pharmacokinetics is often accompanied by and influence of antigen mass, as reported for anti-TNF antibodies [110,111,116,123] , trastuzumab [94,95] and trastuzumab emtansine [131,133] , and bevacizumab. [130] In addition, the apparence of linear pharmacokinetics does not mean that antigenic targets are totally saturated and that dose is optimal.…”

Section: Antigenic Targets Present In Several Tissuesmentioning

confidence: 95%

“…Since techniques of tumor size measurements and their target-antigen density are very different between type of cancer, it is difficult to deliver a global message on the influence of tumor size on mAb pharmacokinetics, even if 7 publications reported and increase in mAb clearance with pre-therapeutic tumour size (table 1): -breast cancer size for trastuzumab [94] and trastuzumab emtansine [131,133] ; -bladder urothelial carcinoma size for atezolizumab [134] ; -size of various solid tumors for olaratumumab [135] and pembrolizumab [136] ; -and the number of extrahepatic metastases for bevacizumab [130] .…”

Section: Influence Of Tumor Sizementioning

confidence: 99%

“…Indeed, for instance, antigenic targets may be both circulating and cellular. Increased clearance of trastuzumab and trastuzumab emtansin was associated with pre-therapeutic tumour burden [94,131,133] and HER2-ECD [95,131] , which may represent cellular and circulating HER2, respectively. Increased bevacizumab clearance was associated with pre-therapeutic VEGF and ACE serum concentrations, and the number of extrahepatic metastases.…”

Section: Antigenic Targets Present In Several Tissuesmentioning

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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“…The second feature is that T-DM1 differs from trastuzumab in terms of dosing (3.6 mg/kg every 3 weeks for T-DM1 vs. 6 mg/kg every 3 weeks for trastuzumab) and half-life ($4 days for conjugated T-DM1 vs. $3-4 weeks for trastuzumab; refs. 37,39,57,58). Furthermore, unlike trastuzumab, T-DM1 undergoes deconjugation, proteolytic degradation, and cytochrome P450-mediated metabolism of DM1-containing catabolites, which likely explains the faster clearance of T-DM1 compared with trastuzumab, an idea that is supported by data from an exploratory model (59).…”

Section: Distinguishing T-dm1 From Trastuzumabmentioning

confidence: 99%

Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2–Positive Cancer

LoRusso

Weiss

Guardino

et al. 2011

Clinical Cancer Research

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Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibodydrug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab-and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1-containing agents are eagerly awaited.

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Clinical Implications of Pathophysiological and Demographic Covariates on the Population Pharmacokinetics of Trastuzumab Emtansine, a HER2‐Targeted Antibody‐Drug Conjugate, in Patients With HER2‐Positive Metastatic Breast Cancer

Cited by 61 publications

References 22 publications

In Vitro Characterization of the Drug-Drug Interaction Potential of Catabolites of Antibody-Maytansinoid Conjugates

In Vitro Characterization of the Drug-Drug Interaction Potential of Catabolites of Antibody-Maytansinoid Conjugates

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

Trastuzumab Emtansine: A Unique Antibody-Drug Conjugate in Development for Human Epidermal Growth Factor Receptor 2–Positive Cancer

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