nic anion transporters (OAT1, OAT3), organic cation transporters (OCT1, OCT2), or organic anion transporting polypeptides (OATP1B1, OATP1B3). Ertugliflozin or ertugliflozin glucuronides do not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 transporters, or transporting polypeptides OATP1B1 and OATP1B3, at clinically relevant concentrations. Overall, ertugliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are substrates of these transporters.
In Vivo Assessment of Drug Interactions
No dose adjustment of SEGLUROMET is recommended when coadministered with commonly prescribed medicinal products. Ertugliflozin pharmacokinetics were similar with and without coadministration of metformin, glimepiride, sitagliptin, and simvastatin in healthy subjects (see Figure 1). Coadministration of ertugliflozin with multiple doses of 600 mg once-daily rifampin (an inducer of UGT and CYP enzymes) resulted in approximately 39% and 15% mean reductions in ertugliflozin AUC and Cmax, respectively, relative to ertugliflozin administered alone. These changes in exposure are not considered clinically relevant. Ertugliflozin had no clinically relevant effect on the pharmacokinetics of metformin, glimepiride, sitagliptin, and simvastatin when coadministered in healthy subjects (see Figure 2). Physiologically-based PK (PBPK) modeling suggests that coadministration of mefenamic acid (UGT inhibitor) may increase the AUC and Cmax of ertugliflozin by 1.51- and 1.19-fold, respectively. These predicted changes in exposure are not considered clinically relevant.
Figure 1: Effects of Other Drugs on the Pharmacokinetics of Ertugliflozin
Figure 1
Figure 2: Effects of Ertugliflozin on the Pharmacokinetics of Other Drugs
Figure 2
Metformin hydrochloride
Table 4: Effect of Metformin on Systemic Exposure of Coadministered Drugs
Coadministered Drug
Dose of Coadministered Drug*
Dose of Metformin*
Geometric Mean Ratio
(ratio with/without metformin)
No Effect = 1.00
AUC†
Cmax
No dosing adjustments required for the following:
* All doses administered as single dose unless otherwise specified. † AUC is reported as AUC 0-∞ unless otherwise specified. ‡ AUC 0-24hr. § Metformin hydrochloride extended-release tablets 500 mg. ¶ Ratio of arithmetic means, p value of difference <0.05. # Ratio of arithmetic means.
Cimetidine 400 mg 850 mg Cimetidine 0.95‡ 1.01
Glyburide 5 mg 500 mg§ Glyburide 0.78¶ 0.63¶
Furosemide 40 mg 850 mg Furosemide 0.87¶ 0.69¶
Nifedipine 10 mg 850 mg Nifedipine 1.10‡ 1.08
Propranolol 40 mg 850 mg Propranolol 1.01‡ 0.94
Ibuprofen 400 mg 850 mg Ibuprofen 0.97# 1.01#
Table 5: Effect of Coadministered Drugs on Systemic Exposure of Metformin
Coadministered Drug
Dose of Coadministered Drug*
Dose of Metformin*
Geometric Mean Ratio
(ratio with/without coadministered drug)
No Effect = 1.00
AUC†
Cmax
