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 (an inactive prodrug converted to LBQ657, neprilysin inhibitor) and valsartan (angiotensin receptor inhibitor). Warfarin, a CYP2C9 substrate and narrow therapeutic index drug , is administered to patients with cardiovascular diseases including heart failure . Since LCZ696 is a known weak inhibitor of CYP2C9, the objective of this study was to determine whether LCZ696 affects the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin. Also, the warfarin effect on the PK of LCZ696 was evaluated.
Methods: This study employed an open label, single blind, two-period, crossover design in 26 healthy subjects. In each period, subjects received either 200 mg LCZ696 or matching placebo b.i.d for 10 days with a single dose of 25 mg warfarin co-administered on Day 5. Serial PK samples were collected on Day 4 and Day 5 and analyzed using validated LCMS/MS methods. Prothrombin time (PTT) and INR values were measured for up to 144 hours post warfarin dose. The PK parameters including Cmax and AUCs of LCZ696 analytes (LBQ657 and valsartan) and warfarin (R-warfarin and S-warfarin) and PD parameters of warfarin (peak PTT, peak INR, AUC-PTT, and AUC-INR) were determined using noncompartmental methods and results were statistically evaluated.
Results: The 90% confidence intervals (CI) of geometric mean ratios of Cmax and AUCs (test/reference) for R-warfarin, S-warfarin, LBQ657, and valsartan were within the 80 - 125% suggesting lack of PK interaction between LCZ696 and warfarin. Further, the 90% CI of geometric mean ratios of average (AUC effect/144) and peak PD effects (PTT and INR) were also within the 80 - 125% range indicating no impact of LCZ696 on warfarin PD.
Conclusion: Co-administration of 200 mg LCZ696 b.i.d with single dose of 25 mg warfarin did not alter the PK exposures of LCZ696 analytes (LBQ657 and valsartan) and warfarin. Also, LCZ696 did not affect the PD effects of warfarin. LCZ696 200 mg b.i.d was safe and well tolerated when administered alone or with single dose of 25 mg warfarin.