Dapagliflozin (DAPA), an SGLT2 inhibitor, reduces blood glucose by increasing urinary glucose excretion (UGE). The pharmacokinetics and pharmacodynamics of DAPA in Japanese and non-Japanese patients (pts) with type 1 diabetes (T1D) have been evaluated in 2 studies (Japanese: NCT01498185, n=42, DAPA 5, 10 mg or placebo [PBO] for 14 days; Non-Japanese: NCT02582814, n=70, DAPA, 1, 2.5, 5, 10 mg or PBO for 7 days). A clear dose-response for 24-hour UGE was seen in the non-Japanese study but not in the Japanese study. An exposure-response model was used to characterize the relationship between DAPA exposure and 24-hour UGE using a nonlinear mixed-effect modeling approach, and the effect of patient-level characteristics (baseline and Day 7) on this was investigated. Covariates were identified using a stepwise procedure. Average self-monitored blood glucose (SMBG) at Day 7, Day 7 change from baseline in total insulin dose, and baseline eGFR all had a significant effect on UGE; SMBG was the most influential. When these covariates are included, the model fits the data well for both populations (Figure; for the Japanese study, 1 and 2.5 mg data were simulated using median AUC from non-Japanese pts, for 5 and 10 mg median covariate values were from the Japanese study). The lack of clear dose-response in UGE in Japanese pts may primarily be caused by high SMBG, which is likely a result of greater insulin dose reductions in the Japanese study.
V. Sokolov: None. T. Yakovleva: None. S. Ueda: Employee; Self; AstraZeneca. J.R. Parkinson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Novartis Pharmaceuticals Corporation. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; Bristol-Myers Squibb Company. W. Tang: Employee; Self; AstraZeneca.
