Pharmacokinetic drug–drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel‐ethinyl estradiol in healthy subjects

Abstract

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 μg 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 AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,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 AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,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.

Evaluation of Pharmacokinetic and Pharmacodynamic Drug–Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild‐to‐Moderate Hypertension

“…Steady‐state levels of sacubitril/valsartan are achieved in 3 days with twice daily administration of sacubitril/valsartan 200 mg or 400 mg q.d. in healthy individuals 13, 35…”

Erratum to: Clinical Pharmacokinetics of Sacubitril/Valsartan (LCZ696): A Novel Angiotensin Receptor–Neprilysin Inhibitor

“…and data of sacubitril/valsartan 400 mg data were pooled from seven studies [21,24,30,49,94,100,101]. Steady-state representative pharmacokinetics: data of sacubitril/valsartan 400 mg QD in healthy subjects was reported by Gan et al [49]; data of sacubitril/valsartan 200 mg in healthy subjects data were pooled from five studies [25,29] (data on file for two studies including DDI study with furosemide and nitroglycerine, EudraCT no.…”

“…Steady-state representative pharmacokinetics: data of sacubitril/valsartan 400 mg QD in healthy subjects was reported by Gan et al [49]; data of sacubitril/valsartan 200 mg in healthy subjects data were pooled from five studies [25,29] (data on file for two studies including DDI study with furosemide and nitroglycerine, EudraCT no. 2013-001783-36; refer to Table 1); data of sacubitril/valsartan 200 mg BID in patients with HF data were pooled from two studies [38] (data on file for 1 study; CLCZ696B2223, clinical trial registry number: NCT01353508; refer to Table 1 …”

“…A total of 13 clinical pharmacology studies were conducted to evaluate the pharmacokinetic and/or pharmacodynamic drug-drug interaction potential with medicines that may be co-administered with sacubitril/valsartan in patients with HFrEF [25,29,[47][48][49]. The mechanistic pharmacokinetic drug interaction potential of sacubitril/valsartan was evaluated with CYP3A4, CYP2C9, CYP2C19, CYP2D6, and other CYP enzyme substrates (carvedilol, omeprazole, warfarin, and amlodipine); P-gp (digoxin); OATP1B1/OATP1B3 (atorvastatin and simvastatin); and OAT3 (furosemide).…”

“…Therefore, a potential for increased bioavailability of sacubitril/valsartan exists when co-administered with omeprazole. Following administration of omeprazole (40 mg QD) for 5 days in healthy subjects and co-administration of single-dose sacubitril/valsartan 400 mg on day 5, the T max of all three sacubitril/valsartan analytes remained unchanged [49]. The AUC remained unchanged [as 90% confidence interval (CI) were within 0.8-0.12], while the marginal decrease in C max of sacubitril was decreased by 7% and is considered not to be clinical relevant [49].…”