In male human-CETP transgenic mice, single intravenous evacetrapib doses of 40 or 120 mg/kg BW produced residual-blood-corrected mean brain concentrations of 1.53 or 16.7 nmol/g at 0.5 h, respectively. The nonperfused-tissue measurement and estimated blood correction do not establish unbound brain exposure or cerebral target engagement. [2]
In a separate mouse study, daily intraperitoneal evacetrapib at 30 mg/kg improved recognition-memory performance in female CETPtg and APPtg/CETPtg mice; male treatment comparisons were nonsignificant. APPtg mice without CETP showed no recognition-memory response, and Y-maze treatment effects were nonsignificant. These findings are specific to the tested transgenic models. [3]
Single-dose plasma-to-brain distribution
Animal study · Male human-CETP transgenic mice on a C57BL/6J background; 1% cholesterol diet for 3–4 weeks after 8 weeks on standard diet [2]
After single intravenous doses, evacetrapib was detected in brain tissue at 0.5 h. Residual-blood-corrected mean concentrations were 1.53 and 16.7 nmol/g at 40 and 120 mg/kg BW, respectively.
Conditions shared by the study groups
- Route
- Intravenous, tail vein
- Frequency
- Once
- Treatment course
- Single dose; sampled through 24 h
- Vehicle
- 20% Kolliphor EL and 80% isotonic glucose solution (50 g/L glucose).
- 40 mg/kg BW intravenous
- Model: Male human-CETP transgenic mice on a C57BL/6J background; 1% cholesterol diet for 3–4 weeks after 8 weeks on standard diet
- Reported limits: Nonperfused tissue; correction assumes average residual plasma rather than measuring it in each brain.
- 120 mg/kg BW intravenous
- Model: Male human-CETP transgenic mice on a C57BL/6J background; 1% cholesterol diet for 3–4 weeks after 8 weeks on standard diet
- Reported limits: Nonperfused tissue; correction assumes average residual plasma rather than measuring it in each brain.
Methods and source locations
Compound reported in the paper: Evacetrapib (LY2484595); Compound label in the paper: Evacetrapib
Compound-level evidence only; no tested lot equivalence or salt conversion is asserted.
Methods: Chemicals; Animal exposure and sample collection; UHPLC-MS-qTOF analysis; Data analysis; Results: Evacetrapib pharmacokinetics in the brain; Table 3; Fig. 4
Brain evacetrapib concentration at 0.5 h after 40 mg/kg BW, corrected for residual blood: UHPLC-MS-qTOF with residual-blood correction; n = 4 mice per time point per dose — Table 3, 0.5 h row, 40 mg/kg calculated concentration column; Fig. 4B/caption; Results
Brain evacetrapib concentration at 0.5 h after 120 mg/kg BW, corrected for residual blood: UHPLC-MS-qTOF with residual-blood correction; n = 4 mice per time point per dose — Table 3, 0.5 h row, 120 mg/kg calculated concentration column; Fig. 4B/caption; Results
40 mg/kg BW intravenous · Table 3, 0.5 h row; Fig. 4B/caption; Methods: Animal exposure and sample collection; UHPLC-MS-qTOF analysis
120 mg/kg BW intravenous · Table 3, 0.5 h row; Fig. 4B/caption; Methods: Animal exposure and sample collection; UHPLC-MS-qTOF analysis
Genotype- and sex-dependent recognition-memory response
Animal study · WT, APPtg, human-CETPtg and APPtg/CETPtg littermate mice of both sexes on a C57BL/6J background and a 1% cholesterol diet [3]
Evacetrapib improved novel-object recognition in CETPtg and APPtg/CETPtg groups, with significant female treatment comparisons and nonsignificant male comparisons. APPtg mice without CETP did not show a recognition-memory response. Y-maze treatment effects were nonsignificant.
Conditions shared by the study groups
- Route
- Intraperitoneal
- Frequency
- Daily
- Treatment course
- Reported 11-week regimen; behavioral assessment at age 20–21 weeks, elapsed exposure uncertain.
- Vehicle
- Kolliphor EL/glucose (one part Kolliphor EL to four parts 50 g/L D-(+)-glucose).
- Daily evacetrapib across four genotypes
- Model: WT, APPtg, human-CETPtg and APPtg/CETPtg littermate mice of both sexes on a C57BL/6J background and a 1% cholesterol diet
- Reported limits: Reported treatment-to-test timeline is not fully aligned; numerical NOR means are not transcribed from scatter plots.
Methods and source locations
Compound reported in the paper: Evacetrapib (LY2484595); Compound label in the paper: Evacetrapib
Compound-level evidence only; no tested lot equivalence or salt conversion is asserted.
Results: Evacetrapib maintains memory in CETPtg and APPtg/CETPtg mice; Fig. 3B–H; Methods: Animal strains and housing, Study design, Drug preparation, NOR, Y-maze, Aβ ELISA, statistics; Appendix Fig. S2 (p. 4)
Female novel-object recognition: evacetrapib versus vehicle in CETP-expressing genotypes: Fig. 3C/D; two-way ANOVA with Tukey post hoc; mean ± SEM plotted; n = 12–14 for sexes combined in panel B, not per sex — Fig. 3C and 3D image annotations and caption; Methods: Novel object recognition test; Statistical analyses for mouse dataset
Recognition-memory response in non-CETP controls: NOR; genotype-matched vehicle control; combined-sex and sex-separated displays — Fig. 3B–D images/caption; Results: Evacetrapib maintains memory
Y-maze spontaneous alternation: Three-way ANOVA (sex, genotype, treatment) with Tukey post hoc; n = 6–8 per sex/group, mean ± SEM — Appendix Fig. S2A–C image/caption, PDF p. 4; Methods: Y-maze test
Soluble and insoluble brain Aβ40/Aβ42 in female APPtg and APPtg/CETPtg mice: Multiplex ELISA of brain homogenates; mean ± SEM plotted; no exact concentrations inferred — Fig. 3E–H image/caption; Results: CETP transgenicity does not exacerbate the amyloidogenic pathway; Methods: Amyloid-beta ELISA
Daily evacetrapib across four genotypes · Methods: Study design, Drug preparation, NOR; Fig. 1B; Fig. 3B–D; Appendix Fig. S2
