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Pharmacokinetics and pharmacodynamics of dapagliflozin in combination with insulin in Japanese patients with type 1 diabetes
Author(s) -
Watada Hirotaka,
Shiramoto Masanari,
Ueda Shinya,
Tang Weifeng,
Asano Michiko,
Thorén Fredrik,
Kim Hyosung,
Yajima Toshitaka,
Boulton David W.,
Araki Eiichi
Publication year - 2019
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.13593
Subject(s) - dapagliflozin , medicine , pharmacodynamics , pharmacokinetics , placebo , diabetic ketoacidosis , insulin , diabetes mellitus , type 2 diabetes , type 1 diabetes , adverse effect , endocrinology , pharmacology , urology , alternative medicine , pathology
Aims To assess the pharmacokinetics/pharmacodynamics (PK/PD) of dapagliflozin, a sodium‐glucose co‐transporter 2 inhibitor that increases urinary glucose excretion (UGE) and its major metabolite, dapagliflozin‐3‐O‐glucuronide (D3OG), in Japanese patients with type 1 diabetes (T1D) and inadequate glycaemic control (HbA1c 7%‐10%). Materials and methods Japanese patients (18‐65 years) with inadequately controlled T1D were randomized 1:1:1 to dapagliflozin 5 mg, 10 mg or placebo (n = 14 each) once daily for 7 days, with adjustable insulin. The PK/PD characteristics of dapagliflozin and D3OG were assessed on Day 7. Patients underwent follow‐up evaluation on Days 8 and 14. Adverse events (AEs), hypoglycaemic episodes and events of diabetic ketoacidosis (DKA) were recorded over the treatment and follow‐up periods. Results A total of 42 randomized patients received dapagliflozin or placebo. PK variables increased in a dose‐dependent manner. D3OG was generated rapidly, with a median time to maximum plasma concentration of 2.0 hours (1.0‐3.0). The dapagliflozin dose‐UGE relationship was attenuated, with larger insulin dose reductions than anticipated. Mean percent (standard error) changes in total daily insulin dose from baseline to Day 7 were − 36.86% (3.32), −39.13% (2.68) and − 4.97% (5.28) for dapagliflozin 5 mg and 10 mg and for placebo, respectively. No DKA was reported. AEs were consistent with the established dapagliflozin safety profile. There was no increase in hypoglycaemia. Conclusions The PK and safety profiles of dapagliflozin in Japanese patients with T1D were consistent with previous studies, but with an unanticipated attenuation of the PD dose‐response measured as UGE.