Table II.
Estimated PK/PD Model Parameters for Dapagliflozin in Healthy Subjects
| Parameter (units) | Definition | Final estimate | % SEM |
|---|---|---|---|
| Pharmacokinetic parameters | |||
| k el (1/hr) | First-order elimination rate constant | 0.26 | 7.7 |
| k a (1/hr) | First-order absorption rate constant | 2.7 | 14.8 |
| k pt (1/hr) | First-order rate constant for distribution of drug from plasma to tissues | 0.14 | 14.3 |
| k tp (1/hr) | First-order rate constant for distribution of drug from tissues to plasma | 0.09 | 22.2 |
| V c,app (L) | Apparent central volume of distribution | 70 | 8.5 |
| Pharmacodynamic parameters | |||
| IC 50, total (ng/ml) | Total plasma concentration associated with half-maximal inhibition of SGLT2- mediated glucose reabsorption | 3.5 | 17.1 |
| IC 50,unbound (nM) | Unbound plasma concentration associated with half-maximal inhibition of SGLT2- mediated glucose reabsorption | 0.55a | – |
| I max | Maximum fractional inhibition of glucose reabsorption | 0.35 | 5.7 |
aCalculated based on a molecular weight of 409 Da and a human unbound plasma fraction of 0.064 estimated by standard equilibrium dialysis techniques. GluFR was assumed to be 7.5 g/h with a 20% inter-cohort coefficient of variation. GluFR was estimated to be 6.6, 7.7, 6.8, 8.6, and 8.6 g/h in the 2.5, 10, 50, 100, and 250 mg dose cohorts