Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects.
OBJECTIVE
Dapagliflozin increases urinary glucose excretion by selectively inhibiting renal sodium-glucose transporter 2, an insulin-independent mechanism of action that may be complementary to that of other oral antidiabetes drugs. The current studies assessed the potential for pharmacokinetic (PK) interaction between dapagliflozin and pioglitazone, metformin, glimepiride or sitagliptin in healthy subjects following single-dose administration.


METHODS
In open-label, randomized, three-period, three-treatment crossover studies, 24 subjects received 50 mg dapagliflozin, 45 mg pioglitazone or the combination, while 18 subjects received 20 mg dapagliflozin, 1000 mg metformin or the combination. In an open-label, randomized, five-period, five-treatment, unbalanced crossover study, 18 subjects first received 20 mg dapagliflozin, 4 mg glimepiride or the combination, and afterward 100 mg sitagliptin or sitagliptin plus 20 mg dapagliflozin. Blood samples were taken over 72 h of each treatment period. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination:monotherapy being within the range of 0.80-1.25.


RESULTS
Co-administration of dapagliflozin with pioglitazone, metformin, glimepiride or sitagliptin had no effect on dapagliflozin maximum plasma concentration (C(max) ) or area under the plasma concentration-time curve (AUC). Similarly, dapagliflozin did not affect the C(max) or AUC for the co-administered drug, except for slight extensions of the 90% CI for the ratio of geometric means for glimepiride AUC (upper limit 1.29) and pioglitazone C(max) (lower limit 0.75). All monotherapies and combination therapies were well tolerated.


CONCLUSIONS
Dapagliflozin can be co-administered with pioglitazone, metformin, glimepiride or sitagliptin without dose adjustment of either drug.
Bristol-Myers Squibb Company, Princeton, NJ 08543-4000, USA. sreeneeranj.kasichayanula@bms.com
S
S
Kasichayanula
X
X
Liu
W C
WC
Shyu
W
W
Zhang
M
M
Pfister
S C
SC
Griffen
T
T
Li
F P
FP
LaCreta
D W
DW
Boulton
D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds; D018592:Cross-Over Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D000077205:Pioglitazone; D011719:Pyrazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068900:Sitagliptin Phosphate; D051297:Sodium-Glucose Transporter 2 / Q000187:drug effects; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D011719:Pyrazines; D051297:Sodium-Glucose Transporter 2; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D014230:Triazoles; C529054:dapagliflozin; C057619:glimepiride; D008687:Metformin; D000068900:Sitagliptin Phosphate; D000077205:Pioglitazone