Pharmacodynamic analysis of eribulin safety in breast cancer patients using real‐world postmarketing surveillance data

Abstract

Postmarketing surveillance is useful to collect safety data in real‐world clinical settings. In this study, we applied postmarketing real‐world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin‐treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony‐stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h−1, neutrophil elimination rate constant = 0.0295 h−1, and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model‐based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin.

Effect of renal function on neutrophil decreases following eribulin administration

“…Therefore, the aforementioned factor is unlikely to cause neutropenia, suggesting the potential existence of other causal factors. Since the mechanism underlying neutrophil reduction due to pre‐treatment ALB levels was not previously reported, 18 a more detailed future study is required. Nonetheless, since our study indicates that the risk of severe neutropenia may be increased owing to a reduction in renal function in Japanese patients, neutropenia may result from a reduction in eribulin CL owing to decreased renal function.…”

“…A previous study 17 reported that decreased ALB levels owing to pre‐treatment may be associated with severe neutropenia, thus affecting the time course of neutrophil reduction 21 . Furthermore, Kawamura et al 18 reported that the severity of neutropenia varies depending on the neutrophil count and ALB levels at the initiation of therapy.…”

Pharmacodynamic analysis of hypertension caused by lenvatinib using real‐world postmarketing surveillance data

“…In a recent report by the US Food and Drug Administration, experts are considering to adapt real‐world evidence for complementing the knowledge gained from traditional clinical trials (in which limitations render generalization to clinical practice difficult) 24 . A prominent example is the PMS data safety management analysis performed by Kawamura et al 25 By using a mechanistic PD model of eribulin‐induced neutropenia, Kawamura et al gained insight into the importance of treatment regimen selection. Our results reflect a real‐world setting, in which follow‐up intervals, dosing schedules, and preventive safety measures are tailored to each patient.…”

Novel RAF/MEK inhibitor CH5126766/VS‐6766 has efficacy in combination with eribulin for the treatment of triple‐negative breast cancer

“…4 Based on the mechanisms underlying chemotherapy-induced immunomodulation, 29 eribulin is a candidate chemotherapeutic agent in combination therapy for TNBC with antagonists of immune checkpoint signaling because it does not always require steroids and is a well-tolerated drug, which is particularly suitable for TNBC. 8,30 Epithelial-mesenchymal transition is a key process in cancer metastasis. It has been shown to contribute to immunosuppression in breast cancer.…”