peptides (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 STEGLUJAN 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
Sitagliptin
In Vitro Assessment of Drug Interactions
Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.
In Vivo Assessment of Drug Interactions
Table 4: Effect of Coadministered Drugs on Systemic Exposure of Sitagliptin
Coadministered Drug
Dose of Coadministered Drug*
Dose of Stagliptin*
Geometric Mean Ratio
(ratio with/without coadministered drug)
No Effect = 1.00
AUC†
Cmax
* All doses administered as single dose unless otherwise specified. † AUC is reported as AUC 0-∞ unless otherwise specified. ‡ Multiple dose. § AUC 0-12hr.
No dosing adjustments required for the following:
Cyclosporine 600 mg once daily 100 mg once daily Sitagliptin 1.29 1.68
Metformin 1,000 mg‡ twice daily for 14 days 50 mg‡ twice daily for 7 days Sitagliptin 1.02§ 1.05
Table 5: Effect of Sitagliptin on Systemic Exposure of Coadministered Drugs
Coadministered Drug
Dose of Coadministered Drug*
Dose of Sitagliptin*
Geometric Mean Ratio
(ratio with/without sitagliptin)
