135 1791 nd 13 NA (M2) Glucuronide 15 4242 96 283 6.4 of (M4) Glucuronide 89 732 232 8.2 2.6 of (M5) 2.5 11 nd 4.4 NA (M8) Glucuronide 1.5 363 nd 242 NA of nalmefene (M9) Unknown 6.4 195 0.75 30 0.12 (M10) nd = not detected; NA = not applicable Acceptable high exposure ratios were achieved in the rat for trial additional metabolites, although for reasons noted above, these values are likely to overestimate the exposures achieved in the pivotal dietary toxicity study. Since the dietary route was mainly used in the rat studies, exposure ratios based on Cmax have also been calculated in this species. The human Cmax values used for calculating exposure ratios were from Study CPH-101-0902 (Day 7 values in healthy subjects given the recommended clinical dose [20 mg] of nalmefene, nornalmefene, and nornalmefene-3-O-glucuronide were 28.5, 3.53, 186 and 17.5 ng.h/mL, respectively). Table 9: Relative exposure in repeat dose toxicity and carcinogenicity studies calculated based on Cmax. Species Study Analyte Dose Cmax Exposure duration (ng/ trial (sampling day) mL) day/week); study number Rat (SD) 4-week 30 9.94 0.3 Nalmefene toxicokinetic 100 51.3 1.8 bridging study 300 150 5 with doses 30 20.8 6 Nornalmefene g to those 100 67.2 19 used in the 52-week 300 68.5 19 study (day 30 505 3 Nalmefene 29/30); glucuronide 100 2,480 13 Study LBK0257 300 9,030 49 30 803 46 Nornalmefene glucuronide 100 2,250 129 300 4,735 271
(M2) 135 1791 nd 13 NA Glucuronide of (M4) 15 4242 96 283 6.4 Glucuronide of (M5) 89 732 232 8.2 2.6 (M8) 2.5 11 nd 4.4 NA Glucuronide of nalmefene (M9) 1.5 363 nd 242 NA Unknown (M10) 6.4 195 0.75 30 0.12 nd = not detected; NA = not applicable Acceptable high exposure ratios were achieved in the rat for additional metabolites, although for reasons noted above, these values are likely to overestimate the exposures achieved in the pivotal dietary toxicity study. Since the dietary route was mainly used in the rat studies, exposure ratios based on Cmax have also been calculated in this species. The human Cmax values used for calculating exposure ratios were from Study CPH-101-0902 (Day 7 values in healthy subjects given the recommended clinical dose [20 mg] of nalmefene, nornalmefene, and nornalmefene-3-O-glucuronide were 28.5, 3.53, 186 and 17.5 ng.h/mL, respectively). Table 9: Relative exposure in repeat dose toxicity and carcinogenicity studies calculated based on Cmax. Species Study duration (sampling day/week); study number Analyte Dose Cmax (ng/ mL) Exposure Rat (SD) 4-week toxicokinetic bridging study with doses to those used in the 52-week study (day 29/30); Study LBK0257 Nalmefene 30 9.94 0.3 100 51.3 1.8 300 150 5 Nornalmefene 30 20.8 6 100 67.2 19 300 68.5 19 Nalmefene glucuronide 30 505 3 100 2,480 13 300 9,030 49 Nornalmefene glucuronide 30 803 46 100 2,250 129 300 4,735 271 day) g trial trial