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, a neprilysin inhibitor) and valsartan (angiotensin receptor inhibitor). Digoxin, a narrow therapeutic index drug, is a commonly administered medication to heart failure patients. Since LCZ696 and digoxin may be co-administered in this patient population, this study was conducted to evaluate the pharmacokinetic drug-drug interaction potential between LCZ696 and digoxin.
Methods: This study employed an open label, two-period, single sequence study design in 24 healthy subjects. In period 1, subjects received 200 mg LCZ696 b.i.d for 3 days and a single dose of 200 mg LCZ696 on Day 4 morning. Following a 4-7 day washout, in period 2, all subjects received 0.25 mg digoxin q.d. for 14 days and 200 mg LCZ696 b.i.d co-administered from Day 11 to Day 14. Serial PK samples were collected in both treatment periods and analyzed using validated LC/MS/MS bioanalytical methods. The PK parameters including Cmaxss and AUCtau of LCZ696 analytes (LBQ657, valsartan) and digoxin were determined using non-compartmental analysis and the results were statistically evaluated.
Results: The 90% confidence intervals of the geometric mean ratios (test/reference) for Cmaxss and AUCtau of digoxin were within the 0.8-1.25 range indicating that LCZ696 did not affect the PK of digoxin. Similarly, the 90% confidence intervals of the geometric mean ratios for Cmaxss and AUCtau for both LBQ657 and valsartan were within the 0.8-1.25 range indicating that digoxin did not affect the PK of LCZ696 analytes.
Conclusion: After co-administration of LCZ696 200 mg b.i.d with digoxin 0.25 mg q.d., exposures of digoxin and the LCZ696 analytes (LBQ657 and valsartan) remained unchanged. LCZ696 200 mg b.i.d was safe and well tolerated in healthy subjects when administered alone and in combination with digoxin 0.25 mg qd.