Here are the method and results of the previous Xanamem multiple ascending dose study, which was conducted in 2016.
The full article is available on the ACW website.
Subject demographicsand safety,. Page 6
"A multiple ascending dose study was conducted in 24 healthy male subjects (4 Caucasians and 20 Asians) with a mean age of 26.7 ± 5.4 years and a mean BMI of 23.9 ± 1.9kg·/m2. No serious TEAEs or TEAEs that led to subject withdrawal from the study were reported, and all TEAEs were mild or moderate in intensity. The most common TEAE was headache reported in 7/24 subjects; diarrhoea was reported in2/24 subjects ,and thrombophlebitis was reported in 3/24 subjects.A study to determine the amount of UE2343 in CSF was conducted in four healthy Asian male subjects with mean age of 29 ±11 years and mean BMI of 24. 6 ±1.4kg·/m2. All TEAEs were mild to moderate in intensity. Vital signs remained stable during the study, and no out of the range values were recorded for any of the subjects during the study. Increased alanine aminotransferase was reported in a single subject."
Pharmokinetics. Pages7- 8
"In the multiple ascending dose study, the pharmacokinetic parameters of UE2343 at dose levels of 10, 20 and 35 mg administered every 12 h were determined on Days 1 and 10. Plasma UE2343 levels as measured by Cmax, and AUC over 12 h (AUC0–12) were approximately dose proportional on Day 10 (Table 4). However, these parameters increased more rapidly than proportionally to dose level on Day 1. Steady state was achieved by Day 5 and the terminal t1/2 ranged from 10 to 14h. The median time to peak concentration following each dose ranged from 4 to 6 h. There was considerable accumulation with 12 hourly dosing, with increase in AUC0-12 from first dose to steady state of greater than fourfold at the highest dose level. The Ae in urine was low, with the fraction excreted in the dosing interval approximately 4% at steady state. The concentrations of UE2343 in plasma and CSF were determined during administration of 35 mg b.i.d for 4 days.Mean Cmax on Days 1 and 4 was reached at 5h post-dose (Table 5). The extent of accumulation of UE2343 in plasma after repeated daily dosing on Day4 was 3.3-fold,consistent with an elimination t1/2 in the order of 1 day.Between-subject variability in the extent of systemic exposure to UE2343 was high with geometric CVs for Cmax and AUC0–12 of 59 to81%. A single CSF sample was taken from each subject at 5 h post-dose on Day 4. The mean concentration ofUE2343 in the CSF was 69.8 ng/·mL,ranging from 41.2 to 99.9 ng·/mL and 7.46 to 11.9% of simultaneous total plasma levels."
Estimation of 11β-HSD1inhibition in brain, Page 9
"It was estimated that the mean CSF nadir at steady state[minimum plasma concentration (Cmin)] was 13, 22 and 50 ng/·mL at 10, 20 and 35 mg b.i.d. respectively.Maximal CSF concentrations were estimated to be 20, 34 and 81 ng/ ·mL at 10, 20 and 35 mg b.i.d, suggesting that steady state brain levels exceeded the IC50 value for UE2343 (9 ng/mL) across the dosing range."
The presence of UE2343 in the CSF samples taken from the human subjects confirmed that the compound crosses the blood brain barrier. UE2343 is 70% bound to plasma proteins; therefore, at plasma Cmax on Day4 (101h), the mean UE2343 CSFlevelswere33%ofthefreeplasmalevels(range:25–40%) and 10% of the total plasma levels(range:7–12%)(Figure5).
It was assumed that these ratios were maintained across all dose levels and time points to calculate the likely concentrations of UE2343 in the CSF at each of the dose levels used in the multiple ascending dose study. From these calculations,it was estimated that the mean CSF nadir at steady state [minimum plasma concentration (Cmin)] was 13, 22 and 50 ng/·mL at 10, 20 and 35 mg b.i.d. respectively. Maximal CSF concentrations were estimated to be 20, 34 and 81 ng/·mL at 10, 20 and 35 mg b.i.d, suggesting that steady state brain levels exceeded the IC50 value for UE2343 (9 ng ·/mL) across the dosing range."
Citation for published version:
Webster, SP, McBride, A, Binnie, M, Sooy, K, Seckl, JR, Andrew, R, Pallin, TD, Hunt, HJ, Perrior, TR, Ruffles, VS, Ketelbey, JW, Boyd, A & Walker, BR 2017, 'Selection and early clinical evaluation of the brain penetrant 11-hydroxysteroid dehydrogenase type 1 (11-HSD1) inhibitor UE2343 (Xanamem™)
British Journal of Pharmacology, 23 December 2016
DOI: 10.1111/bph.13699
