Effect of Mild or Moderate Hepatic Impairment on the Pharmacokinetics of Avacopan, a Small-Molecule Complement C5a Receptor Antagonist, for the Treatment of Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Avacopan is currently approved in several regions of the world as an oral treatment in combination with standard therapy, including glucocorticoids, for adult patients with severe active antineutrophil cytoplasmic autoantibody-associated vasculitis. In vitro and clinical studies have established that avacopan is primarily eliminated through cytochrome P450 3A4 metabolism. This Phase 1, open-label, single-dose study (ClinicalTrials.gov identifier: NCT06004934) was conducted to evaluate the effect of mild (n = 8) or moderate (n = 8) hepatic impairment compared with normal hepatic function (n = 8) on the pharmacokinetics, safety, and tolerability of a single oral dose of 30 mg of avacopan in patients without active antineutrophil cytoplasmic autoantibody-associated vasculitis. Relative to participants with normal hepatic function, in participants with mild or moderate hepatic impairment, the avacopan area under the plasma concentration-time curve from time 0 to infinity geometric mean ratios (90% confidence intervals) were 1.3 (0.9-2.0) and 1.1 (0.6-2.0), respectively, and the avacopan maximum plasma concentration geometric mean ratios (90% CIs) were 1.0 (0.8-1.3) and 0.8 (0.6-1.1), respectively. The geometric mean ratios of metabolite M1 also revealed no pharmacokinetically relevant increase in the peak exposure of M1 in participants with mild or moderate hepatic impairment. Thus, no avacopan dosage adjustment is necessary for patients with mild or moderate hepatic impairment.

Food Effect and Pharmacokinetic Bridging of Avacopan in Caucasian and Japanese Healthy Participants.

Avacopan 30 mg twice daily (BID) is approved for the treatment of severe active antineutrophil cytoplasmic autoantibody-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis). Food effect on avacopan pharmacokinetics (PKs) and PK bridging in Japanese participants were examined through 2 phase 1 studies involving healthy adult participants. In Study 1, an open-label, crossover trial, participants received oral administration of a single 30-mg dose of avacopan under fasted and fed conditions. Study 2 was a randomized, single-blind, placebo-controlled trial in Caucasian and Japanese participants: Part A investigated single doses of 10 and 30 mg of avacopan under fasted and fed conditions and Part B investigated 30 and 50 mg BID avacopan. The PKs of single-dose administrations of 10 and 30 mg in Japanese participants was compared with that in Caucasian participants under fasted conditions. Food substantially increased plasma avacopan area under the plasma concentration-time curve from time 0 to time infinity (AUC0-inf) by 1.72-fold, supporting the recommendation of taking avacopan with food. Maximum plasma concentration (Cmax) remained relatively unchanged. The median time to reach Cmax (tmax) was delayed by 3 hours. No significant food effect was observed on the active metabolite CCX168-M1 (M1) AUC. Avacopan and M1 exposures were <1.5-fold higher in Japanese participants than in Caucasian participants following multiple-dose administration of avacopan.

Pharmacokinetic Evaluation of the CYP3A4 and CYP2C9 Drug-Drug Interaction of Avacopan in 2 Open-Label Studies in Healthy Participants.

Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60 mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite ß-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).

A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients.

PURPOSE: AMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF). METHODS: Healthy adults (Parts A/B) and HF patients (Part C) aged 18-85 years were randomized 3:1 to single-dose oral/IV AMG 986 or placebo (Part A); multiple-dose oral/IV AMG 986 or placebo (Part B); or escalating-dose oral AMG 986 or placebo (Part C). PRIMARY ENDPOINT: treatment-emergent adverse events, laboratory values/vital signs/ECGs; others included AMG 986 pharmacokinetics, left ventricular (LV) function. RESULTS: Overall, 182 subjects were randomized (AMG 986/healthy: n = 116, placebo, n = 38; AMG 986/HF: n = 20, placebo, n = 8). AMG 986 had acceptable safety profile; no clinically significant dose-related impact on safety parameters up to 650 mg/day was observed. AMG 986 exposures increased nonlinearly with increasing doses; minimal accumulation was observed. In HF with reduced ejection fraction patients, there were numerical increases in percent changes from baseline in LV ejection fraction and stroke volume by volumetric assessment with AMG 986 vs placebo (stroke volume increase not recapitulated by Doppler). CONCLUSIONS: In healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03276728. DATE OF REGISTRATION: September 8, 2017.

Evaluation of the Pharmacokinetics and Safety of AMG 986 Tablet and Capsule Formulations in Healthy Adult Subjects: A Phase I, Open-Label, Randomized Study.

BACKGROUND AND OBJECTIVE: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure. The current phase I study was conducted to evaluate the pharmacokinetics and safety of a single-dose 200-mg capsule formulation of AMG 986 relative to the tablet formulation in 12 healthy subjects. METHODS: In a two-period, two-way crossover design, eligible subjects were randomized 1:1 to tablet/capsule or capsule/tablet treatment sequences; each treatment sequence lasted for approximately 6 days and comprised six subjects. RESULTS: Following a single oral dose of AMG 986, the geometric mean maximum observed concentration (Cmax) values were 9670 ng/mL and 6920 ng/mL and the geometric mean area under the curve from time zero to 120 h (AUC0-120h) values were 68,000 ng*h/mL and 59,900 ng*h/mL for the tablet and capsule, respectively. The geometric least squares means (90% confidence interval [90% CI]) for the ratios of capsule/tablet were 0.88 (90% CI 0.81-0.96) and 0.72 (90% CI 0.57-0.91) for AUC0-120h and Cmax, respectively. AMG 986 had an acceptable safety profile; all adverse events were grade 1 or 2 in severity. CONCLUSION: There was a modest 12% decrease in AUC0-120h and a 28% decrease in Cmax with the AMG 986 capsule versus the tablet. These differences are not considered to be clinically relevant, suggesting the capsule formulation can be used in subsequent clinical studies of AMG 986.

A Phase 1, Open-Label Study to Evaluate the Effect of Food and Concomitant Itraconazole Administration on the Pharmacokinetics of AMG 986 in Healthy Subjects.

This phase 1, open-label study evaluated the effect of food and administration of the cytochrome P450 3A4 and P-glycoprotein inhibitor itraconazole (ITZ) on the pharmacokinetics of AMG 986. In cohort 1, 12 healthy subjects received a single oral dose of AMG 986 200 mg ± food on days 1 and 10. In cohort 2, 15 healthy subjects received oral ITZ 200 mg once daily on days 8 to 15 and a single oral dose of AMG 986 10 mg on days 1 and 11. The geometric least squares mean ratios of fed/fasted for AMG 986 maximum observed concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity (AUCinf ) were 0.76 (90%CI, 0.61-0.95) and 1.07 (90%CI, 0.94-1.22), respectively. The geometric least squares mean ratios of AMG 986 10 mg plus ITZ 200 mg/AMG 986 10 mg alone for AMG 986 Cmax and AUCinf were 1.36 (90%CI, 1.25-1.48) and 5.13 (90%CI, 4.71-5.59), respectively. Overall, 3 subjects experienced mild treatment-related adverse events; there were no serious or fatal adverse events. In conclusion, food had no apparent effect on the exposure of AMG 986 200 mg; therefore, food restrictions are not required. Potent cytochrome P450 3A4 and/or P-glycoprotein inhibitors may warrant AMG 986 dose reduction and should be coadministered with caution in patients with heart failure treated with AMG 986.

A Phase I, Open-label, Single-Dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of AMG 986 in Healthy Japanese Subjects.

BACKGROUND AND OBJECTIVE: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed as a treatment for patients with heart failure (HF). Previously, a first-in-human study of AMG 986 was conducted in healthy and HF subjects; however, AMG 986 was not evaluated in Japanese subjects. METHODS: This was a phase I, open-label, single-dose, single-center study conducted to evaluate the safety and pharmacokinetics (PK) of AMG 986 200 mg and 400 mg in 12 healthy Japanese subjects. Six subjects received AMG 986 200 mg and six subjects received AMG 986 400 mg. RESULTS: Following oral administration, median time to maximum observed plasma concentration (tmax) was 1.0 h for both the AMG 986 200 mg and 400 mg groups, and mean terminal half-life (t½) was 15.1 h and 17.6 h, respectively. When comparing the AMG 986 200 mg and 400 mg groups, 1.33-fold and 1.18-fold higher maximum observed plasma concentration (Cmax) and AUC∞, respectively, were observed for the 2-fold increase in dose. AMG 986 exhibited an acceptable safety and tolerability profile; all adverse events were mild in severity. CONCLUSION: AMG 986 exposure increased with increasing dose, and the increase was less than dose proportional in healthy Japanese subjects. The results of this study could facilitate the subsequent clinical development of AMG 986 for the treatment of Japanese patients with HF.

Population Pharmacokinetic Properties of Omecamtiv Mecarbil in Healthy Subjects and Patients With Heart Failure With Reduced Ejection Fraction.

ABSTRACT: Omecamtiv mecarbil is a small molecule that has been shown to improve cardiac function in patients with heart failure (HF) with reduced ejection fraction and is currently being developed as an oral modified release tablet for subjects with chronic HF. The objectives of this study were to analyze the pharmacokinetic (PK) properties of omecamtiv mecarbil and to investigate the effects of potential covariates on pertinent PK parameters using population PK modeling of data from 3 clinical trials in healthy subjects (n = 85) and 3 clinical trials in patients with HF (n = 4261). The population PK analysis was performed using a nonlinear mixed effects modeling approach. Omecamtiv mecarbil has a clearance of 11.7 L/h (0.701% relative standard error) and a central volume distribution of 275 L (2.12% relative standard error). The estimated half-life of omecamtiv mecarbil was 33 hours. Body weight and estimated glomerular filtration rate were significant covariates, but their effect on exposure was modest and lacked clinical relevance. Additional covariates, including sex, race, bilirubin, albumin, concomitant medications, New York Heart Association Functional Classification, N-terminal-pro hormone B-type natriuretic peptide, troponin I, creatine kinase MB, serum hemoglobin, tablet formulation, aspartate aminotransferase, and serum urea, were tested and found to have no impact on omecamtiv mecarbil exposures. The results of this integrated evaluation of the impact of covariates on the systemic exposure of omecamtiv mecarbil suggest that dose adjustment is not required for the studied subpopulations of patients with HF.

Effect of Severe Renal Impairment on the Safety, Tolerability, and Pharmacokinetics of AMG 986.

INTRODUCTION: AMG 986 is a first-in-class, novel apelin receptor small molecule agonist initially developed for the treatment of heart failure (HF). The safety and pharmacokinetics (PK) of AMG 986 in participants with renal impairment (RI) remains unknown. METHODS: This phase 1 study compared the safety and PK of AMG 986 200 mg in six participants with severe RI (estimated glomerular filtration rate [eGFR] 15-29 mL/min/1.73 m2) versus six participants with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). RESULTS: Following a single oral dose of AMG 986 200 mg on day 1, the maximum observed concentration increased 1.41-fold (90% confidence interval [CI] 0.88-2.27) and the area under the curve from time zero to infinity increased 1.23-fold (90% CI 0.73-2.06) in participants with severe RI versus normal renal function. AMG 986 had an acceptable safety profile; all adverse events were mild in severity. CONCLUSIONS: The results of this study support the enrollment of HF patients with RI to clinical trials of AMG 986 without the need for dose adjustments. TRIAL REGISTRATION NUMBER: NCT03318809 (registered: October 24, 2017).

Pharmacokinetic Drug-Drug Interaction Study of Omecamtiv Mecarbil With Omeprazole, a Proton Pump Inhibitor, in Healthy Subjects.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure (HF) with reduced ejection fraction. OM is administered as a 25-, 37.5-, or 50-mg modified-release formulation in patients with HF. Proton pump inhibitors are one of the most commonly prescribed drugs in this patient population. Given the potential for coadministration of both drugs in patients with HF, we evaluated the potential for omeprazole to affect the pharmacokinetics of OM in an open-label study in 14 healthy subjects. Subjects received a single 50-mg dose of OM on day 1, followed by 40-mg once-daily doses of omeprazole on days 4 to 8. On day 9, a single 40-mg dose of omeprazole was administered first and immediately followed by 50-mg of OM. Blood samples were collected up to 144 hours after dosing following administration of OM on days 1 and 9 to characterize plasma concentrations of OM. The ratios of the geometric least-square means (90% confidence intervals) of OM coadministered with omeprazole compared to OM alone were 94.5% (81.7%-109.3%), 94.3% (81.5%-109.1%), and 101.2% (95.4%-107.3%) for area under the plasma concentration-time curve from time 0 to infinity, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and maximum observed plasma concentration, respectively. Coadministration of OM with omeprazole was not associated with any clinically significant pharmacokinetic drug interactions. Single doses of OM were safe and well tolerated when coadministered with omeprazole.

Pharmacokinetic Drug-Drug Interaction Study of Omecamtiv Mecarbil With Amiodarone and Digoxin in Healthy Subjects.

Omecamtiv mecarbil (OM), a novel cardiac myosin activator, is being evaluated for the treatment of heart failure with reduced ejection fraction. In vitro studies demonstrate OM as a substrate and inhibitor of P-glycoprotein (P-gp), which can result in drug-drug interactions. Two phase 1, open-label studies assessed the effect of coadministration of OM (50-mg single dose) on the pharmacokinetics of digoxin (0.5-mg single dose; N = 15), a P-gp substrate, and the effect of coadministration of amiodarone (600-mg single dose), a P-gp inhibitor, on the pharmacokinetics of OM (50-mg single dose; N = 14) in healthy subjects. The ratios of the geometric least squares mean (90% confidence interval [CI]) of digoxin coadministered with OM vs digoxin alone for area under the plasma concentration-time curve (AUC) from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.06 (90%CI, 0.99-1.14), 1.06 (90%CI, 0.98-1.14), and 1.08 (90%CI, 0.92-1.26), respectively. The ratios of the geometric least squares mean of OM coadministered with amiodarone vs OM alone for AUC from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.21 (90%CI, 1.08-1.36), 1.21 (90%CI, 1.07-1.36), and 1.08 (90%CI, 0.96-1.22), respectively. In conclusion, OM coadministered with digoxin or amiodarone did not result in any clinically relevant pharmacokinetic drug-drug interactions.

Pharmacokinetic Evaluation of the CYP3A4 and CYP2D6 Drug-Drug Interaction and CYP3A4 Induction Potential of Omecamtiv Mecarbil: Two Open-Label Studies in Healthy Subjects.

Omecamtiv mecarbil (OM) is a cardiac myosin activator under development for the treatment of heart failure. The effect of CYP3A4 and CYP2D6 inhibition on OM pharmacokinetics and the potential for OM to induce CYP3A4 was assessed in 2 studies. Study 1, part A, assessed the effect of ketoconazole 200 mg on the pharmacokinetics of OM 10 mg in CYP2D6 extensive metabolizers (EMs; n = 8) or poor metabolizers (PMs; n = 8). Study 1, part B, assessed the effect of diltiazem 240 mg on the pharmacokinetics of OM 10 mg (EM; n = 8). Study 2 assessed the effect of OM 25 mg on the pharmacokinetics of midazolam 5 mg (n = 14). Coadministration with ketoconazole led to 51% and 31% increases in OM AUCinf in EM and PM subjects, respectively, whereas OM Cmax remained similar (3% higher and 14% lower for EM and PM subjects, respectively). No changes in OM pharmacokinetics were observed in EM subjects following coadministration with diltiazem. Midazolam AUCinf and Cmax decreased by 18% and 10%, respectively, when coadministered with OM. In conclusion, CYP3A4 and CYP2D6 inhibitors are unlikely to have a clinically significant effect on the pharmacokinetics of OM. In addition, OM is unlikely to have a clinically relevant effect on the pharmacokinetics of CYP3A4 substrates.

Omecamtiv mecarbil does not prolong QTc intervals at therapeutic concentrations.

AIMS: Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure. This study aimed to evaluate the effect of therapeutic concentrations of OM on electrocardiogram (ECG) parameters and exclude a clinically concerning effect on the rate-corrected QT (QTc) interval. METHODS: In part A, 70 healthy subjects received a 25 mg oral dose of OM, and pharmacokinetics were assessed. Only subjects with maximum observed plasma concentration ≤ 350 ng/mL (n = 60) were randomized into part B, where they received a single oral dose of placebo, 50 mg OM and 400 mg moxifloxacin in a 3-period, 3-treatment, 6-sequence crossover study with continuous ECG collection. RESULTS: After a 50-mg dose of OM, mean placebo-corrected change from baseline QTcF (∆∆QTcF; Fridericia correction) ranged from -6.7 ms at 1 hour postdose to -0.8 ms at 4 hours postdose. The highest upper bound of the 1-sided 95% confidence interval (CI) was 0.7 ms (4 h postdose). Moxifloxacin resulted in a clear increase in mean ∆∆QTcF, with a peak value of 13.1 ms (90% CI: 11.71-14.57) at 3 hours; lower bound of the 1-sided 95% CI was > 5 ms at all of the 3 prespecified time points. Based on a concentration-QTc analysis, an effect on ∆∆QTcF exceeding 10 ms can be excluded up to OM plasma concentrations of ~800 ng/mL. There were no serious or treatment-emergent adverse events leading to discontinuation from the study. CONCLUSION: OM does not have a clinically relevant effect on the studied ECG parameters.

Pharmacokinetics, Tolerability, and Safety of Single and Multiple Omecamtiv Mecarbil Doses in Healthy Japanese and Caucasian Subjects.

BACKGROUND AND OBJECTIVES: Omecamtiv mecarbil (OM) is a cardiac myosin activator under development for the treatment of heart failure. The pharmacokinetics of single and multiple doses of OM were investigated in healthy Japanese subjects in two clinical studies. METHODS: Study 1 (n = 36) evaluated the bioavailability and pharmacokinetics after intravenous infusion (15 mg/h for 4 h) and an oral modified release (MR) tablet in healthy Japanese and Caucasian subjects using 25 mg single and multiple doses and 50 mg single dose. Study 2 (n = 50) evaluated the pharmacokinetics of OM with multiple oral doses of 25 mg MR tablets twice a day (BID) followed by up-titration to either 37.5 mg or 50 mg BID in healthy Japanese subjects. RESULTS: In Study 1, the maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUCinf) in Japanese subjects after a single oral dose of 50 mg were twice that at the 25 mg dose, consistent with that observed in Caucasian subjects. Following single oral doses of 25 mg and 50 mg, absolute bioavailability was 56.5% and 59.2% for Japanese subjects and 63.1 and 83.6% for Caucasian subjects, respectively. No ethnic differences were observed in the pharmacokinetics of OM and its metabolites following single and multiple doses of 25 mg and 50 mg. In Study 2, the mean accumulation ratios based on AUC from 0 to 12 h (AUC12) were approximately four-fold from day 1 to day 8 and from day 20 to day 27 across ethnic groups. The mean ratios of Cmax to predose concentrations (Cpredose) ranged from 1.25 to 1.38 across subgroups. CONCLUSIONS: OM showed consistent and predictable pharmacokinetics after multiple dosing in Japanese subjects.

Evaluation of drug-drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically-based pharmacokinetic model.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure. The potential for a pharmacokinetic (PK) drug-drug interaction (DDI) was investigated, specifically to determine whether a single 50 mg dose of OM would impact the PKs of a single 10 mg dose of rosuvastatin in an open-label study in 14 healthy subjects. The ratios of the geometric least-square means (90% confidence intervals [CIs]) of rosuvastatin co-administered with OM compared to rosuvastatin alone were 127.1% (90% CI 113.8-141.9), 132.8% (90% CI 120.7-146.1), and 154.2% (90% CI 132.8-179.1) for area under the plasma-concentration time curve from time zero to infinity (AUCinf ), area under the plasma-concentration time curve from time zero to time of last quantifiable concentration (AUClast ), and maximum observed plasma concentration (Cmax ), respectively. Whereas the DDI study with rosuvastatin was conducted with the co-administration of a single dose of OM, in the clinical setting, patients receive OM at doses of 25, 37.5, or 50 mg twice daily (b.i.d.). Hence, to extrapolate the results of the DDI study to a clinically relevant scenario of continuous b.i.d. dosing with OM, physiologically-based pharmacokinetic (PBPK) modeling was performed to explore the potential of BCRP inhibition following continuous b.i.d. dosing of OM at the highest 50 mg dose. Modeling results indicated that following 50 mg b.i.d. dosing of OM, the predicted ratios of the geometric means (90% CIs) for rosuvastatin AUCinf and Cmax were 1.18 (90% CI 1.16-1.20) and 2.04 (90% CI 1.99-2.10), respectively. Therefore, these results suggest that OM, following multiple dose administration, is a weak inhibitor of BCRP substrates and is in accordance with that observed in the single dose OM DDI clinical study.

Effect of Omecamtiv Mecarbil on the Pharmacokinetics of Metformin, a Probe Substrate for MATE1/MATE2-K, in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure with reduced ejection fraction. The objective of this study was to evaluate the potential for OM to affect the pharmacokinetics of metformin. METHODS: This was an open-label, fixed-sequence study in 14 healthy subjects. On Day 1, subjects received an 850 mg oral dose of metformin. From Days 4 to 9, subjects received twice-daily 25 mg oral doses of OM tablets. On Day 10, subjects received an 850 mg oral dose of metformin and a single 25 mg tablet of OM. Blood and urine samples were collected up to 36 h post-dose following administration of metformin on Days 1 and 10 to characterize concentrations of metformin in plasma and urine. RESULTS: The ratios of the geometric least square means of metformin coadministered with OM compared to metformin alone were 98.7%, 99.3%, and 110.2% for AUCinf, AUClast, and Cmax, respectively. The mean renal clearance of metformin was similar following metformin administered alone (34.2 L/h) compared to metformin coadministered with OM (32.9 L/h). All adverse events were mild in severity and resolved prior to the end of the study. No serious adverse events or treatment-emergent adverse events led to discontinuation from the study. CONCLUSIONS: There was no clinically relevant effect of OM on the pharmacokinetics of metformin in healthy subjects.

Switchability and minimal effect of food on pharmacokinetics of modified release tablet strengths of omecamtiv mecarbil, a cardiac myosin activator.

Omecamtiv mecarbil (OM) is a cardiac myosin activator in clinical development for the treatment of heart failure. The effect of food on the pharmacokinetics (PK) of 25, 37.5, and 50 mg strength modified release (MR) tablets and the bioequivalence of two 25 mg tablets versus one 50 mg MR tablet were evaluated in two open-label, randomized, cross-over studies in healthy subjects. Subjects received two 25 mg tablets or one 50 mg OM MR tablet under fed or fasted states in Study 1 (n = 39), and single oral doses of 25 and 37.5 mg OM MR tablets and to assess its relative bioavailability to the 25 mg MR tablet, a 25 mg oral solution under fed or fasted states in Study 2 (n = 34). The area under the concentration-time curve (AUC) and the maximum observed concentration (Cmax ) of 25, 37.5, or 50 mg OM MR tablets were approximately 13%-22% higher and 31%-40% higher, respectively, when taken with food. The two 25 mg and one 50 mg OM MR tablets were bioequivalent (90% confidence intervals) of the geometric mean ratios for Cmax and AUC of OM were within 0.8-1.25 under the fasted or fed state. OM was well tolerated and all treatment-emergent events were mild in severity and resolved by the end of the study. In conclusion, these studies demonstrated that the effect of food on the PK of OM was minimal at all three studied strengths of the MR tablets, and two 25 mg MR tablets may be switched for one 50 mg MR tablet (EudraCT Number: 2019-003683-44).

Effect of Varying Degrees of Hepatic Impairment on the Pharmacokinetics of Omecamtiv Mecarbil.

Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure with reduced ejection fraction. OM is primarily eliminated via metabolism mediated by multiple cytochrome P450 enzymes. This phase 1 single-dose, multicenter, open-label, nonrandomized study evaluated the pharmacokinetics (PK) of OM and major metabolites M3 and M4, safety, and tolerability following oral administration of a single dose of 25-mg MR tablet in subjects with mild (n = 6) or moderate (n = 6) hepatic impairment (according to Child-Pugh classification) versus subjects with normal hepatic function (n = 6). Relative to subjects with normal hepatic function, for subjects with mild or moderate hepatic impairment, OM AUCinf was 103.2% (90%CI, 58.0%-183.6%) and 94.8% (90%CI, 54.7%-164.1%), respectively, and OM Cmax was 126.8% (90%CI, 85.7%-187.7%) and 117.3% (90%CI, 80.7%-170.5%), respectively. Exposures to M3 were similar across groups, whereas slightly lower exposures were observed for M4 with worsening hepatic function. The OM, M3, and M4 tmax and t1/2 values were similar between groups. There were no serious adverse events (AEs) or treatment-related treatment-emergent AEs. Overall, OM, M3, and M4 PK were not meaningfully affected by mild or moderate hepatic impairment, suggesting the same dosing strategy can be used in subjects with mild or moderate hepatic impairment.

Relative Bioavailability of Omecamtiv Mecarbil Pediatric Minitablet Formulations in Healthy Adult Subjects.

BACKGROUND AND OBJECTIVE: Omecamtiv mecarbil (OM) is a cardiac myosin activator under clinical development for the treatment of heart failure. Two modified-release (MR) novel OM minitablet formulations were developed to support the planned investigation of chronic heart failure in pediatric patients. The primary objective of this study was to determine the bioavailability of the minitablets relative to the adult matrix MR formulation tablets. METHODS: In a randomized, 5-period, crossover study, 20 healthy subjects received each of the following treatments orally: one 25-mg adult matrix MR tablet, 25 1-mg slow-release minitablets, 25 1-mg fast-release minitablets, six 1-mg slow-release minitablets, or six 1-mg fast-release minitablets after an overnight fast of at least 10 h with a minimum washout of 7 days between treatments. Blood samples were collected for up to 168 h. OM pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: When OM was administered as 25 1-mg OM slow-release minitablets, AUClast, AUCinf, and Cmax were 0.998-, 1.00-, and 1.29-fold of a single 25-mg OM matrix MR tablet, respectively. When OM was administered as 25 1-mg OM fast-release minitablets, AUClast, AUCinf, and Cmax were 1.26-, 1.25-, and 2.21-fold of a single 25-mg OM matrix MR tablet, respectively. The slow- and fast-release minitablets display approximately dose-proportional pharmacokinetics. There were no serious adverse events or treatment-emergent adverse events leading to discontinuation from the study. CONCLUSIONS: Relative bioavailability of slow-release minitablets was demonstrated to be similar to the adult matrix MR formulation.

Pharmacokinetics, Disposition, and Biotransformation of [14C]Omecamtiv Mecarbil in Healthy Male Subjects after a Single Intravenous or Oral Dose.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator that is currently in clinical development for the treatment of heart failure. The absorption and disposition of [14C]OM (60 µCi) were studied after a single intravenous infusion (35 mg over 1 hour) or oral solution dose (35 mg) in 14 healthy male subjects. Mean recovery of the administered [14C]OM dose was 85.1% and 86.5% over 336 hours for the intravenous and oral routes, respectively. After intravenous dosing, 47.8% and 37.3% of the dose was recovered in urine and feces, respectively; after oral dosing, 48.6% and 38.0% was recovered in urine and feces, respectively. Unchanged OM accounted for a minor percentage of radioactivity in urine (mean 7.7% of dose) and feces (mean 4.1% of dose) across all subjects. The major metabolites recovered in urine and feces were M3 (decarbamoylation product) and sequential metabolite M4 (lactam of M3), which accounted for means of 26.5% and 11.6% of the administered dose, respectively. The CYP4 family of enzymes was primarily responsible for the formation of M3 based on in vitro studies. Other metabolic pathways accounted for 14.9% of the administered dose. In pooled plasma, OM, M3, and M4 accounted for 83.8%, 6.0%, and 3.3% of the total [14C]OM-related materials. No other plasma metabolites constituted more than 3% of the administered dose. The bioavailability for OM solution was 93.5% after rapid and extensive absorption. SIGNIFICANCE STATEMENT: This study characterized the absorption and disposition of OM, a novel small molecule being developed for the treatment of heart failure. OM was primarily cleared through metabolism by the CYP4 family through oxidative cleavage of a terminal carbamate moiety that resembles hydrolysis.