Pharmacokinetic Drug-Drug Interaction Assessment of LCZ696 (an Angiotensin Receptor Neprilysin Inhibitor) With Omeprazole, Metformin or Levonorgestrel-Ethinyl Estradiol in Healthy Subjects

LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 mu g single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUC(inf) of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the C-max of sacubitril, and 11% and 13% decreases in AUC(inf) and C-max of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUC(tau,ss) and C-max, ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUC(inf) of levonorgestrel. The C-max of levonorgestrel decreased by 15%, and AUC(tau,ss) and C-max,C-ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions.