Zemidapa Drug Interactions

Gemigliptin: In vitro assessment of interactions: The responsible enzyme for the metabolism of gemigliptin is CYP3A4. In vitro studies indicated that gemigliptin and its active metabolite are not inhibitors of CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 or 3A4 and are not inducers of CYP1A2, 2C8, 2C9, 2C19, or 3A4. Therefore, gemigliptin is unlikely to cause interactions with other drugs that utilize these metabolic pathways. In vitro studies further indicated that gemigliptin did not induce P-glycoprotein (P-gp) while mildly inhibited P-gp mediated transport at high concentration. Therefore, gemigliptin is unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.
In vivo assessment of interactions: Effects of gemigliptin on other medicinal products: In clinical studies, gemigliptin did not meaningfully alter the pharmacokinetics of metformin, pioglitazone, glimepiride, rosuvastatin, dapagliflozin, or empagliflozin providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP2C8, CYP2C9, CYP3A4, organic cation transporter (OCT), and UDP-glucuronosyltransferase (UGT).
Metformin: Repeated co-administration of 50 mg gemigliptin with 2,000 mg metformin, a substrate of OCT1 and OCT2, decreased the C_max of metformin by 13% but did not affect the AUC of metformin at steady state.
Pioglitazone: Repeated co-administration of 200 mg gemigliptin with 30 mg pioglitazone, a substrate of CYP2C8 and 3A4, decreased the AUC and C_max of pioglitazone by 15% and 17%, respectively. However, those of the active metabolites of pioglitazone were not changed at steady state.
Glimepiride: Co-administration of multiple doses of 50 mg gemigliptin with a single dose of 4 mg glimepiride, a substrate of CYP2C9, did not meaningfully alter the pharmacokinetics of glimepiride at steady state.
Rosuvastatin: Repeated co-administration of 50 mg gemigliptin with 20 mg rosuvastatin, a substrate of CYP2C9 and 3A4, did not meaningfully alter the pharmacokinetics of rosuvastatin at steady state.
Dapagliflozin: Repeated co-administration of 50 mg gemigliptin with 10 mg of dapagliflozin, substrate of UGT1A9, did not meaningfully alter the pharmacokinetics of dapagliflozin at steady state.
Empagliflozin: Repeated co-administration of 50 mg gemigliptin with 25 mg of empagliflozin, substrate of UGT2B7, UGT1A3, UGT1A8, and UGT1A9, did not meaningfully alter the pharmacokinetics of empagliflozin at steady state.
Effects of other medical products on gemigliptin: In clinical studies, metformin, pioglitazone, rosuvastatin, dapagliflozin, and empagliflozin did not meaningfully alter the pharmacokinetics of gemigliptin. Ketoconazole did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite. Therefore, strong and moderate CYP3A4 inhibitors would not cause clinically meaningful drug interactions. Rifampicin (rifampin), on the other hand, significantly decreased exposure of gemigliptin. Therefore, co-administration with other strong CYP3A4 inducers, including rifampicin (rifampin), dexamethasone, phenytoin, carbamazepine, rifabutin and phenobarbital, is not recommended.
Metformin: Repeated co-administration of 50 mg gemigliptin with 2,000 mg metformin did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite at steady state.
Pioglitazone: Repeated co-administration of 200 mg gemigliptin with 30 mg of pioglitazone did not meaningfully alter the pharmacokinetics of gemigliptin and its active metabolite at steady state.
Ketoconazole: Co-administration of multiple doses of 400 mg ketoconazole once daily, a strong inhibitor of CYP3A4, with a single dose of 50 mg gemigliptin increased the AUC of active moiety, the sum of gemigliptin and its active metabolite, by 1.9-fold at steady state.
Rifampicin: Co-administration of multiple doses of 600 mg rifampicin once daily, a strong inducer of CYP3A4, with a single dose of 50 mg gemigliptin, decreased the AUC and C_max of gemigliptin by 80% and 59%, respectively. The C_max of active metabolite of gemigliptin was not significantly affected while the AUC was decreased by 36% at steady state.
Rosuvastatin: Repeated co-administration of 50 mg gemigliptin with 20 mg rosuvastatin did not meaningfully alter the pharmacokinetics of gemigliptin at steady state.
Dapagliflozin: Repeated co-administration of 50 mg gemigliptin with 10 mg of dapagliflozin did not meaningfully alter the pharmacokinetics of gemigliptin at steady state.
Empagliflozin: Repeated co-administration of 50 mg gemigliptin with 25 mg of empagliflozin did not meaningfully alter the pharmacokinetics of gemigliptin at steady state.
Dapagliflozin: Pharmacodynamics interactions: Diuretics: Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension.
Insulin and insulin secretagogues: Insulin and insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with dapagliflozin in patients with type 2 diabetes mellitus.
Pharmacokinetic interactions: The metabolism of dapagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyltransferase 1A9 (UGT1A9).
In in vitro studies, dapagliflozin neither inhibited cytochrome P450 (CYP) 1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, nor induced CYP1A2, CYP2B6 or CYP3A4. Therefore, dapagliflozin is not expected to alter the metabolic clearance of coadministered medicinal products that are metabolized by these enzymes.
Effect of other medicinal products on dapagliflozin: Interaction studies conducted in healthy subjects, using mainly a single-dose design, suggest that the pharmacokinetics of dapagliflozin are not altered by metformin, pioglitazone, sitagliptin, glimepiride, voglibose, hydrochlorothiazide, bumetanide, valsartan, or simvastatin.
Following coadministration of dapagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes) a 22% decrease in dapagliflozin systemic exposure (AUC) was observed, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended. A clinically relevant effect with other inducers (e.g. carbamazepine, phenytoin, phenobarbital) is not expected.
Following coadministration of dapagliflozin with mefenamic acid (an inhibitor of UGT1A9), a 55% increase in dapagliflozin systemic exposure was seen, but with no clinically meaningful effect on 24-hour urinary glucose excretion. No dose adjustment is recommended.
Effect of dapagliflozin on other medicinal products: In interaction studies conducted in healthy subjects, using mainly a single-dose design, dapagliflozin did not alter the pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, digoxin (a P-gp substrate) or warfarin (S-warfarin, a CYP2C9 substrate), or the anticoagulatory effects of warfarin as measured by INR. Combination of a single dose of dapagliflozin 20 mg and simvastatin (a CYP3A4 substrate) resulted in a 19% increase in AUC of simvastatin and 31% increase in AUC of simvastatin acid. The increase in simvastatin and simvastatin acid exposures are not considered clinically relevant.
Interference with 1,5-anhydroglucitol (1,5-AG) assay: Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use of alternative methods to monitor glycemic control is advised.