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Background: Dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, lowers blood glucose levels by preventing renal glucose reabsorption, resulting in urinary glucose excretion. Because dapagliflozin-induced glycosuria produces a modest reduction in body weight, it may benefit patients with type 2 diabetes who are overweight or obese. Pathophysiologic alterations associated with obesity may lead to clinically significant differences in drug pharmacokinetic (PK) and pharmacodynamic (PD) properties. Purpose: This study aimed to evaluate the PK and PD characteristics of dapagliflozin in obese and nonobese healthy adults and assess the effect of obesity on these profiles by comparing outcomes between the two groups following multiple oral doses. Methods: In this open-label, multiple-dose study, dapagliflozin 10 mg tablets were administered once daily for 5 days to healthy adults. Serial blood samples for PK analysis were collected before and up to 48 h after the last dose on day 5. PK parameters were determined using noncompartmental analysis. Sensitivity analyses were conducted, including correlation analysis of PK parameters with weight or BMI using Pearson’s correlation coefficients ( r ), as well as analysis of covariance (ANCOVA) with body weight as a covariate, supplemented by bootstrap analysis, to evaluate the effect of obesity on the primary PK and PD parameters. Results: Thirteen nonobese and nine obese participants completed the study. The geometric mean ratio (obese/nonobese) (90% CIs) of the area under the plasma concentration-time curve during a dosing interval at steady state (AUC tau,ss ) and maximum plasma concentration at steady state (C max,ss ) were 0.6855 (0.5503– 0.8538) and 0.7673 (0.6145– 0.9581), respectively. There was no moderate correlation ( r > 0.6) between any of the PK parameters analyzed and weight or BMI. The ANCOVA least squares mean differences between the nonobese and obese groups were 163.6 h*ng/mL, 38.4 ng/mL, 2.4 mg/dL, for AUC tau,ss , C max,ss , and serum glucose levels from baseline to maximum level on day 5 (ΔG max ), respectively ( p value > 0.05, ANCOVA), which were consistent with the median values of bootstrap estimates. Conclusion: The AUC tau,ss and C max,ss values for the obese group were lower than those of the nonobese group (31% and 23%, respectively). The sensitivity analyses revealed no moderate correlation between the primary PK and PD parameters and weight or BMI, nor any statistically significant differences in systemic exposure and ΔG max between the nonobese and obese groups; however, this finding should be interpreted with caution due to the exploratory nature of the study and its limited sample size. Dapagliflozin was safe and well-tolerated following multiple oral doses. Keywords: dapagliflozin, obesity, pharmacokinetics, pharmacodynamics, type 2 diabetes
Lee et al. (Fri,) studied this question.