ABSTRACT
PURPOSE: Apixaban is often coadministered with treatments for cardiovascular comorbidities, which may lead to unintended drug-drug interactions (DDIs). The effects of apixaban on pharmacokinetics (PK) of multidose Lanoxin® (digoxin) and single-dose Tenormin® (atenolol) and the effects of single-dose atenolol on apixaban PK in healthy subjects were investigated in two Phase 1 studies. PATIENTS AND METHODS: The digoxin DDI study was an open-label, multidose, two-treatment, single-sequence study in which subjects received digoxin 0.25 mg q6h on day 1, then once daily on days 2-10, followed by apixaban 20 mg and digoxin 0.25 mg once daily on days 11-20. The atenolol DDI study was an open-label, single-dose, randomized, three-period, three-treatment, crossover study in which subjects received a single oral dose of apixaban 10 mg, atenolol 100 mg, or apixaban 10 mg plus atenolol 100 mg. The 90% confidence intervals (CIs) for the ratios of geometric means of peak plasma concentration (Cmax) and area under the concentration-time curve (AUCtau), with and without apixaban were calculated. Absence of effect was concluded if the point estimates and 90% CI were within the equivalence interval of 80%-125% (digoxin) or 70%-143% (atenolol). A similar analysis was performed to assess the effect of atenolol on apixaban. RESULTS: Apixaban had no clinically relevant effect on the PK of either atenolol or digoxin: point estimates and 90% CI for both digoxin and atenolol Cmax and AUC were entirely within their respective no-effect intervals. Apixaban Cmax and AUCinf were slightly decreased (ie, 18% and 15% lower, respectively) following atenolol coadministration. No serious or major bleeding-related adverse events were reported during either study. CONCLUSION: Apixaban had no effect on the PK of digoxin and there was no clinically relevant interaction between apixaban and atenolol. Coadministration of digoxin or atenolol with apixaban in healthy subjects was generally well tolerated.
ABSTRACT
PURPOSE: In patients with type 2 diabetes mellitus, fixed-dose combinations (FDCs) of antihyperglycemic medications may provide complementary efficacy while reducing tablet burden and improving compliance. The aim of this study was to assess the bioequivalence and tolerability of 2 FDCs of dapagliflozin and metformin extended-release (XR) versus their individual component (IC) tablets. METHODS: An open-label, balanced, randomized, 2-way crossover, 4-arm study was conducted in 129 healthy Brazilian subjects (aged 18-55 years). Two oral doses of the FDCs (5 mg dapagliflozin and 500 mg metformin XR, and 10 mg dapagliflozin and 1000 mg metformin XR) were evaluated in fed and fasted states. FINDINGS: Under fed and fasted conditions the 5 mg dapagliflozin and 500 mg metformin XR FDC showed bioequivalence to its ICs. The 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent to its ICs in fed subjects. Although AUC for the 10 mg dapagliflozin and 1000 mg metformin XR FDC was bioequivalent in fasted subjects, the Cmax for metformin was not bioequivalent to its ICs in fasted subjects (upper 90% CI was 127.5%, and thus outside the 80%-125% bioequivalence interval). The small increase in the fasted state is not considered clinically meaningful due to the small magnitude of the difference (9.2%), the lack of metformin Cmax being associated with efficacy or tolerability concerns, and the fasted state not being the recommended state for dosing of metformin XR. The safety profile and tolerability of the FDCs were similar to those of their ICs and no deaths or serious adverse events were reported. IMPLICATIONS: Both FDCs of dapagliflozin and metformin XR were bioequivalent to their ICs in fed and fasted subjects, except for the metformin Cmax from the 10 mg dapagliflozin and 1000 mg metformin XR FDC in fasted subjects. These data support the use of a dapagliflozin and metformin XR FDC in patients with type 2 diabetes mellitus.
