TY - JOUR
T1 - Single-dose pharmacokinetics of boceprevir in subjects with impaired hepatic or renal function
AU - Treitel, Michelle
AU - Marbury, Thomas
AU - Preston, Richard A.
AU - Triantafyllou, Ilias
AU - Feely, William
AU - Omara, Edward
AU - Kasserra, Claudia
AU - Gupta, Samir
AU - Hughes, Eric A.
N1 - Funding Information:
Richard A. Preston has received grant funding from Merck Sharp & Dohme Corp. Ilias Triantafyllou is a current employee of Merck Sharp & Dohme Corp. Michelle Treitel, William Feely, Edward O’Mara, Claudia Kasserra, Samir Gupta and Eric Hughes are former employees of Merck Sharp & Dohme Corp. Michelle Treitel and Eric Hughes are current employees of Bristol-Myers Squibb. Thomas Marbury has no relevant conflicts of interest. Medical writing and editorial assistance were provided by Tim Ibbotson, PhD, and Santo D’Angelo, PhD, MS, of ApotheCom, Yardley, PA, USA. This assistance was funded by Merck Sharp & Dohme Corp.
Funding Information:
The authors acknowledge Diana Deckman, Bhavna Kantesaria and David Marchisin for support with bioanalytical procedures. The authors also acknowledge Fengjuan Xuan for her assistance with statistical analyses. This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. Merck Sharp & Dohme Corp. is responsible for the design and conduct of this study, as well as the collection, management, analysis and interpretation of study data. They are also responsible for preparation of this manuscript.
PY - 2012
Y1 - 2012
N2 - Background and Objective: Boceprevir is a novel inhibitor of the hepatitis C virus NS3 protease and was recently approved for the treatment of patients with chronic hepatitis C infection. The objective of this study was to evaluate the impact of impaired hepatic or renal function on boceprevir pharmacokinetics and safety/tolerability. Methods: We conducted two open-label, single-dose, parallel-group studies comparing the safety and pharmacokinetics of boceprevir in patients with varying degrees of hepatic impairment compared with healthy controls in one study and patients with end-stage renal disease (ESRD) on haemodialysis with healthy controls in the other. Patients with hepatic impairment (mild [n = 6], moderate [n = 6], severe [n = 6] and healthy controls [n = 6]) received a single dose of boceprevir (400 mg) on day 1, and whole blood was collected at selected timepoints up to 72 hours postdose to measure plasma drug concentrations. Patients with ESRD and healthy subjects received a single dose of boceprevir 800mg orally on days 1 and 4, with samples for pharmacokinetic analyses collected at selected timepoints up to 48 hours postdose on both days. In addition, 4 hours after dosing on day 4, patients with ESRD underwent haemodialysis with arterial and venous blood samples collected up to 8 hours postdose. Results: In the hepatic impairment study, there was a trend toward increased mean maximum (peak) plasma concentration (C max) and area under the plasma concentration-time curve (AUC) of boceprevir with increasing severity of liver impairment. Point estimates for the geometric mean ratio for Cmax ranged from 100% in patients with mild hepatic impairment to 161% in patients with severe hepatic impairment, with the geometric mean ratio for AUC ranging from 91% in patients with mild hepatic impairment to 149% for patients with severe hepatic impairment, relative to healthy subjects. The mean elimination half-life (t1/2) and median time to Cmax (tmax) values of boceprevir were similar in healthy subjects and patients with hepatic impairment. In the renal impairment study, mean boceprevir Cmax and AUC values were comparable in patients with ESRD and in healthy subjects, with point estimates for the geometric mean ratio of 81% and 90%, respectively, compared with healthy subjects. Mean t1/2, median tmax and mean apparent oral total clearance (CL/F) values were similar in healthy subjects and patients with ESRD. Boceprevir exposure was also similar in patients with ESRD on day 1 (no dialysis) and day 4 (dialysis beginning 4 hours postdose), with point estimates for the geometric mean ratio of Cmax and AUC to the last measurable sampling time (AUClast) on day 1 compared with day 4 of 88% and 98%, respectively. Treatment-emergent adverse events were reported in one patient with severe hepatic impairment (mild vomiting) and two patients with ESRD (moderate ventricular extrasystoles, flatulence and catheter thrombosis). Conclusion: In the present studies, the pharmacokinetic properties of boceprevir were not altered to a clinically meaningful extent in patients with impaired liver or renal function. These data indicate that boceprevir dose adjustment is not warranted in patients with impaired hepatic function or ESRD, including those receiving dialysis. Boceprevir is not removed by haemodialysis.
AB - Background and Objective: Boceprevir is a novel inhibitor of the hepatitis C virus NS3 protease and was recently approved for the treatment of patients with chronic hepatitis C infection. The objective of this study was to evaluate the impact of impaired hepatic or renal function on boceprevir pharmacokinetics and safety/tolerability. Methods: We conducted two open-label, single-dose, parallel-group studies comparing the safety and pharmacokinetics of boceprevir in patients with varying degrees of hepatic impairment compared with healthy controls in one study and patients with end-stage renal disease (ESRD) on haemodialysis with healthy controls in the other. Patients with hepatic impairment (mild [n = 6], moderate [n = 6], severe [n = 6] and healthy controls [n = 6]) received a single dose of boceprevir (400 mg) on day 1, and whole blood was collected at selected timepoints up to 72 hours postdose to measure plasma drug concentrations. Patients with ESRD and healthy subjects received a single dose of boceprevir 800mg orally on days 1 and 4, with samples for pharmacokinetic analyses collected at selected timepoints up to 48 hours postdose on both days. In addition, 4 hours after dosing on day 4, patients with ESRD underwent haemodialysis with arterial and venous blood samples collected up to 8 hours postdose. Results: In the hepatic impairment study, there was a trend toward increased mean maximum (peak) plasma concentration (C max) and area under the plasma concentration-time curve (AUC) of boceprevir with increasing severity of liver impairment. Point estimates for the geometric mean ratio for Cmax ranged from 100% in patients with mild hepatic impairment to 161% in patients with severe hepatic impairment, with the geometric mean ratio for AUC ranging from 91% in patients with mild hepatic impairment to 149% for patients with severe hepatic impairment, relative to healthy subjects. The mean elimination half-life (t1/2) and median time to Cmax (tmax) values of boceprevir were similar in healthy subjects and patients with hepatic impairment. In the renal impairment study, mean boceprevir Cmax and AUC values were comparable in patients with ESRD and in healthy subjects, with point estimates for the geometric mean ratio of 81% and 90%, respectively, compared with healthy subjects. Mean t1/2, median tmax and mean apparent oral total clearance (CL/F) values were similar in healthy subjects and patients with ESRD. Boceprevir exposure was also similar in patients with ESRD on day 1 (no dialysis) and day 4 (dialysis beginning 4 hours postdose), with point estimates for the geometric mean ratio of Cmax and AUC to the last measurable sampling time (AUClast) on day 1 compared with day 4 of 88% and 98%, respectively. Treatment-emergent adverse events were reported in one patient with severe hepatic impairment (mild vomiting) and two patients with ESRD (moderate ventricular extrasystoles, flatulence and catheter thrombosis). Conclusion: In the present studies, the pharmacokinetic properties of boceprevir were not altered to a clinically meaningful extent in patients with impaired liver or renal function. These data indicate that boceprevir dose adjustment is not warranted in patients with impaired hepatic function or ESRD, including those receiving dialysis. Boceprevir is not removed by haemodialysis.
KW - boceprevir
KW - haemodialysis
KW - hepatitis-C
KW - hepatitis-C-virus-NS3-protein-inhibitors
KW - liver-dysfunction
KW - liver-function
KW - pharmacokinetics
KW - renal-failure
KW - renal-function
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U2 - 10.2165/11633440-000000000-00000
DO - 10.2165/11633440-000000000-00000
M3 - Article
C2 - 22799589
AN - SCOPUS:84864756342
VL - 51
SP - 619
EP - 628
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
SN - 0312-5963
IS - 9
ER -