Table 1.

Summary of key PK parameters for remimazolam and CNS7054

Parameter	IV	IN powder			IN solution
Dose	4 mg	10 mg	20 mg	40 mg	10 mg	20 mg	40 mg
n	12	11	11	10	11	11	10
Remimazolam (active parent compound)
Cmax (ng/mL), mean ± SD	213 ± 144	108 ± 44	188 ± 59	330 ± 90	112 ± 36	165 ± 106	209 ± 100
Tmax (h), median (min–max)	0.03 (0.017, 0.083)	0.167 (0.167, 0.333)	0.167 (0.083, 0.333)	0.175 (0.083, 0.367)	0.167 (0.083, 0.183)	0.167 (0.083, 0.167)	0.167 (0.083, 0.333)
AUC(0-last) (ng h/mL), mean ± SD	55 ± 16	69 ± 20	135 ± 42	262 ± 80	60 ± 25	93 ± 37	133 ± 15
AUC(0-inf) (ng h/mL), mean ± SD	59 ± 16	72 ± 19	141 ± 45	268 ± 83	62 ± 26	98 ± 39	144 ± 16
t1/2, (h), mean ± SD	0.49 ± 0.19	0.66 ± 0.20	0.87 ± 0.19	0.69 ± 0.11	0.71 ± 0.27	0.97 ± 0.19	1.17 ± 0.18
F (%), mean ± SD	NA	49 ± 12	49 ± 18	48 ± 22	47 ± 23	34 ± 9.8	26 ± 8.7
Statistical comparison of bioavailability expressed as relative exposure to parent drug for IN vs IV
Relative exposure vs IV (%) (Cmax/D), LS mean (90% CI)	NA	0.22 (0.14, 0.30)	0.20 (0.15, 0.27)	0.18 (0.23, 0.24)	0.24 (0.18, 0.32)	0.16 (0.12, 0.21)	0.11 (0.08, 0.14)
Relative exposure vs IV (%) AUC(0-last)/D, LS mean (90% CI)	NA	0.49 (0.42, 0.58)	0.48 (0.41, 0.57)	0.47 (0.40, 0.56)	0.42 (0.36, 0.50)	0.34 (0.29, 0.40)	0.25 (0.21, 0.29)
CNS7054 (inactive metabolite)
Cmax (ng/mL), mean ± SD	275 ± 41	655 ± 103	1191 ± 217	2300 ± 556	960 ± 172	1710 ± 361	3572 ± 1221
Tmax (h), median (min–max)	0.5 (0.167–1.00)	1.0 (0.500–1.50)	1.0 (1.00–1.50)	1.0 (1.00–1.50)	1.0 (0.500–1.02)	1.0 (0.500–1.50)	1.0 (0.333–3.00)
AUC(0-last) (ng h/mL), mean ± SD	703 ± 121	1553 ± 236	3003 ± 598	5678 ± 1352	2143 ± 293	3913 ± 701	7871 ± 1741
AUC(0-inf) (ng h/mL), mean ± SD	NC a)	1571 ± NC	2729 ± NC	6560 ± NC	2626 ± 205	2915 ± 548	9422 ± 370
t1/2 (h), mean ± SD	NC a)	1.32 ± NC	1.37 ± NC	1.40 ± NC	1.52 ± 0.14	1.30 ± 0.11	1.29 ± 0.04
Statistical comparison of bioavailability expressed as relative exposure to metabolite for IN vs IV
Relative exposure vs IV (%) (Cmax/D), LS mean (90% CI)	NA	0.94 (0.84, 1.04)	0.85 (0.76, 0.95)	0.81 (0.72, 0.91)	1.40 (1.25, 1.56)	1.24 (1.11, 1.38)	1.23 (1.09, 1.37)
Relative exposure vs IV (%) AUC(0-last)/D, LS mean (90% CI)	NA	0.87 (0.80, 0.94)	0.83 (0.77, 0.90)	0.78 (0.73, 0.85)	1.23 (1.14, 1.33)	1.12 (1.03, 1.20)	1.09 (1.01, 1.18)

AUC area under the plasma concentration time curve, C_max maximum observed plasma concentration, F bioavailability, IN intranasal, IV intravenous, RMZ remimazolam, T_max time to C_max, t_1/2 elimination half-life

^aFor subjects with %AUC_ext > 20%, the following parameters are not summarized: AUC_0-inf, AUC_0-inf/D, and t_1/2