| Autor: |
Fukudo, Masahide, Ishibashi, Kei, Kitada, Masahiro |
| Předmět: |
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| Zdroj: |
Investigational New Drugs; Dec2021, Vol. 39 Issue 6, p1707-1715, 9p |
| Abstrakt: |
Summary: Purpose This study investigated the relationship between the pharmacokinetics and pharmacodynamics of everolimus in patients with metastatic breast cancer (mBC) in real-world practice.Methods Twenty-two patients with mBC treated with everolimus plus exemestane were enrolled. Blood everolimus concentrations were measured at outpatient visits. The inhibition of the mammalian target of rapamycin (mTOR) activity in peripheral blood mononuclear cells (PBMCs) was examined. The efficacy and safety endpoints were progression-free survival (PFS) and the cumulative incidence of dose-limiting toxicities (DLTs), respectively. Results Blood samples were obtained from 19 consenting patients. Everolimus did not completely inhibit mTOR activity in PBMCs at therapeutic concentrations (~ 56 % maximal inhibition). The most common adverse event was stomatitis (any grade 77 %). The trough concentration (Ctrough) was significantly higher in patients experiencing DLTs than in those without any DLTs (P = 0.030). The optimal Ctrough cutoff predicting DLT development was 17.3 ng/mL. The cumulative incidence of DLTs was significantly higher in patients with Ctrough ≥17.3 ng/mL than in other patients (sub-hazard ratio 4.87, 95 % confidence interval [CI] 1.53–15.5; P = 0.007). Furthermore, the median PFS was numerically longer in patients who maintained a steady-state Ctrough below the threshold than in those who did not (327 days [95 % CI 103–355 days] vs. 194 days [95 % CI 45 days–not estimable]; P = 0.35). Conclusions The suggested upper threshold for the therapeutic window of everolimus Ctrough was 17.3 ng/mL. Pharmacokinetically guided dosing may improve the efficacy and safety of everolimus for mBC, warranting further investigation in a larger study. Clinical trial registry: Not applicable. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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