Table 2.
Geometric mean AUC and Cmax from PBPK model simulations compared with observed clinical data of dapagliflozin exposure following single or multiple doses
| Population and dose | Parameters from observed data | Parameters from simulation | Mean ratio of simulated/observed | |||
|---|---|---|---|---|---|---|
| AUCINF, h·ng/mL (95% CI) | Cmax, ng/mL (95% CI) | AUCINF, h·ng/mL (95% CI) | Cmax, ng/mL (95% CI) | AUC | Cmax | |
| Dapagliflozin exposure following a single dose in healthy volunteers | ||||||
| Healthy volunteers, 5 mg | 185 (157–219) | 67 (57–80) | 290.25 (266.49–316.14) | 94.49 (85.09–104.93) | 1.57 | 1.41 |
| Healthy volunteers, 10 mg | 368 (316–433) | 116 (83–135) | 411.49 (377.24–448.85) | 146.23 (128.08–166.94) | 1.12 | 1.26 |
| Healthy volunteers, 20 mg | 977 (813–1177) | 269 (233–310) | 822.9 (754.49–897.70) | 292.45 (256.17–333.87) | 0.84 | 1.09 |
| Healthy volunteers, 100 mg | 4363 (3867–494) | 1112 (867–1468) | 5881.00 (5400.66–6404.06) | 1899.21 (1712.82–2105.89) | 1.35 | 1.71 |
| Dapagliflozin exposure following multiple doses in healthy volunteers | ||||||
| Healthy volunteers, 10 mg q.d. | 506 (438–613) | 119 (87–168) | 430.89 (393.31–472.07) | 150.71 (132.70–171.15) | 0.85 | 1.27 |
| Dapagliflozin exposure following a single dose in severely renal and hepatic impaired adults | ||||||
| Moderate hepatic impairment, 10 mg | 632 (1129–2575) | 153 (200–492) | 710.59 (650.26–776.52) | 168.64 (145.93–194.90) | 1.12 | 1.10 |
| Severe hepatic impairment, 10 mg | 776 (834–1419) | 190 (119–242) | 1023.38 (936.15–1118.74) | 175.42 (152.94–201.21) | 1.32 | 0.92 |
| Moderate renal impairment, 50 mg | 5182 (4191–6681) | 897 (696–1250) | 2930.48 (2635.97–3257.91) | 848.92 (732.98–983.20) | 0.57 | 0.95 |
| Severe renal impairment, 50 mg | 4884 (4409–5358) | 772 (692–857) | 2757.40 (2443.21–311.98) | 788.90 (685.35–908.08) | 0.56 | 1.02 |
| Mean AUC and Cmax from PBPK model simulations with default virtual pediatric population (scenario 1) compared with observed clinical data of dapagliflozin exposure following single doses in adolescents with T2DM | ||||||
|---|---|---|---|---|---|---|
| Dapagliflozin single dose | AUCINF, h·ng/mL (95% CI) | Cmax, ng/mL (95% CI) | AUCINF, h·ng/mL (95% CI) | Cmax, ng/mL (95% CI) | AUC | Cmax |
| 2.5 mg | 101.0 (83.7–120) | 24.8 (14–31) | 79.82 (73.51–86.67) | 26.76 (23.57–30.38) | 0.79 | 1.08 |
| 10 mg | 427.0 (346–535) | 118.0 (94–155) | 335.24 (307.46–365.54) | 112.85 (99.35–128.18) | 0.79 | 0.96 |
Data are expressed as geometric means. Single‐dose and multiple‐dose PK analyses are from clinical studies MB102001 and MB102002, respectively. Single‐dose 10‐mg oral dapagliflozin in a hepatically impaired population and single‐dose 50‐mg oral dapagliflozin in a renally impaired population PK analysis are from clinical studies MB102007, and MB102027, respectively. Single‐dose PK is from clinical study NCT01525238. Oral and 14C intravenous monotherapy single dose in healthy adults is from clinical study NCT00908271. AUC, area under the curve; AUCINF, extrapolated area under the plasma concentration‐time curve from time zero to infinity; CI, confidence interval; Cmax, highest drug concentration in the plasma; PBPK, physiologically based pharmacokinetic; q.d., once daily; T2DM, type 2 diabetes mellitus.