PMID- 34041638
OWN - NLM
STAT- MEDLINE
DCOM- 20220216
LR  - 20220216
IS  - 1573-0646 (Electronic)
IS  - 0167-6997 (Linking)
VI  - 39
IP  - 6
DP  - 2021 Dec
TI  - Real-world pharmacokinetics and pharmacodynamics of everolimus in metastatic 
      breast cancer.
PG  - 1707-1715
LID - 10.1007/s10637-021-01131-4 [doi]
AB  - 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 (C(trough)) was significantly higher in patients experiencing DLTs 
      than in those without any DLTs (P = 0.030). The optimal C(trough) cutoff 
      predicting DLT development was 17.3 ng/mL. The cumulative incidence of DLTs was 
      significantly higher in patients with C(trough) >/=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 C(trough) 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 C(trough) 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.
CI  - (c) 2021. The Author(s), under exclusive licence to Springer Science+Business 
      Media, LLC, part of Springer Nature.
FAU - Fukudo, Masahide
AU  - Fukudo M
AUID- ORCID: 0000-0002-7703-7827
AD  - Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical University, 
      Asahikawa, Japan. fukudom@sapmed.ac.jp.
AD  - Department of Pharmacy, Sapporo Medical University Hospital, South-1, West-16, 
      Chuo-ku, Sapporo, 060-8543, Japan. fukudom@sapmed.ac.jp.
FAU - Ishibashi, Kei
AU  - Ishibashi K
AD  - Breast Disease Center, Asahikawa Medical University Hospital, Asahikawa, Japan.
FAU - Kitada, Masahiro
AU  - Kitada M
AD  - Breast Disease Center, Asahikawa Medical University Hospital, Asahikawa, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210526
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 (Antineoplastic Agents)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/adverse effects/pharmacokinetics/*pharmacology/*therapeutic 
      use
MH  - Breast Neoplasms/*drug therapy
MH  - Dose-Response Relationship, Drug
MH  - Everolimus/adverse effects/pharmacokinetics/*pharmacology/*therapeutic use
MH  - Female
MH  - Genotype
MH  - Humans
MH  - Male
MH  - Maximum Tolerated Dose
MH  - Middle Aged
MH  - Progression-Free Survival
MH  - Prospective Studies
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
OTO - NOTNLM
OT  - Breast cancer
OT  - Everolimus
OT  - Pharmacodynamics
OT  - Pharmacokinetics
OT  - Therapeutic drug monitoring
EDAT- 2021/05/28 06:00
MHDA- 2022/02/17 06:00
CRDT- 2021/05/27 07:01
PHST- 2021/04/21 00:00 [received]
PHST- 2021/05/16 00:00 [accepted]
PHST- 2021/05/28 06:00 [pubmed]
PHST- 2022/02/17 06:00 [medline]
PHST- 2021/05/27 07:01 [entrez]
AID - 10.1007/s10637-021-01131-4 [pii]
AID - 10.1007/s10637-021-01131-4 [doi]
PST - ppublish
SO  - Invest New Drugs. 2021 Dec;39(6):1707-1715. doi: 10.1007/s10637-021-01131-4. Epub 
      2021 May 26.