Population pharmacokinetics and exposure–response analyses of trastuzumab in patients with advanced gastric or gastroesophageal junction cancer

Cosson, Valérie; Ng, Vivian; Lehle, Michaela; Lum, Bert L.

doi:10.1007/s00280-014-2400-5

Cited by 96 publications

(113 citation statements)

References 20 publications

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“…However, in multiple sclerosis, which has a lower antigen burden, the pharmacokinetics are linear [112]. Similar dependencies were seen with trastuzumab, a MAb targeting the her2-neu antigen expressed on the surface of tumor cells, when used to treat metastatic breast cancer [113]; higher clearance was seen when trastuzumab was used to treat advanced gastric cancer [114]. Even with MAbs that do not exhibit TMDD, clearance has been reported to change across different indications (Table 2).…”

Section: The Effect Of Disease and Disease Stagementioning

confidence: 86%

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: The Effect Of Disease and Disease Stagementioning

confidence: 86%

Drug Development of Therapeutic Monoclonal Antibodies

Mould¹,

Meibohm

2016

BioDrugs

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“…Moreover, the 840 mg q3w pertuzumab dose produced trough concentrations in patients with HER2-positive aGC similar to those observed in HER2-positive MBC in CLEOPATRA, whereas the 840/420 mg dose produced lower trough concentrations. Exposure-response analysis of data from the ToGA trial in aGC showed that patients with the lowest trastuzumab serum trough concentrations had the highest rate of disease progression and shortest overall survival (Yang et al , 2013; Cosson et al , 2014). Therefore, the 840 mg q3w pertuzumab dose is expected to provide greater treatment benefit than the 840/420 mg dose in patients with HER2-positive aGC.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in a separate analysis, patients with the lowest trastuzumab serum trough concentrations had the highest rate of disease progression and shortest overall survival (Cosson et al , 2014). Therefore, we aimed to study the pharmacokinetics (PK) of pertuzumab in combination with trastuzumab and chemotherapy to identify the pertuzumab dose that produces a steady-state trough serum concentration ( C min ) of ⩾20 μ g ml −1 in at least 90% of patients with HER2-positive gastric cancer.…”

mentioning

confidence: 99%

A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer

et al. 2014

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Background:Pertuzumab plus trastuzumab provides a more comprehensive blockade of HER2 signalling than trastuzumab alone. Therefore, we conducted a phase IIa study of the pharmacokinetics and safety of pertuzumab plus trastuzumab and chemotherapy in advanced gastric cancer (aGC).Methods:Patients received pertuzumab 840 mg for cycle 1 and 420 mg q3w for cycles 2–6 (Arm A) or pertuzumab 840 mg q3w for six cycles (Arm B). Trastuzumab, cisplatin and capecitabine were also given for six cycles, then trastuzumab q3w until disease progression or unmanageable toxicity. The co-primary endpoints were day 43 pertuzumab serum trough concentration (Cmin) and safety.Results:Thirty patients were randomised. Mean pertuzumab Cmin at day 43 was 40.0 μg ml−1 (s.d.: 17.3) in Arm A and 62.7 μg ml−1 (29.1) in Arm B. Mean day 43 Cmin in Arm A was ∼37% lower than that seen in metastatic breast cancer. The safety profiles were similar between arms and treatment was well tolerated. Partial responses were achieved by 86% and 55% of patients in Arms A and B, respectively.Conclusions:On the basis of the pharmacokinetic and safety data, the 840 mg q3w pertuzumab dose has been selected for a phase III study of pertuzumab, trastuzumab and chemotherapy in HER2-positive aGC.

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“…Pharmacokinetic analyses from previous studies had shown that, at the same starting dose, trastuzumab serum concentrations were lower in patients with gastric cancer as compared to those with BC [18][19][20]. According to the GATSBY trial, the safety profile of T-DM1 was comparable between gastric cancer and BC patients, without any new safety concerns being identified.…”

Section: Landmark Studies Providing Toxicity Data On T-dm1mentioning

confidence: 91%

Adverse Events of Trastuzumab Emtansine (T-DM1) in the Treatment of HER2-Positive Breast Cancer Patients

et al. 2017

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The human epidermal growth factor receptor 2 (HER2) is commonly associated with poor prognosis and is overexpressed in approximately 15-20% of all breast cancers. The introduction of HER2-targeted therapies led to significant improvement in the prognosis of patients with HER2-positive breast cancer, for both early and advanced disease. These targeted therapies include the antibodies trastzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib, and the antibody-drug conjugate trastuzumab emtansine (T-DM1). T-DM1 combines the anti-tumor activity of trastuzumab with that of DM1, a highly potent derivative of the anti-microtubule agent maytansine, resulting in increased anti-tumor activity. Notably, this agent has been demonstrated to be safe and is associated with low toxicity rates. However, maytansinoid, the cytotoxic component of T-DM1, does have the potential to induce various adverse events, particularly radiation necrosis, when used in combination with stereotactic radiosurgery. In this review, we aimed to summarize the current literature regarding T-DM1 safety and toxicity, with special emphasis on the existing landmark studies.

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Population pharmacokinetics and exposure–response analyses of trastuzumab in patients with advanced gastric or gastroesophageal junction cancer

Cited by 96 publications

References 20 publications

Drug Development of Therapeutic Monoclonal Antibodies

Drug Development of Therapeutic Monoclonal Antibodies

A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer

Adverse Events of Trastuzumab Emtansine (T-DM1) in the Treatment of HER2-Positive Breast Cancer Patients

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