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Saxagliptin and Dapagliflozin: The lack of pharmacokinetic interaction between saxagliptin and dapagliflozin was demonstrated in a drug-drug interaction study between saxagliptin and dapagliflozin. No dose adjustment of either saxagliptin or dapagliflozin is needed when the two drugs are co-administered.
See Saxagliptin and Dapagliflozin subsections for drug interactions. In summary, there are no clinically meaningful drug interactions expected for either saxagliptin or dapagliflozin.
Saxagliptin: The metabolism of saxagliptin is primarily mediated by cytochrome (CYP)450 3A4/5 (CYP3A4/5).
In in vitro studies, saxagliptin and its major metabolite neither inhibited CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4, nor induced CYP1A2, 2B6, 2C9, or CYP3A4. Therefore, saxagliptin is not expected to alter the metabolic clearance of coadministered drugs that are metabolised by these enzymes. Saxagliptin is neither a significant inhibitor of P-glycoprotein (P-gp) nor an inducer of P-gp.
The in vitro protein binding of saxagliptin and its major metabolite in human serum is below measurable levels. Thus, protein binding would not have a meaningful influence on the pharmacokinetics of saxagliptin or other drugs.
Effect of other drugs on saxagliptin: In interaction studies conducted in healthy subjects, using either single dose or multiple once daily design, the pharmacokinetics of saxagliptin, its major metabolite, or the exposure to the total active components of saxagliptin (parent + metabolite), were not meaningfully altered by metformin (a human organic cation transporter [hOCT]-1 and hOCT-2 substrate), glyburide (a CYP2C9 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), digoxin (a P-glycoprotein [P-gp] substrate), simvastatin (a CYP3A4/5 substrate), diltiazem (a moderate inhibitor of CYP3A4/5), ketoconazole (a potent inhibitor of CYP3A4/5 and P-gp), rifampin (a potent inhibitor of CYP3A4/5 and P-gp), omeprazole (a CYP2C19 [major] and CYP3A4 substrate, an inhibitor of CYP2C19, and an inducer of MRP-3), aluminum hydroxide + magnesium hydroxide + simethicone combination (antacid and antigas formulations), or famotidine (an inhibitor of hOCT-1, hOCT-2, and hOCT-3). Therefore, meaningful interaction of saxagliptin with other substrates of hOCT-1, hOCT-2, P-gp, CYP2C8, CYP2C9, CYP-2C19, CYP3A4/5, and with other inhibitors of hOCT-1, hOCT-2, hOCT-3, CYP3A4/5, CYP2C19, P-gp, and with other inducers of CYP3A4, P-gp, MRP-3, would not be expected.
Effect of saxagliptin on other drugs: In interaction studies conducted in healthy subjects, using either single dose or multiple once daily design, saxagliptin did not meaningfully alter the pharmacokinetics of metformin (a hOCT-1 and hOCT-2 substrate), glyburide (a CYP2C9 substrate), pioglitazone (a CYP2C8 substrate), digoxin (a P-gp substrate), simvastatin (a CYP3A4/5 substrate), diltiazem (a moderate inhibitor of CYP3A4/5), or ketoconazole (a potent inhibitor of CYP3A4/5 and P-gp). Therefore, saxagliptin is not a clinical meaningful inhibitor of hOCT-1, hOCT-2, P-gp transporter pathway, and CYP2C8, CYP2C9, CYP3A4/5 mediated metabolic pathway.
Oral Contraceptives: Coadministration of multiple once-daily doses of saxagliptin (5 mg) and Ortho-Cyclen (0.035 mg ethinyl estradiol/0.250 mg norgestimate), a combined oral contraceptive for 21 days, did not alter the steady state pharmacokinetics of the primary active estrogen component, ethinyl estradiol, or the primary active progestin component, norelgestromin. When saxagliptin was coadministered with Ortho-Cyclen, the plasma AUC of norgestrel, an active metabolite of norelgestromin, was increased by 13% and the plasma Cmax of norgestrel was increased by 17%. This small magnitude change in AUC and Cmax of norgestrel is not considered to be clinically meaningful. Based on these findings, saxagliptin would not be expected to meaningfully alter the pharmacokinetics of an estrogen/progestin combined oral contraceptive.
Dapagliflozin: The metabolism of dapagliflozin is primarily mediated by uridine 5' -diphospho-glucuronosyltransferase [UGT]1A9-dependent glucuronide conjugation. The major metabolite, dapagliflozin 3-O-glucuronide, is not an SGLT2 inhibitor.
In in vitro studies, dapagliflozin and dapagliflozin 3-O-glucuronide neither inhibited CYP1A2, 2C9, 2C19, 2D6, 3A4, nor induced CYP1A2, 2B6, or 3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered drugs that are metabolised by these enzymes, and drugs that inhibit or induce these enzymes are not expected to alter the metabolic clearance of dapagliflozin. Dapagliflozin is a weak substrate of the P-glycoprotein (P-gp) active transporter and dapagliflozin 3-O-glucuronide is a substrate for the OAT3 active transporter. Dapagliflozin or dapagliflozin 3-O-glucuronide did not meaningfully inhibit P-gp, OCT2, OAT1, or OAT3 active transporters. Overall, dapagliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-gp, OCT2, OAT1, or OAT3 substrates.
Effect of other drugs on dapagliflozin: In interaction studies conducted in healthy subjects, using mainly single dose design, the pharmacokinetics of dapagliflozin were not meaningfully altered by metformin (an hOCT-1 and hOCT-2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (an hOAT-3 substrate, and P-gp substrate), glimepiride (a CYP2C9 substrate), voglibose (an α-glucosidase inhibitor), hydrochlorothiazide, bumetanide, valsartan, or simvastatin (a CYP3A4 substrate). Therefore, meaningful interaction of dapagliflozin with other substrates of hOCT-1, hOCT-2, hOAT-3, P-gp, CYP2C8, CYP2C9, CYP3A4, and other α-glucosidase inhibitor would not be expected.
Coadministration of dapagliflozin and bumetanide did not meaningfully alter the pharmacodynamic effect of dapagliflozin to increase urinary glucose excretion in healthy subjects.
Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolizing enzymes) or mefenamic acid (an inhibitor of UGT1A9), a 22% decrease and a 51% increase, respectively, in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion in either case. No dose adjustment of dapagliflozin is recommended when dapagliflozin is coadministered with rifampicin or with mefenamic acid.
Effect of dapagliflozin on other drugs: Concomitant use of dapagliflozin and lithium may lead to a reduction in serum lithium concentrations due to a possible increased urinary clearance of lithium. The dose of lithium may need to be adjusted.
In interaction studies conducted in healthy subjects, using mainly a single dose design, dapagliflozin did not meaningfully alter the pharmacokinetics of metformin (an hOCT-1 and hOCT-2 substrate), pioglitazone (a CYP2C8 [major] and CYP3A4 [minor] substrate), sitagliptin (an hOAT-3 substrate, and P-gp substrate), glimepiride (a CYP2C9 substrate), hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate), or warfarin (S-warfarin is a CYP2C substrate). Therefore, dapagliflozin is not a clinical meaningful inhibitor of hOCT-1, hOCT-2, hOAT-3, P-gp transporter pathway, and CYP2C8, CYP2C9, CYP2C19 and CYP3A4 mediated metabolism.
Coadministration of a single dose of dapagliflozin (20 mg) and simvastatin (40 mg) (a CYP3A4 substrate), did not affect the Cmax of simvastatin but increased the AUC by 20%, which was not considered to be clinically relevant.
Coadministration of dapagliflozin and bumetanide did not meaningfully alter the steady-state pharmacodynamic responses (urinary sodium excretion, urine volume) to bumetanide in healthy subjects.
Dapagliflozin did not affect the anticoagulant activity of warfarin (a CYP2C19 substrate) as measured by the prothrombin time (International Normalized Ratio [INR]).
Other interactions: The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of saxagliptin and dapagliflozin have not been specifically studied.
Interference with 1,5-anhydroglucitol (1,5-AG) Assay: Monitoring glycaemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycaemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycaemic control.
