Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of a Single Dose of Oral Ivosidenib in Otherwise Healthy Participants

2020 ◽  
Author(s):  
Bin Fan ◽  
David Dai ◽  
Marvin Cohen ◽  
Huansheng Xu ◽  
Feng Yin ◽  
...  
Keyword(s):  
Single Dose ◽  
Hepatic Impairment ◽  
Moderate Hepatic Impairment ◽  
Healthy Participants

scholarly journals Single-dose pharmacokinetics of BMS-986177/JNJ-70033093 in participants with mild or moderate hepatic impairment compared to healthy participants

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Perera ◽  
G Abelian ◽  
D Li ◽  
Z Wang ◽  
L Zhang ◽  
...  
Keyword(s):  
Single Dose ◽  
Hepatic Impairment ◽  
Hepatic Function ◽  
Moderate Hepatic Impairment ◽  
Funding Source ◽  
Antithrombotic Agents ◽  
Normal Hepatic Function ◽  
Pugh Class ◽  
Healthy Participants ◽  
Mild Hepatic Impairment

Abstract Background According to the scientific evidence accumulated to date (ie, genetic, epidemiological, preclinical, clinical), the modulation of Factor XI (FXI) function may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically significant bleeding in a variety of conditions predisposing patients to a high risk of thrombotic or bleeding events. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a small molecule that inhibits the active form of FXI (FXIa) with high affinity and selectivity. Depending on the indication, BMS-177/JNJ-3093 may provide benefit to patients as add-on or potentially replacement therapy to the current standard of care antithrombotic agents. Patients with hepatic impairment may have an increased risk of bleeding when using existing antithrombotic agents and therefore may benefit from drugs with an improved safety profile. Purpose To assess the effect of mild or moderate hepatic impairment on the pharmacokinetic (PK) properties of BMS-177/JNJ-3093. Methods This was a multicenter, open-label, non-randomized, single-dose study. A single 60-mg oral dose of BMS-177/JNJ-3093 was administered to 9 participants with mild hepatic impairment (Child-Pugh class A), 8 participants with moderate hepatic impairment (Child-Pugh class B), and 9 healthy participants with normal hepatic function. Healthy participants were matched to participants with hepatic impairment in each Child-Pugh class with regard to body weight. To assess the effects of hepatic impairment on BMS-177/JNJ-3093 PK, an analysis of variance was performed on the natural log-transformed Cmax, AUC(INF), and AUC(0-T) with hepatic function group as a fixed effect. Results BMS-177/JNJ-3093 was well tolerated when administered as an oral dose of 60 mg in participants with mild or moderate hepatic impairment and healthy participants with normal hepatic function. There were no deaths, serious adverse events (AEs), severe AEs, bleeding AEs, or discontinuations due to an AE reported during the study. The geometric mean ratios (GMRs) (90% CI) comparing mild hepatic impairment to normal hepatic function were 1.180 (0.735, 1.895) and 1.168 (0.725, 1.882) for total BMS-177/JNJ-3093 maximum concentration (Cmax) and area under the curve from time 0 to infinity (AUC(INF)), respectively. The GMRs (90% CI) comparing moderate hepatic impairment to normal hepatic function were 1.140 (0.699, 1.857) and 0.996 (0.609, 1.628) for total BMS-177/JNJ-3093 Cmax and AUC(INF), respectively. Overall, levels of activated partial thromboplastin time (aPTT) increased in an exposure-related manner following single oral doses of 60 mg BMS-177/JNJ-3093 in all groups. Conclusion BMS-177/JNJ-3093 was well tolerated in the normal healthy participants and those with mild or moderate hepatic impairment. The observed changes indicate that a dose adjustment in these populations may not be necessary. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This work was sponsored by Bristol-Myers Squibb and Janssen Research & Development, LLC

scholarly journals Pharmacokinetics and Safety of Single-Dose Esaxerenone in Japanese Subjects with Mild to Moderate Hepatic Impairment

2019 ◽  
Vol 37 (1) ◽  
pp. 253-264 ◽  
Author(s):  
Akifumi Kurata ◽  
Takafumi Yoshida ◽  
Megumi Inoue ◽  
Tomoko Ishizuka ◽  
Takafumi Nakatsu ◽  
...  
Keyword(s):  
Single Dose ◽  
Hepatic Impairment ◽  
Moderate Hepatic Impairment ◽  
Japanese Subjects

Sa1031 Mild to Moderate Hepatic Impairment Has No Effect on the Single Dose Pharmacokinetics of Alisporivir (ALV)

2013 ◽  
Vol 144 (5) ◽  
pp. S-977
Author(s):  
Steven J. Kovacs ◽  
June Ke ◽  
Jens Praestgaard ◽  
Avantika Barve ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Single Dose ◽  
Hepatic Impairment ◽  
Moderate Hepatic Impairment

scholarly journals Pharmacokinetics of Single‐Dose Dolutegravir in HIV‐Seronegative Subjects With Moderate Hepatic Impairment Compared to Healthy Matched Controls

2013 ◽  
Vol 2 (4) ◽  
pp. 342-348 ◽  
Author(s):  
Ivy H. Song ◽  
Julie Borland ◽  
Paul M. Savina ◽  
Shuguang Chen ◽  
Parul Patel ◽  
...  
Keyword(s):  
Single Dose ◽  
Hepatic Impairment ◽  
Moderate Hepatic Impairment

scholarly journals Pharmacokinetics of Cabotegravir in Subjects with Moderate Hepatic Impairment

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S429-S429 ◽  
Author(s):  
Jafar Sadik Shaik ◽  
Susan Ford ◽  
Yu Lou ◽  
Zhiping Zhang ◽  
Kalpana Bakshi ◽  
...  
Keyword(s):  
Single Dose ◽  
Hepatic Impairment ◽  
Healthy Subjects ◽  
Equilibrium Dialysis ◽  
Control Group ◽  
Moderate Hepatic Impairment ◽  
Open Label ◽  
Post Dose ◽  
Unbound Fraction ◽  
Control Subjects

Abstract Background Cabotegravir (CAB) is an integrase inhibitor in phase 3 clinical trials for the treatment and prevention of HIV. CAB undergoes hepatic metabolism primarily via UGT1A1; thus hepatic impairment has the potential to affect CAB exposure. Methods This was a multi-center, single-dose, open-label, parallel group study to evaluate the effect of moderate hepatic impairment on the pharmacokinetics (PK) and safety of CAB. Adults with moderate hepatic impairment as determined by Child-Pugh classification score of 7–9 (n = 8) and matched healthy control subjects (n = 8) were enrolled. Control subjects were matched for gender, age (±10 years), and body mass index (BMI) (±25%). Subjects received oral CAB 30 mg as a single dose in the fasted state followed by serial PK sampling for 168 hours. CAB unbound concentrations at 2 and 24 hours after dosing were determined by equilibrium dialysis. Non-compartmental PK analysis was performed; geometric least squares (GLS) mean ratios (hepatic impaired group/control group) and 90% confidence intervals (CI) were generated. Results Sixteen subjects completed study; 12 (75%) male, mean age 59 years (range: 51–67), mean BMI 29 kg/m2 (range: 21–37), and total Child Pugh score in range of 7–9. CAB PK parameters were similar between subjects with moderate hepatic impairment and matched healthy subjects. The GLS mean ratios (90% CI) for AUC(0-∞), Cmax, C24, CL/F, and t1/2 were 0.73 (0.50, 1.06), 0.69 (0.51, 0.93), 0.73 (0.53, 1.02), 1.38 (0.95, 2.01), and 0.82 (0.65, 1.04), respectively. Although highly protein bound, the unbound fraction of CAB was increased in subjects with moderate hepatic impairment relative to healthy subjects with GLS mean ratio (90%CI) of 2.14 (1.57, 2.90) at 2 hours post dose and 1.90 (1.14, 3.18) at 24 hours post dose; this was associated with lower serum albumin concentrations and was not considered clinically significant. All adverse events (AE) were reported as mild (Grade 1) to moderate (Grade 2) in severity and no serious AEs were reported. Conclusion Plasma exposures of CAB in subjects with moderate hepatic impairment were similar to those in healthy subjects. No dose adjustment of CAB is required for subjects with mild to moderate hepatic impairment. Disclosures J. S. Shaik, GlaxoSmithKline: Employee and Shareholder, Salary; S. Ford, PAREXEL International: Employee, Salary; Y. Lou, PAREXEL International: Employee, Salary; Z. Zhang, PAREXEL International: Employee, Salary; K. Bakshi, GlaxoSmithKline: Employee and Shareholder, Salary; A. Tenorio, ViiV Healthcare: Employee and Shareholder, Salary; C. Trezza, ViiV Healthcare: Employee and Shareholder, Salary; W. Spreen, ViiV Healthcare: Employee and Shareholder, Salary; P. Patel, ViiV Healthcare: Employee and Shareholder, Salary

Effect of Mild and Moderate Hepatic Impairment on Azimilide Pharmacokinetics Following Single Dose Oral Administration

2004 ◽  
Vol 93 (5) ◽  
pp. 1279-1286 ◽  
Author(s):  
Alfred E. Corey ◽  
Jeffrey R. Agnew ◽  
Eileen C. King ◽  
Nikhil J. Parekh ◽  
James H. Powell ◽  
...  
Keyword(s):  
Single Dose ◽  
Oral Administration ◽  
Hepatic Impairment ◽  
Moderate Hepatic Impairment ◽  
Dose Oral
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