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.

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.

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.

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.

A clinical therapeutic protein drug-drug interaction study: coadministration of denosumab and midazolam in postmenopausal women with osteoporosis.

Drug-disease interactions involving therapeutic proteins that target cytokines and potentially impact cytochrome P450 (CYP) enzymes have been of increased interest to drug regulatory agencies and industry sponsors in recent years. This parallel-group open-label study evaluated the effects of the monoclonal antibody denosumab, an inhibitor of the cytokine RANKL, on the pharmacokinetics of the probe CYP3A4 substrate midazolam in postmenopausal women with osteoporosis. The pharmacokinetics of a 2 mg oral dose of midazolam was evaluated on days 1 and 16. Subjects in Group A received a 60 mg subcutaneous dose of denosumab on day 2, 2 weeks before the second midazolam dose, while subjects in Group B did not. For Group A (n = 17), point estimates for the ratio of least square means for midazolam exposures based on maximum observed plasma concentration (C max) and areas under the plasma concentration-time curve (AUCs) on day 16 versus day 1 ranged from 1.02 to 1.04 and 90% confidence intervals were within 0.80-1.25. No period effect was observed for Group B (n = 8). Midazolam and denosumab coadministration was safe and well tolerated. Inhibition of the cytokine RANKL by denosumab does not affect CYP3A4 in postmenopausal women with osteoporosis and will not alter the pharmacokinetics of drugs metabolized by this enzyme. These results are consistent with data suggesting that RANKL does not impact markers of inflammation and represent the first clinical data demonstrating a lack of effect on CYP3A4 of a therapeutic protein that is a cytokine modulator.

The pharmacokinetics and pharmacodynamics of denosumab in patients with advanced solid tumours and bone metastases: a systematic review.

AIM: The objective of this systematic review was to characterize the pharmacokinetics and pharmacodynamics of denosumab (XGEVA®), a fully human IgG2 monoclonal antibody which binds to receptor activator of nuclear factor kappa-B ligand (RANKL), for the treatment of skeletal-related events (SREs) in patients with advanced cancer and bone metastases. METHODS: A total of 708 patients (116 healthy patients and 592 patients with solid tumours or multiple myeloma and bone metastases) included in seven clinical studies were evaluated for denosumab pharmacokinetics. Denosumab was administered as a single subcutaneous (s.c.) dose or multiple s.c. doses, ranging from 0.1 to 3.0 mg kg(-1) or 30 mg to 180 mg fixed dosing, every 1 or 3 months for up to 45 months. RESULTS: Consistent with the results in healthy adults, single s.c. doses of denosumab demonstrated dose-dependent, non-linear pharmacokinetics in advanced cancer patients with bone metastases across a wide dose range (0.1-3.0 mg kg(-1) ). Reductions in levels of the bone turnover marker, uNTx/Cr, were observed within 1 day. The duration of reductions generally increased with dose and dosing frequency. In patients with solid tumours and bone metastases, pharmacokinetics and pharmacodynamic comparisons across tumour types and concomitant cancer therapies (chemotherapies and/or hormone therapies) suggest that neither tumour type nor type of concomitant therapy markedly affects denosumab pharmacokinetics or pharmacodynamics. CONCLUSIONS: Denosumab displayed non-linear pharmacokinetics at doses below 60 mg but at higher doses, denosumab exposure increased approximately dose-proportionally in advanced cancer patients with bone metastases. Following a 120 mg, every 4 weeks dosing schedule, similar denosumab pharmacokinetics and pharmacodynamics were observed across tumour types and were independent of concomitant cancer therapies.