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.