3.2 Clinical study
3.2.1 Safety and tolerability
A total of 32 subjects received study treatment and were assessed for
safety. Baseline demographics were similar across dosing cohorts, with a
mean age of 36.4 years (range, 25–76 years), mean BMI of 25.0
kg/m2 and 24 subjects were male (75%) (Table 3).
SPL026 was found to be safe and well tolerated with treatment-emergent
adverse events categorised as either mild or moderate and all were
transient in nature. Further details of the SPL026 safety profile will
be reported elsewhere.
3.2.2 PK analysis
As mean measured levels of DMT at the 120 min and 240 min timepoints
were low (<0.1 ng/mL) (Table 4), these timepoints were
excluded from (Figure 1) to improve graphical data representation. Due
to dosing errors, 1 subject from Cohort 1, and 1 subject from Cohort 3
were excluded from PK analyses. The PK parameters from each dosing group
are presented in Table 5.
PK analysis of 5 evaluable subjects from the first dosing cohort (Cohort
1) that received a total dose of 9 mg SPL026 (Table 1) revealed a large
observed inter-individual variability for both Cmax(mean, 20.8 ng/mL; range, 5.0–34.9) and AUClast (mean,
349 ng.min/mL; range, 71–705) (Table 5, Figure 1). Median
Tmax was approximately 10 min (close to the end of the
infusion), before an observed gradual decline over the remaining
sampling period (Figure 1). Mean t1/2 was 12.1 min
(range, 5.8–18.3).
For the 6 subjects in Cohort 2 that received 12 mg SPL026 (6 mg over 5
min and then 6 mg over 5 min) mean DMT Cmax = 30.6 ng/mL
(range, 12.7–62.3), mean AUClast = 451 ng.min/mL
(range, 245–755) (Table 5, Figure 1) and mean t1/2 was
9.5 min (range, 6.0–17.0).
With respect to the 5 subjects from Cohort 3 that received a dose of 17
mg SPL026 (6 mg over 5 min then 11 mg over 5 min), sampling issues for
PK data resulted in 9 missing data points. It was therefore not possible
to calculate any parameters for DMT other than Cmax(mean, 72.1 ng/mL; range, 16.2–126.0), Tmax (median,
9.8 min; range, 9.7–11.3 min) and AUClast (mean, 842
ng.min/mL; range, 204–1298) (Table 5).
The final cohort (Cohort 4) received SPL026 infused as 6 mg over 5 min
followed by 15.5 mg over 5 min (total dose 21.5 mg). For these 6
subjects mean Cmax was 62.7 ng/mL (range, 29.0–107)
(Table 5) and mean AUClast was 835 ng.min/mL (range,
477–1052); the median Tmax of 9.7 min and mean
t1/2 (12.1 min; range, 6.3–20.3) were in line with the
previous dose cohorts.
Individual C5min following a 6 mg dose, ranged from 3.32
ng/mL to 43.0 ng/mL across all dose cohorts. A one-way ANOVA revealed
that there were no significant differences between cohorts
(F(3,20)=1.628, p=0.214).
IAA concentrations were measured from 4 subjects from Cohort 2 and
Cohort 4. However, IAA was detectable at 30 min for Cohort 4 only
(1260–1780 ng/mL).
3.2.3 Dose proportionality
There was no statistical difference between cohorts in dose-normalised
Cmax (p=0.346) and AUClast (p=0.792).
Linear regression for log(dose) vs log(Cmax) and
log(AUClast) were fit resulting in the following model
parameters: Cmax (adjusted R2=0.367,
p=0.002) and AUClast (adjusted
R2=0.330, p=0.003). In the analysis of dose
proportionality using the power model of Cmax and
AUClast, each slope (β) was greater than 1, with
corresponding CI crossing 1 (Table 6),26 indicating
dose proportionality for each of tested PK parameters.
Post-hoc analysis showed no relationship across all dose cohorts between
BMI (R2=0.048, p=0.327), weight
(R2=0.009, p=0.681) or age
(R2=0.024, p=0.489) with dose-normalised
Cmax, and no relationship between BMI
(R2=0.177, p=0.051), weight
(R2=0.061, p=0.269) or age
(R2=0.046, p=0.336) with C5min.