Daphne Williams | Ashford University (original) (raw)

Papers by Daphne Williams

Research paper thumbnail of Phase I Clinical Study of Eltrombopag, an Oral, Non-peptide Thrombopoietin Receptor Agonist

Research paper thumbnail of Eltrombopag does not affect cardiac repolarization: results from a definitive QTc study in healthy subjects: Thorough QT study of eltrombopag

British Journal of Clinical Pharmacology, 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTSome non-anti-arrhythmic drugs delay cardiac repolarizati... more WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTSome non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QTc study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QTc.WHAT THIS STUDY ADDSThis study found no clinically significant QT prolongation for eltrombopag when administered as 50 mg or 150 mg every day for 5 days. There were no safety or tolerability signals of clinical concern. A small incidence of ventricular premature beats was observed, but this was consistent with previously reported incidences in healthy volunteers without apparent heart disease.WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTSome non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QTc study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QTc.WHAT THIS STUDY ADDSThis study found no clinically significant QT prolongation for eltrombopag when administered as 50 mg or 150 mg every day for 5 days. There were no safety or tolerability signals of clinical concern. A small incidence of ventricular premature beats was observed, but this was consistent with previously reported incidences in healthy volunteers without apparent heart disease.AIMTo evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QTc.To evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QTc.METHODSThis was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences.This was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences.RESULTSEighty-seven subjects entered the study and 48 completed. There was no prolongation of QTc (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QTcF between drug and placebo (ddQTcF) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag Cmax and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52–66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug.Eighty-seven subjects entered the study and 48 completed. There was no prolongation of QTc (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QTcF between drug and placebo (ddQTcF) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag Cmax and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52–66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug.CONCLUSIONSNo clinically significant QTc prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.No clinically significant QTc prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.

Research paper thumbnail of Effect of Hepatic or Renal Impairment on Eltrombopag Pharmacokinetics

Journal of Clinical Pharmacology, 2011

Eltrombopag, an oral, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatmen... more Eltrombopag, an oral, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of thrombocytopenia, is highly protein bound and primarily eliminated via metabolism in the liver and gastrointestinal tract. Single-dose eltrombopag pharmacokinetics were evaluated in participants with hepatic or renal impairment given possible changes in systemic exposure due to reduced plasma protein binding or reduced metabolism. All participants received a single 50-mg dose of eltrombopag. The adverse event profile was similar across groups, with headache, nausea, and back pain most frequently reported. Compared with healthy participants, participants with mild, moderate, or severe hepatic impairment had mean increases in AUC(0-∞) of 41%, 93%, and 80%, and participants with mild, moderate, or severe renal impairment had mean decreases in AUC(0-∞) of 32%, 36%, and 60%. There was high pharmacokinetic variability and significant overlap in exposures between participants with hepatic or renal impairment and healthy participants. Results suggest that patients with renal impairment may initiate eltrombopag with the standard 50-mg once-daily starting regimen, whereas patients with moderate or severe hepatic impairment should consider a lower 25-mg once-daily regimen. Patients with hepatic or renal impairment should be closely monitored for platelet response and safety, and eltrombopag doses should be adjusted accordingly.

Research paper thumbnail of Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist

Research paper thumbnail of Eltrombopag, an oral thrombopoietin receptor agonist, has no impact on the pharmacokinetic profile of probe drugs for cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C9 and CYP2C19 in healthy men: a cocktail analysis

European Journal of Clinical Pharmacology, 2010

Purpose It is likely that the thrombopoietin receptor agonist eltrombopag will be administered co... more Purpose It is likely that the thrombopoietin receptor agonist eltrombopag will be administered concomitantly with other medications in the treatment of thrombocytopenia. Therefore the potential for eltrombopag to interact with cytochrome P450 activity was investigated. Methods Twenty-four healthy men received eltrombopag 75 mg/day on days 3–9, midazolam 5 mg (a probe for CYP3A4) on days 1 and 8 and a probe cocktail on days 2 and 9 that included caffeine 100 mg (CYP1A2), flurbiprofen 50 mg (CYP2C9) and omeprazole 20 mg (CYP2C19). Results Midazolam pharmacokinetic parameters were comparable before and after eltrombopag administration; geometric least squares (GLS) mean ratio (90% confidence intervals, CI) area under the curve from zero to infinity (AUC0-∞) was 1.03 (0.94,1.12) and maximum plasma concentration (Cmax) was 0.98 (0.86,1.07). Metabolic indices for other CYP isozymes were also equivalent before and after eltrombopag. GLS mean ratio (90% CI) for the paraxanthine:caffeine concentration ratio at 8 h postdose was 0.97 (0.92,1.03), for conjugated + unconjugated and unconjugated 4-hydroxy-flurbiprofen recovery in urine over 0–8 h was 0.95 (0.93,0.97) and 0.93 (0.88,0.98), respectively, and for the plasma omeprazole:5-hydroxyomeprazole concentration ratio at 2- and 3-h postdose was 1.00 (0.93,1.08) and 1.02 (0.88,1.18), respectively. Conclusion Once-daily administration of eltrombopag 75 mg for 7 days did not alter CYP3A4, CYP1A2, CYP2C9 or CYP2C19 activity in healthy volunteers.

Research paper thumbnail of Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: Two single-dose, open-label, randomized-sequence, crossover studies

Clinical Therapeutics, 2009

Background: Eltrombopag is the first orally selfadministered, small-molecule, nonpeptide thrombop... more Background: Eltrombopag is the first orally selfadministered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura.

Research paper thumbnail of Clinical Pharmacokinetics, Platelet Response, and Safety of Eltrombopag at Supratherapeutic Doses of up to 200 mg Once Daily in Healthy Volunteers

Journal of Clinical Pharmacology, 2011

This was a double-blind, placebo-controlled, randomized, parallel, dose-escalation study to asses... more This was a double-blind, placebo-controlled, randomized, parallel, dose-escalation study to assess the pharmacokinetics, platelet response, safety, and tolerability of supratherapeutic doses of eltrombopag (100 mg, 150 mg, and 200 mg once daily) administered for 5 days to 33 healthy adult volunteers. Plasma eltrombopag concentrations accumulated between days 1 and 5, with average increases of 66% to 81% for area under the plasma concentration-time curve from time zero to the end of the 24-hour dosing interval (AUC0-τ) and 32% to 45% for maximum observed plasma concentration (Cmax) across doses. After 5 days of dosing, AUC0-τ was dose-proportional and Cmax was less than dose-proportional over eltrombopag 100 to 200 mg with slope estimates (90% confidence intervals) of 0.92 (0.45-1.39) and 0.76 (0.29-1.22), respectively. Platelet counts peaked at day 14, and maximum change from baseline platelet count increased dose-dependently, with mean platelet count increases of 14, 67, 107, and 150 Gi/L for placebo and eltrombopag 100 mg, 150 mg, and 200 mg, respectively. There was no notable difference in day 14 mean platelet aggregation between eltrombopag (59 to 74%) and placebo (67%), although this was not tested statistically. There was no notable difference in adverse event frequency across eltrombopag doses. Eltrombopag pharmacokinetics and platelet response were dose-dependent, and doses up to 200 mg/d were well tolerated, with safety profiles similar to placebo.

Research paper thumbnail of thrombopoietin receptor agonist Phase 1 clinical study of eltrombopag, an oral, nonpeptide

Eltrombopag (SB-497 115) is a first-inclass, oral, small-molecule, nonpeptide agonist of the thro... more Eltrombopag (SB-497 115) is a first-inclass, oral, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), being developed as a treatment for thrombocytopenia of various etiologies. In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects, eltrombopag was administered as oncedaily oral capsules for 10 days at doses of 5, 10, 25, 30, 50, and 75 mg. The pharmacokinetics of eltrombopag were dose dependent and linear, and eltrombopag increased platelet counts in a dosedependent manner. There were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication. These observations indicate that el-trombopag is a once-daily, oral TpoR agonist with demonstrated thrombopoietic activity in human subjects, encouraging further studies in patients with thrombocytopenia. (Blood. 2007;109:4739-4741)

Research paper thumbnail of Phase I Clinical Study of Eltrombopag, an Oral, Non-peptide Thrombopoietin Receptor Agonist

Research paper thumbnail of Eltrombopag does not affect cardiac repolarization: results from a definitive QTc study in healthy subjects: Thorough QT study of eltrombopag

British Journal of Clinical Pharmacology, 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTSome non-anti-arrhythmic drugs delay cardiac repolarizati... more WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTSome non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QTc study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QTc.WHAT THIS STUDY ADDSThis study found no clinically significant QT prolongation for eltrombopag when administered as 50 mg or 150 mg every day for 5 days. There were no safety or tolerability signals of clinical concern. A small incidence of ventricular premature beats was observed, but this was consistent with previously reported incidences in healthy volunteers without apparent heart disease.WHAT IS ALREADY KNOWN ABOUT THIS SUBJECTSome non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QTc study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QTc.WHAT THIS STUDY ADDSThis study found no clinically significant QT prolongation for eltrombopag when administered as 50 mg or 150 mg every day for 5 days. There were no safety or tolerability signals of clinical concern. A small incidence of ventricular premature beats was observed, but this was consistent with previously reported incidences in healthy volunteers without apparent heart disease.AIMTo evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QTc.To evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QTc.METHODSThis was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences.This was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences.RESULTSEighty-seven subjects entered the study and 48 completed. There was no prolongation of QTc (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QTcF between drug and placebo (ddQTcF) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag Cmax and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52–66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug.Eighty-seven subjects entered the study and 48 completed. There was no prolongation of QTc (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QTcF between drug and placebo (ddQTcF) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag Cmax and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52–66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug.CONCLUSIONSNo clinically significant QTc prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.No clinically significant QTc prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.

Research paper thumbnail of Effect of Hepatic or Renal Impairment on Eltrombopag Pharmacokinetics

Journal of Clinical Pharmacology, 2011

Eltrombopag, an oral, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatmen... more Eltrombopag, an oral, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of thrombocytopenia, is highly protein bound and primarily eliminated via metabolism in the liver and gastrointestinal tract. Single-dose eltrombopag pharmacokinetics were evaluated in participants with hepatic or renal impairment given possible changes in systemic exposure due to reduced plasma protein binding or reduced metabolism. All participants received a single 50-mg dose of eltrombopag. The adverse event profile was similar across groups, with headache, nausea, and back pain most frequently reported. Compared with healthy participants, participants with mild, moderate, or severe hepatic impairment had mean increases in AUC(0-∞) of 41%, 93%, and 80%, and participants with mild, moderate, or severe renal impairment had mean decreases in AUC(0-∞) of 32%, 36%, and 60%. There was high pharmacokinetic variability and significant overlap in exposures between participants with hepatic or renal impairment and healthy participants. Results suggest that patients with renal impairment may initiate eltrombopag with the standard 50-mg once-daily starting regimen, whereas patients with moderate or severe hepatic impairment should consider a lower 25-mg once-daily regimen. Patients with hepatic or renal impairment should be closely monitored for platelet response and safety, and eltrombopag doses should be adjusted accordingly.

Research paper thumbnail of Phase 1 clinical study of eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist

Research paper thumbnail of Eltrombopag, an oral thrombopoietin receptor agonist, has no impact on the pharmacokinetic profile of probe drugs for cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C9 and CYP2C19 in healthy men: a cocktail analysis

European Journal of Clinical Pharmacology, 2010

Purpose It is likely that the thrombopoietin receptor agonist eltrombopag will be administered co... more Purpose It is likely that the thrombopoietin receptor agonist eltrombopag will be administered concomitantly with other medications in the treatment of thrombocytopenia. Therefore the potential for eltrombopag to interact with cytochrome P450 activity was investigated. Methods Twenty-four healthy men received eltrombopag 75 mg/day on days 3–9, midazolam 5 mg (a probe for CYP3A4) on days 1 and 8 and a probe cocktail on days 2 and 9 that included caffeine 100 mg (CYP1A2), flurbiprofen 50 mg (CYP2C9) and omeprazole 20 mg (CYP2C19). Results Midazolam pharmacokinetic parameters were comparable before and after eltrombopag administration; geometric least squares (GLS) mean ratio (90% confidence intervals, CI) area under the curve from zero to infinity (AUC0-∞) was 1.03 (0.94,1.12) and maximum plasma concentration (Cmax) was 0.98 (0.86,1.07). Metabolic indices for other CYP isozymes were also equivalent before and after eltrombopag. GLS mean ratio (90% CI) for the paraxanthine:caffeine concentration ratio at 8 h postdose was 0.97 (0.92,1.03), for conjugated + unconjugated and unconjugated 4-hydroxy-flurbiprofen recovery in urine over 0–8 h was 0.95 (0.93,0.97) and 0.93 (0.88,0.98), respectively, and for the plasma omeprazole:5-hydroxyomeprazole concentration ratio at 2- and 3-h postdose was 1.00 (0.93,1.08) and 1.02 (0.88,1.18), respectively. Conclusion Once-daily administration of eltrombopag 75 mg for 7 days did not alter CYP3A4, CYP1A2, CYP2C9 or CYP2C19 activity in healthy volunteers.

Research paper thumbnail of Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: Two single-dose, open-label, randomized-sequence, crossover studies

Clinical Therapeutics, 2009

Background: Eltrombopag is the first orally selfadministered, small-molecule, nonpeptide thrombop... more Background: Eltrombopag is the first orally selfadministered, small-molecule, nonpeptide thrombopoietin receptor agonist for the treatment of chronic idiopathic thrombocytopenic purpura.

Research paper thumbnail of Clinical Pharmacokinetics, Platelet Response, and Safety of Eltrombopag at Supratherapeutic Doses of up to 200 mg Once Daily in Healthy Volunteers

Journal of Clinical Pharmacology, 2011

This was a double-blind, placebo-controlled, randomized, parallel, dose-escalation study to asses... more This was a double-blind, placebo-controlled, randomized, parallel, dose-escalation study to assess the pharmacokinetics, platelet response, safety, and tolerability of supratherapeutic doses of eltrombopag (100 mg, 150 mg, and 200 mg once daily) administered for 5 days to 33 healthy adult volunteers. Plasma eltrombopag concentrations accumulated between days 1 and 5, with average increases of 66% to 81% for area under the plasma concentration-time curve from time zero to the end of the 24-hour dosing interval (AUC0-τ) and 32% to 45% for maximum observed plasma concentration (Cmax) across doses. After 5 days of dosing, AUC0-τ was dose-proportional and Cmax was less than dose-proportional over eltrombopag 100 to 200 mg with slope estimates (90% confidence intervals) of 0.92 (0.45-1.39) and 0.76 (0.29-1.22), respectively. Platelet counts peaked at day 14, and maximum change from baseline platelet count increased dose-dependently, with mean platelet count increases of 14, 67, 107, and 150 Gi/L for placebo and eltrombopag 100 mg, 150 mg, and 200 mg, respectively. There was no notable difference in day 14 mean platelet aggregation between eltrombopag (59 to 74%) and placebo (67%), although this was not tested statistically. There was no notable difference in adverse event frequency across eltrombopag doses. Eltrombopag pharmacokinetics and platelet response were dose-dependent, and doses up to 200 mg/d were well tolerated, with safety profiles similar to placebo.

Research paper thumbnail of thrombopoietin receptor agonist Phase 1 clinical study of eltrombopag, an oral, nonpeptide

Eltrombopag (SB-497 115) is a first-inclass, oral, small-molecule, nonpeptide agonist of the thro... more Eltrombopag (SB-497 115) is a first-inclass, oral, small-molecule, nonpeptide agonist of the thrombopoietin receptor (TpoR), being developed as a treatment for thrombocytopenia of various etiologies. In this phase 1 placebo-controlled clinical trial in 73 healthy male subjects, eltrombopag was administered as oncedaily oral capsules for 10 days at doses of 5, 10, 25, 30, 50, and 75 mg. The pharmacokinetics of eltrombopag were dose dependent and linear, and eltrombopag increased platelet counts in a dosedependent manner. There were no apparent differences in the incidence or severity of adverse events in subjects receiving active or placebo study medication. These observations indicate that el-trombopag is a once-daily, oral TpoR agonist with demonstrated thrombopoietic activity in human subjects, encouraging further studies in patients with thrombocytopenia. (Blood. 2007;109:4739-4741)