Abstract 456: Assessment of Pharmacokinetic Drug Interaction between LCZ696 and Metformin

Abstract

Objective: LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) being developed for the treatment of cardiovascular diseases, including hypertension and heart failure. Ingestion of LCZ696 results in systemic exposure to AHU377 (inactive prodrug that is converted to LBQ657, a neprilysin inhibitor) and valsartan (angiotensin receptor blocker). Metformin is the most commonly prescribed oral treatment for type 2 diabetes mellitus (T2DM), a condition prevalent in patients with cardiovascular diseases. Since LCZ696 and metformin may be co-administered, the potential for a pharmacokinetic (PK) interaction was assessed between these drugs. Methods: The study was conducted in 27 healthy subjects of Japanese descent using an open-label, three-period, single-sequence design. In Period 1, subjects received metformin 1000 mg once daily (q.d.) for 4 days. Following a metformin washout of 4-10 days, subjects received LCZ696 400 mg q.d. for 5 days in Period 2. In Period 3, LCZ696 400 mg q.d. and metformin 1000 mg q.d. were co-administered for 4 days. Serial PK samples were taken during all treatment periods and analyzed using validated LC/MS/MS bioanalytical techniques. The PK parameters (Cmax,ss, AUCtau,ss) of active LCZ696 analytes (LBQ657 and valsartan) and metformin were determined using non-compartmental analysis, and the results were evaluated by statistical analysis. Results: The 90% confidence intervals for the geometric mean ratios for Cmax,ss and AUCtau,ss of LCZ696 analytes (LBQ657 and valsartan) were within the 0.8-1.25 range indicating that metformin did not affect the PK of the LCZ696 analytes. The lower bound of the 90% confidence intervals for the geometric mean ratios for metformin exposures were below the 0.8-1.25 range (Cmax,ss: 0.77, 0.70-0.84; AUCtau,ss: 0.77, 0.71-0.82), indicating a decrease in Cmax,ss and AUCtau,ss of metformin by 23%. Conclusion: After co-administration of LCZ696 400 mg q.d. and metformin 1000 mg q.d., the exposures of LBQ657 and valsartan remained unchanged whereas the exposure to metformin decreased by 23%. LCZ696 400 mg q.d. was safe and well tolerated in healthy subjects when administered alone and in combination with metformin 1000 mg q.d..