Figure 3
Antinociception/Analgesia is mediated via AM404 production in the periaqueductal gray (PAG) region of the brain and human single and multiple ascending doses (SAD and MAD) Phase 1 clinical trial reveals a favorable pharmacokinetic profile. (a) Detection of deuterated (D10-SRP-001) in the rat brain 30 min after IP injection. The full fragmentation spectrum of D10-SRP-001 detected in the brain (red) matches (b) the standard SRP-001 compound spectrum (blue). (c) The structure of D10-SRP-001 shows fragmentation patterns of D10-SRP-001 that match the spectra shown in the brain (red) and with the deuterated standard (blue). (d) The MRM (m/z 416 → 186) for D10-SRP-001 shows the elution time at ~ 2.2 min. (e) Quantification of AM404 production in the CNS periaqueductal gray region. (f) AM404 is expressed in the periaqueductal gray area of the brain following SRP-001 IP injection. LC–MS/MS detection of AM404 in the rat periaqueductal gray area after SRP-001 (top panel) and ApAP (bottom panel) IP injections. The AM404 structure and major fragments. (g) The peaks are confirmed to be AM404 by co-spiking AM404 standard to the samples (red and orange, respectively). The major peaks detected by LC–MS/MS demonstrate that the peak 9.9 min from LC is the AM404 compound. These peaks align to the (e) AM404 fragments. (h) Design of the first-in-human Phase 1 clinical trial for SRP-001. A randomized, double-blind, placebo-controlled study to assess the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of SRP-001 and to characterize the effect of food on the pharmacokinetics of SRP-001 in healthy male and female subjects. Single ascending dose (SAD) escalation from 300 to 2000 mg (fasted state) and 900 mg (fed state). (i) and (j) Geometric mean SRP-001 plasma concentration–time profiles following oral administration (logarithmic plot) show a proportional or super-proportional increase in Cmax (peak time to concentration at 1 h post-dose) with a mono- or bi-phasic concentration decline in the SAD (i) and the MAD cohorts with an arithmetic mean T1/2 of 5.57 h and a geometric mean T1/2 of 4.92 h.
