TABLE 4

Drug Y clearance values used in various scenarios

Drug YDosing RegimenτCLm0aCLPDCLp0CLf0CLMPCLPM
l/h
Figure 3, a and bWeek 40, 0.63 mg/h continuous i.v. infusionN/A12 vs. 4322.50000
Figure 3, c and dWeek 40, 15-mg single oral doseN/A12 vs. 4322.50000
Figure 3, e and fWeek 40, 2.5-mg multiple oral doses4 h12 vs. 4322.50000
Figure 3, g and hWeek 40, 15-mg multiple oral doses24 h12 vs. 4322.50000
Figure 5, a and bWeek 40, 0.63 mg/h continuous i.v. infusionN/A432.25 vs. 22.50000
Figure 5, c and dWeek 40, 15-mg single oral doseN/A432.25 vs. 22.50000
Figure 5, e and fWeek 40, 15-mg multiple oral doses24 h432.25 vs. 22.50000
Figure 7aWeek 40, 15-mg single oral dosesN/A4322.50, 2, 3, 11.3, 22, 5000
Figure 7b00, 2, 3, 11.3, 22, 500
Figure 7c0, 2, 3, 11.3, 22, 50, 2, 3, 11.3, 22, 500
Figure 7d000, 2, 3, 11.3, 22, 50
Figure 7e0000, 2, 3, 11.3, 22, 5
Figure 9, a–c (Scenario 1)400-mg single oral doseWeek 20N/A34.82.20000
Week 404322.50000
Figure 9, c–e (Scenario 2)Week 2034.82.20000
Week 4064.122.50000
Figure 9, e–g (Scenario 3)Week 2034.82.20004.5
Week 404322.50007.4
Figure 9, h–j (Scenario 4)Week 2034.82.20004.5
Week 4064.122.50007.4
  • CLMP,u, unbound placental efflux clearance; CLPM,u, unbound placental uptake clearance; CLp0,u, unbound placental metabolism; CLf0,u, unbound fetal metabolism; N/A, not applicable; week, gestational week.

  • a At week 20, baseline value CLm0 was set at 43 l/h based on the published midazolam clinical data at term (Ke et al., 2012), whereas CLPD,u was estimated through sensitivity analysis to match reported fetal UV plasma midazolam drug C-T profile (Zhang and Unadkat, 2017). At week 20, CLm0 was slightly decreased primarily resulting from more plasma albumin binding.