PubMed:23881566 JSONTXT

{"project":"PubmedHPO","denotations":[{"id":"T1","span":{"begin":314,"end":351},"obj":"HP_0006510"}],"text":"Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a double-blind, randomized clinical trial.\nBACKGROUND: Umeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99 % of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate.\nOBJECTIVE: The objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism.\nMETHODS: This was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7 days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [n = 20] and poor CYP2D6 metabolizers (HVT-PMs) [n = 16] participated in the study. The subjects received umeclidinium (100-1,000 μg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints.\nRESULTS: Thirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration-time curve over the dosing interval (from 0 to 24 h for the once-daily drug) [AUC(τ) (ng·h/mL)] and the maximum plasma concentration [C(max) (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing with 500 μg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79-1.34) and 0.80 (0.59-1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24 h (Ae(24)) [ng] ratio was 1.01 (0.82-1.26). Following repeat dosing with umeclidinium 1,000 μg, the plasma AUC(τ) [ng·h/mL] and C(max) (ng/mL) ratios (with 90 % CIs) were 1.33 (0.98-1.81) and 1.07 (0.76-1.51); the urine Ae(24) (ng) ratio was 1.47 (1.15-1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens.\nCONCLUSION: Umeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations."}

{"project":"Allie","denotations":[{"id":"SS1_23881566_2_0","span":{"begin":314,"end":351},"obj":"expanded"},{"id":"SS2_23881566_2_0","span":{"begin":353,"end":357},"obj":"abbr"},{"id":"SS1_23881566_3_0","span":{"begin":457,"end":476},"obj":"expanded"},{"id":"SS2_23881566_3_0","span":{"begin":478,"end":484},"obj":"abbr"},{"id":"SS1_23881566_9_0","span":{"begin":1097,"end":1115},"obj":"expanded"},{"id":"SS2_23881566_9_0","span":{"begin":1117,"end":1121},"obj":"abbr"},{"id":"SS1_23881566_13_0","span":{"begin":1488,"end":1502},"obj":"expanded"},{"id":"SS2_23881566_13_0","span":{"begin":1504,"end":1507},"obj":"abbr"},{"id":"SS1_23881566_14_0","span":{"begin":1646,"end":1664},"obj":"expanded"},{"id":"SS2_23881566_14_0","span":{"begin":1666,"end":1670},"obj":"abbr"},{"id":"SS1_23881566_15_0","span":{"begin":2021,"end":2041},"obj":"expanded"},{"id":"SS2_23881566_15_0","span":{"begin":2043,"end":2046},"obj":"abbr"}],"relations":[{"id":"AE1_23881566_2_0","pred":"abbreviatedTo","subj":"SS1_23881566_2_0","obj":"SS2_23881566_2_0"},{"id":"AE1_23881566_3_0","pred":"abbreviatedTo","subj":"SS1_23881566_3_0","obj":"SS2_23881566_3_0"},{"id":"AE1_23881566_9_0","pred":"abbreviatedTo","subj":"SS1_23881566_9_0","obj":"SS2_23881566_9_0"},{"id":"AE1_23881566_13_0","pred":"abbreviatedTo","subj":"SS1_23881566_13_0","obj":"SS2_23881566_13_0"},{"id":"AE1_23881566_14_0","pred":"abbreviatedTo","subj":"SS1_23881566_14_0","obj":"SS2_23881566_14_0"},{"id":"AE1_23881566_15_0","pred":"abbreviatedTo","subj":"SS1_23881566_15_0","obj":"SS2_23881566_15_0"}],"text":"Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a double-blind, randomized clinical trial.\nBACKGROUND: Umeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99 % of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate.\nOBJECTIVE: The objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism.\nMETHODS: This was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7 days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [n = 20] and poor CYP2D6 metabolizers (HVT-PMs) [n = 16] participated in the study. The subjects received umeclidinium (100-1,000 μg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints.\nRESULTS: Thirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration-time curve over the dosing interval (from 0 to 24 h for the once-daily drug) [AUC(τ) (ng·h/mL)] and the maximum plasma concentration [C(max) (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing with 500 μg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79-1.34) and 0.80 (0.59-1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24 h (Ae(24)) [ng] ratio was 1.01 (0.82-1.26). Following repeat dosing with umeclidinium 1,000 μg, the plasma AUC(τ) [ng·h/mL] and C(max) (ng/mL) ratios (with 90 % CIs) were 1.33 (0.98-1.81) and 1.07 (0.76-1.51); the urine Ae(24) (ng) ratio was 1.47 (1.15-1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens.\nCONCLUSION: Umeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations."}

{"project":"PCI_RCT","denotations":[{"id":"T1","span":{"begin":201,"end":213},"obj":"CI"},{"id":"T2","span":{"begin":414,"end":426},"obj":"CI"},{"id":"T3","span":{"begin":85,"end":97},"obj":"CI"},{"id":"T4","span":{"begin":734,"end":746},"obj":"CI"},{"id":"T5","span":{"begin":986,"end":998},"obj":"CI"},{"id":"T6","span":{"begin":1275,"end":1287},"obj":"CI"},{"id":"T7","span":{"begin":2085,"end":2097},"obj":"CI"},{"id":"T8","span":{"begin":2634,"end":2646},"obj":"CI"},{"id":"T9","span":{"begin":2342,"end":2354},"obj":"CI"}],"text":"Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a double-blind, randomized clinical trial.\nBACKGROUND: Umeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99 % of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate.\nOBJECTIVE: The objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism.\nMETHODS: This was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7 days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [n = 20] and poor CYP2D6 metabolizers (HVT-PMs) [n = 16] participated in the study. The subjects received umeclidinium (100-1,000 μg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints.\nRESULTS: Thirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration-time curve over the dosing interval (from 0 to 24 h for the once-daily drug) [AUC(τ) (ng·h/mL)] and the maximum plasma concentration [C(max) (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing with 500 μg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79-1.34) and 0.80 (0.59-1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24 h (Ae(24)) [ng] ratio was 1.01 (0.82-1.26). Following repeat dosing with umeclidinium 1,000 μg, the plasma AUC(τ) [ng·h/mL] and C(max) (ng/mL) ratios (with 90 % CIs) were 1.33 (0.98-1.81) and 1.07 (0.76-1.51); the urine Ae(24) (ng) ratio was 1.47 (1.15-1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens.\nCONCLUSION: Umeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations."}

{"project":"yangbin123xm_800_3","denotations":[{"id":"T1","span":{"begin":201,"end":213},"obj":"CI"},{"id":"T2","span":{"begin":2634,"end":2646},"obj":"CI"},{"id":"T3","span":{"begin":986,"end":998},"obj":"CI"},{"id":"T4","span":{"begin":85,"end":97},"obj":"CI"},{"id":"T5","span":{"begin":414,"end":426},"obj":"CI"},{"id":"T6","span":{"begin":734,"end":746},"obj":"CI"},{"id":"T7","span":{"begin":1275,"end":1287},"obj":"CI"},{"id":"T8","span":{"begin":2085,"end":2097},"obj":"CI"},{"id":"T9","span":{"begin":2342,"end":2354},"obj":"CI"},{"id":"T10","span":{"begin":1307,"end":1314},"obj":"CI"}],"text":"Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a double-blind, randomized clinical trial.\nBACKGROUND: Umeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99 % of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate.\nOBJECTIVE: The objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism.\nMETHODS: This was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7 days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [n = 20] and poor CYP2D6 metabolizers (HVT-PMs) [n = 16] participated in the study. The subjects received umeclidinium (100-1,000 μg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints.\nRESULTS: Thirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration-time curve over the dosing interval (from 0 to 24 h for the once-daily drug) [AUC(τ) (ng·h/mL)] and the maximum plasma concentration [C(max) (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing with 500 μg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79-1.34) and 0.80 (0.59-1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24 h (Ae(24)) [ng] ratio was 1.01 (0.82-1.26). Following repeat dosing with umeclidinium 1,000 μg, the plasma AUC(τ) [ng·h/mL] and C(max) (ng/mL) ratios (with 90 % CIs) were 1.33 (0.98-1.81) and 1.07 (0.76-1.51); the urine Ae(24) (ng) ratio was 1.47 (1.15-1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens.\nCONCLUSION: Umeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations."}

{"project":"chenxin_473849_800_3","denotations":[{"id":"T1","span":{"begin":1275,"end":1287},"obj":"CI"},{"id":"T2","span":{"begin":85,"end":97},"obj":"CI"},{"id":"T3","span":{"begin":414,"end":426},"obj":"CI"},{"id":"T4","span":{"begin":734,"end":746},"obj":"CI"},{"id":"T5","span":{"begin":986,"end":998},"obj":"CI"},{"id":"T6","span":{"begin":2085,"end":2097},"obj":"CI"},{"id":"T7","span":{"begin":2342,"end":2354},"obj":"CI"},{"id":"T8","span":{"begin":201,"end":213},"obj":"CI"},{"id":"T9","span":{"begin":2634,"end":2646},"obj":"CI"},{"id":"T10","span":{"begin":1307,"end":1314},"obj":"CI"}],"text":"Safety, tolerability and pharmacokinetics and pharmacodynamics of inhaled once-daily umeclidinium in healthy adults deficient in CYP2D6 activity: a double-blind, randomized clinical trial.\nBACKGROUND: Umeclidinium is a new, long-acting, muscarinic receptor antagonist currently in development for the treatment of chronic obstructive pulmonary disease (COPD). In vitro cell culture data suggest that up to 99 % of umeclidinium is potentially metabolized by cytochrome P450 2D6 (CYP2D6), but without a definitive human metabolism radiolabel study, the extrapolation of in vitro to in vivo is only an estimate.\nOBJECTIVE: The objective of this study was to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of umeclidinium in patients with normal and deficient CYP2D6 metabolism.\nMETHODS: This was a randomized, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled single and repeat doses (for 7 days) of umeclidinium. The study took place at a single clinical site, at which subjects remained throughout the study. Healthy volunteers (HVTs) who were normal CYP2D6 metabolizers (HVT-NMs) [n = 20] and poor CYP2D6 metabolizers (HVT-PMs) [n = 16] participated in the study. The subjects received umeclidinium (100-1,000 μg) and placebo as single and repeat doses. The primary outcome measurements were protocol-defined safety and tolerability endpoints.\nRESULTS: Thirteen subjects in each population reported adverse events (AEs); none were considered serious. No clinically significant abnormalities in vital signs, lung function, haematology, biochemistry, 12-lead electrocardiograms (ECGs) or 24-h Holter ECGs were attributable to the study drug. There were no differences in plasma and urine pharmacokinetics between populations: the plasma area under the concentration-time curve over the dosing interval (from 0 to 24 h for the once-daily drug) [AUC(τ) (ng·h/mL)] and the maximum plasma concentration [C(max) (ng/mL)] ratios (with 90 % confidence intervals [CIs]) following repeat dosing with 500 μg umeclidinium for HVT-PMs (as compared with HVT-NMs) were 1.03 (0.79-1.34) and 0.80 (0.59-1.08), respectively; the cumulative amount of the unchanged drug excreted into the urine at 24 h (Ae(24)) [ng] ratio was 1.01 (0.82-1.26). Following repeat dosing with umeclidinium 1,000 μg, the plasma AUC(τ) [ng·h/mL] and C(max) (ng/mL) ratios (with 90 % CIs) were 1.33 (0.98-1.81) and 1.07 (0.76-1.51); the urine Ae(24) (ng) ratio was 1.47 (1.15-1.88). Similar ratios for urine and plasma were observed following single and repeat-dose regimens.\nCONCLUSION: Umeclidinium has favourable safety and pharmacokinetic profiles in both HVT-NM and HVT-PM populations."}