Qtern Drug Interactions

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 either separately or as the QTERN fixed-dose combination.
See saxagliptin and dapagliflozin subsections for drug interactions. In summary, there are no clinically meaningful drug interactions expected for either saxagliptin or dapagliflozin or the QTERN fixed-dose combination.
Saxagliptin: The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5) which converts it to an active metabolite. Therefore, drugs which inhibit the activity of this enzyme system may increase plasma concentrations of saxagliptin but reduce those of its metabolite, whereas CYP3A inducers will tend to do the opposite. However, the overall biological effect of saxagliptin is unaffected by coadministration with inhibitors or inducers of 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 3A4, nor inhibited UGT1A9. 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.
In studies conducted in healthy subjects, the pharmacokinetics of saxagliptin, its major metabolite, were altered by some drugs which affect the CYP3A4/5 system. However, total exposure to the total active components of saxagliptin (parent+metabolite), were not meaningfully altered by metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem, ketoconazole, rifampicin, omeprazole, aluminum hydroxide+magnesium hydroxide+simethicone combination, or famotidine. Saxagliptin also did not meaningfully alter the pharmacokinetics of metformin, glibenclamide, pioglitazone, digoxin, simvastatin, diltiazem, ketoconazole or an estrogen/progestin combined oral contraceptive.
Other interactions: The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of saxagliptin have not been specifically studied.
The safety and efficacy of saxagliptin in combination with alpha-glucosidase inhibitors or orlistat has not been established.
Dapagliflozin: The metabolism of dapagliflozin is primarily mediated by UGT1A9-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, 2A6, 2B6, 2C8, 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.
In interaction studies conducted in healthy subjects, using mainly single dose design, the pharmacokinetics of dapagliflozin were not 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-glycoprotein substrate), glimepiride (a CYP2C9 substrate), voglibose (an α-glucosidase inhibitor), hydrochlorothiazide, bumetanide, valsartan, or simvastatin.
Dapagliflozin also did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, simvastatin, 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.
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.
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 either rifampicin or mefenamic acid.
Other interactions: The effects of smoking, diet, herbal products, and alcohol use on the pharmacokinetics of dapagliflozin have not been specifically studied.