Abstract 457: Assessment of Pharmacokinetic Drug-drug Interaction between LCZ696 and Carvedilol

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Objective: LCZ696 is a first-in-class angiotensin receptor neprlysin inhibitor (ARNI) being developed for the treatment of hypertension and heart failure. Ingestion of LCZ696 results in systemic exposure to AHU377 (inactive prodrug of LBQ657, a neprilysin inhibitor) and valsartan (angiotensin receptor blocker). Carvedilol is a third-generation, non-selective beta-blocker with vasodilating properties and one of three beta-blockers with efficacy in reducing the risk of death in patients with heart failure. Since LCZ696 may be co-administered with carvedilol for optimal blood pressure control, this study was conducted to evaluate the pharmacokinetic (PK) drug-drug interaction potential between LCZ696 and carvedilol.

Methods: An open-label, three-period, single sequence study in 28 healthy subjects was conducted. In Period 1, subjects received oral LCZ696 400 mg qd x 5 days and were discharged for a 4-10 day washout. In Period 2, subjects received oral carvedilol 12.5 mg bid x first 2 days, then 25 mg bid x 4 days, and in Period 3, LCZ696 400 mg qd + carvedilol 25 mg bid x 5 days. Serial PK samples were collected and analyzed by a validated LC-MS/MS method. PK parameters (AUCtau,ss, Cmax,ss) of LCZ696 analytes(LBQ657, valsartan) and carvedilol (R(+)-and S(-)-carvedilol) in plasma were determined using non-compartmental analysis, and results were statistically evaluated.

Results: The 90% CIs of the geometric mean ratio for AUCtau,ss and Cmax,ss of LBQ657, and AUCtau,ss of valsartan fell within the range of (0.80-1.25); the lower bound for Cmax,ss of valsartan (0.88, 0.78-0.98) was below the range, indicating PK of LBQ567 was not altered but Cmax,ss of valsartan decreased by 12% when co-administered with carvedilol. Those for AUCtau,ss and Cmax,ss of both R(+)-and S(-)carvedilol fell within the range (0.80-1.25), indicating no change in PK of Carvedilol in combination with LCZ696.

Conclusion: When LCZ696 400 mg qd and carvedilol 25 mg bid were co-dministered, PK of carvedilol (R(+)-and S(-)-carvedilol) was unchanged. PK of LBQ657 or AUCtau,ss of valsartan was unchanged, while Cmax,ss decreased by 12%. LCZ696 400 mg qd was safe and well tolerated in healthy subjects when administered alone and in combination with carvedilol 25 mg bid.

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