Influence of mild and moderate hepatic impairment on the pharmacokinetics (PK) of the pan-HER inhibitor dacomitinib.

2568 Background: Dacomitinib (D) is a highly selective irreversible small molecule inhibitor of the HER family of tyrosine kinases in clinical development for NSCLC.Prior clinical studies of D, which has minimal renal excretion (~3%), enrolled pts with protocol-defined adequate liver function. Liver metastases, leading to abnormal liver function tests, are common in pts with advanced cancer. This study evaluated the effect of hepatic impairment on PK and safety of D following a single oral dose in subjects with mild or moderate hepatic impairment. Methods: In this phase I, open-label, parallel group study, 25 subjects with either normal hepatic function (n=8) or mild (Child-Pugh A; n=8) or moderate (Child-Pugh B; n=9) hepatic impairment were administered a single, oral dose of D (30 mg). PK samples were collected at intervals up to 264 h post-dose and safety was assessed by laboratory abnormalities, physical examination, vital signs, ECGs, and AE monitoring. Analysis of variance was performed on natural log-transformed AUC and Cmaxto estimate adjusted mean differences between groups and 90% CIs, which were exponentiated to produce the adjusted GMR and 90% CI of the ratios. Results: GMR and 90% CI for AUCinf and Cmax (preliminary analyses) are listed.Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Moderate hepatic impairment decreased D exposure by 15% and 20% for AUCinf and Cmax, respectively, vs normal hepatic function, but the 90% CI was relatively wide, and included 1. Plasma protein binding of D was similar in the 3 groups. No clinically significant treatment-related AEs were reported. Conclusions: Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Mean D exposure appeared slightly lower in subjects with moderate impairment. Dose reduction of D in subjects with mild or moderate hepatic impairment may not be necessary. A single 30 mg dose of D was well tolerated in subjects with mild or moderate hepatic impairment. Clinical trial information: NCT01571388. [Table: see text]

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A Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics and Safety and Tolerability of a Single Oral Dose of Risdiplam Compared to Matched Healthy Participants With Normal Hepatic Function

Case Medical Research ◽

10.31525/ct1-nct03920865 ◽

2019 ◽

Author(s):

Keyword(s):

Oral Dose ◽

Single Oral Dose ◽

Hepatic Impairment ◽

Hepatic Function ◽

Normal Hepatic Function ◽

Healthy Participants

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Atezolizumab and Bevacizumab in Patients with Unresectable Hepatocellular Carcinoma: Pharmacokinetic and Safety Assessments Based on Hepatic Impairment Status and Geographic Region

Liver Cancer ◽

10.1159/000515817 ◽

2021 ◽

pp. 1-15

Author(s):

Colby S. Shemesh ◽

Phyllis Chan ◽

Hui Shao ◽

Derek-Zhen Xu ◽

Daniel Combs ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Adverse Event ◽

Hepatic Impairment ◽

Hepatic Function ◽

Geographic Region ◽

Moderate Hepatic Impairment ◽

Unresectable Hepatocellular Carcinoma ◽

Drug Concentrations ◽

Normal Hepatic Function ◽

Mild Impairment

Introduction: Phase 1b GO30140 and phase 3 IMbrave150 studies evaluated first-line atezolizumab + bevacizumab for unresectable hepatocellular carcinoma (HCC). Here, we evaluated pharmacokinetics (PK) and safety by hepatic impairment status and geographic region. Methods: Patients received atezolizumab 1,200 mg + bevacizumab 15 mg/kg IV every 3 weeks. Drug concentrations were evaluated by descriptive statistics and population PK. PK and adverse event frequencies were evaluated by hepatic impairment status and region. Results: 323 IMbrave150 patients and 162 GO30140 patients were PK evaluable. Compared with IMbrave150 patients who had normal hepatic function per the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria (n = 123), patients with mild impairment (n = 171) had a geometric mean ratio (GMR) of 0.92 for cycle 1 atezolizumab area under the concentration-time curve (AUC); patients with moderate impairment (n = 27) had a GMR of 0.88. Patients in Asia ([n = 162] vs. outside [n = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [n = 61]), patients with mild impairment (n = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (n = 9) had a GMR of 0.94. Patients in Asia (n = 111) versus outside Asia (n = 51) had a GMR of 0.94 for cycle 1 peak bevacizumab concentration. PK results were generally comparable when evaluated based on additional hepatic functional definitions (Child-Pugh or albumin/bilirubin criteria) or study enrollment in Japan. No associations between atezolizumab PK and HCC etiology were seen. Adverse event frequencies were similar across evaluated groups. Conclusions: IMbrave150 and GO30140 patients with unresectable HCC had varying baseline hepatic impairment and high enrollment from Asia. PK data demonstrated considerable exposure overlap across groups. Treatment was tolerable across groups. No need for dose adjustment based on mild or moderate hepatic impairment or region is recommended based on this analysis.

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Pharmacokinetics and safety following a single oral dose of niraparib in patients with moderate hepatic impairment.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6054 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6054-6054

Author(s):

Mehmet Akce ◽

Anthony B. El-Khoueiry ◽

Sarina Anne Piha-Paul ◽

Emeline Bacque ◽

Peng Pan ◽

...

Keyword(s):

Hepatic Impairment ◽

Safety Data ◽

Hepatic Function ◽

Moderate Hepatic Impairment ◽

Open Label ◽

Time Curve ◽

Measured Concentration ◽

Single Dose Study ◽

Normal Hepatic Function ◽

Platinum Based Chemotherapy

6054 Background: Niraparib is approved for the maintenance treatment of adult patients (pts) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, or with similar cancers but advanced, associated with homologous recombination deficiency (HRD) and have been treated with ³3 prior chemotherapy regimens. Niraparib is extensively metabolized in the liver and eliminated via both hepatobiliary and renal routes. Objectives of this study included characterization of niraparib pharmacokinetics (PK) and safety in pts with normal hepatic function vs. pts with moderate hepatic impairment. Methods: This phase I, open-label, parallel-group, single-dose study enrolled pts with advanced solid tumors into 2 groups: normal hepatic function and moderately impaired hepatic function, defined as bilirubin >1.5 to 3 times the upper limit of normal and any aspartate aminotransferase elevation. Pts received a single 300-mg dose and underwent PK sampling for 7 days. Exposure parameters included maximum concentration (Cmax), area under the concentration-time curve calculated to last measured concentration (AUClast), and extrapolated to infinity (AUCinf). PK parameters were determined using a non-compartmental analysis in WinNonlin. Results: Seventeen pts were enrolled; 9 with normal hepatic function and 8 with hepatic impairment. Niraparib Cmax was 7% lower in pts with moderate hepatic impairment compared with pts with normal hepatic function (Table). Overall exposure was increased in pts with moderate hepatic impairment, with niraparib AUClast and AUCinf increased 45% and 60%, respectively. Safety data during the PK phase of the study is consistent with the known profile for niraparib. Conclusions: Pts with moderate hepatic impairment experienced increased niraparib exposure which did not noticeably alter the toxicity profile in this population. Clinical trial information: NCT03359850. [Table: see text]

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P291 Pharmacokinetics, safety, and tolerability of etrasimod (APD334) in subjects with mild, moderate, or severe hepatic impairment: a single-dose, open-label, parallel-group study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab076.415 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S321-S322

Author(s):

C Lee ◽

Y Tang ◽

C Schroeder ◽

J Zhang ◽

T Nguyen-Cleary ◽

...

Keyword(s):

Single Dose ◽

Oral Dose ◽

Single Oral Dose ◽

Normal Control ◽

Hepatic Impairment ◽

Hepatic Function ◽

Control Groups ◽

Severe Hepatic Impairment ◽

Open Label ◽

Mean Values

Abstract Background Etrasimod is an oral, selective sphingosine 1-phosphate receptor modulator in clinical development for immune-mediated inflammatory disorders, including ulcerative colitis, Crohn’s disease, and eosinophilic esophagitis. The objective of this study was to evaluate the effect of hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of etrasimod. Methods This single-dose, open-label, parallel-group study included 36 adult subjects (aged 18-80 years; body mass index ≥18 kg/m2) with hepatic impairment, based on Child-Pugh score at screening (mild=5 to 6 [n=8], moderate=7 to 9 [n=8], severe=10 to 14 [n=6]), and their demographically matched control subjects with normal hepatic function (n=14 total). The first subject with severe hepatic impairment was enrolled after ≥2 subjects with mild and ≥2 subjects with moderate hepatic impairment had been enrolled and followed for ≥48 hours after dosing to ensure no observed significant safety signals. On Day 1, subjects received a single oral dose of etrasimod 2 mg after a ≥10 hour fast. PK and safety data were collected over a 21-day follow-up period. Results Thirty-six subjects were enrolled and dosed; 35 subjects completed the study. When compared with their respective demographically matched normal control groups, single dose etrasimod peak exposure (Cmax) was comparable for all hepatic impairment groups, whereas etrasimod total exposure (AUC) measures were progressively higher (up to 57.3% higher) in the mild, moderate, and severe hepatic impairment groups (Table 1). Unbound etrasimod Cmax values were progressively lower (up to 42.0% lower) in the mild, moderate, and severe hepatic impairment groups, whereas unbound etrasimod AUC values were typically comparable for all hepatic impairment groups, when compared with their respective demographically matched normal control groups (Table 2). Etrasimod t1/2 only moderately increased as hepatic function decreased, with mean values ranging from 43.9 to 59.5 hours in the demographically matched normal control groups and mean values of 55.7, 69.7, and 76.5 hours in the mild, moderate, and severe hepatic impairment groups, respectively. A single oral dose of etrasimod 2 mg was well tolerated; there were no clinically significant safety findings when administered to subjects with normal hepatic function or subjects with mild, moderate, or severe hepatic impairment. Conclusion A single oral dose of etrasimod 2 mg was well tolerated, with relatively modest changes in etrasimod exposure observed in subjects with mild, moderate, or severe hepatic impairment. These results suggest that etrasimod dose adjustment may not be warranted in subjects with hepatic impairment.

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Pharmacokinetics of Temsavir, the Active Moiety of the Prodrug Fostemsavir, in Subjects with Hepatic Impairment

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.1086 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S430-S430 ◽

Cited By ~ 4

Author(s):

Heather Sevinsky ◽

Mindy Magee ◽

Peter Ackerman ◽

Robert Adamczyk ◽

Jennifer Karkas ◽

...

Keyword(s):

Hepatic Impairment ◽

Geometric Mean ◽

Hepatic Function ◽

Open Label ◽

Post Dose ◽

Viral Attachment ◽

Linear Mixed Effects ◽

Active Moiety ◽

Impaired Hepatic Function ◽

Hiv 1

Abstract Background Fostemsavir (FTR) is a prodrug of temsavir (TMR), a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T cells. TMR is primarily metabolized via hydrolytic and oxidative pathways; impaired hepatic function may alter TMR pharmacokinetics (PK). Methods AI438053 (NCT02467335) was an open-label, nonrandomized study in healthy subjects (HS) and subjects with hepatic impairment (HI), defined by Child-Pugh (CP) score: mild (CPA), moderate (CPB), or severe (CPC). HS were matched for age, body weight, and sex. Subjects received a single oral dose of FTR 600 mg fasted and serial PK samples for TMR were collected up to 96 hours post-dose. Unbound TMR at 1 and 3 hours post-dose was determined. Total and unbound PK parameters were derived by noncompartmental methods. Geometric mean ratios (GMR) and 90% confidence intervals (CI) for HI vs.. HS were derived using linear mixed-effects models. Subjects were monitored for adverse events (AEs). Results 18 subjects with HI (N = 6/CP group) and 12 HS received FTR and completed the study. Total and unbound TMR exposures increased with increasing HI severity (see Table). Total and unbound TMR CLT/F decreased with increasing HI severity. Mean % protein binding of TMR was 81.0% in HS and 79.9%, 81.9%, and 76.5% in CPA, CPB, and CPC HI, respectively, and was independent of TMR concentration. There were no deaths, serious AEs, or discontinuations during the treatment period. Conclusion TMR exposures increase with increasing severity of HI. The increase in TMR exposures in patients with mild or moderate HI is not expected to alter the safety profile of FTR. The risk/benefit of higher TMR exposures in severe HI is under evaluation. Disclosures H. Sevinsky, ViiV Healthcare: Employee, Salary; M. Magee, GlaxoSmithKline: Employee and Shareholder, Salary; P. Ackerman, ViiV Healthcare/GSK: Employee and Shareholder, Salary and Stock; R. Adamczyk, Bristol-Myers Squibb: Employee, Salary; J. Karkas, Bristol Myers Squibb: Employee and Shareholder, Salary; S. Lubin, Bristol-Myers Squibb: Employee, Salary; P. Ravindran, Bristol-Myers Squibb: Employee, Salary; C. Llamoso, ViiV Healthcare: Employee, Salary; T. Eley, Bristol-Myers Squibb: Former Employee during study conduct, Salary; K. Moore, ViiV Healthcare: Employee, Salary

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Abstract 2770: An open-label comparative study of the pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with mild, moderate, or severe hepatic impairment, or normal hepatic function

10.1158/1538-7445.am10-2770 ◽

2010 ◽

Author(s):

John Kemp ◽

Helen Tomkinson ◽

Maria Taboada ◽

Blanka Cieslarová ◽

Stuart Oliver ◽

...

Keyword(s):

Comparative Study ◽

Hepatic Impairment ◽

Hepatic Function ◽

Severe Hepatic Impairment ◽

Open Label ◽

Normal Hepatic Function

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

European Heart Journal ◽

10.1093/ehjci/ehaa946.3371 ◽

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

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Effects of Child-Pugh B Cirrhosis on Pharmacokinetics of Tofogliflozin, a New Sodium-Glucose Co-Transporter (SGLT2) Inhibitor

Drug Research ◽

10.1055/a-1202-0818 ◽

2020 ◽

Vol 70 (09) ◽

pp. 401-409

Author(s):

Haruki Yamada ◽

Hiromasa Ohira ◽

Fumiaki Ikegami ◽

Koichi Nakamura ◽

Atsushi Takahashi ◽

...

Keyword(s):

Adverse Events ◽

Oral Dose ◽

Laboratory Test ◽

Single Oral Dose ◽

Hepatic Impairment ◽

Geometric Mean ◽

Sglt2 Inhibitor ◽

Mean Value ◽

Moderate Hepatic Impairment ◽

Urinary Glucose

Abstract Background Tofogliflozin is a highly selective sodium-glucose co-transporter 2 (SGLT2) inhibitor. A mass balance study with combinations of microdoses revealed that tofogliflozin has high oral bioavailability (97.5%) and that tofogliflozin in circulation is eliminated primarily by metabolic pathways, with the liver playing a prominent role in elimination. Objectives This study aimed to evaluate the effect of moderate hepatic impairment on the pharmacokinetics of tofogliflozin and on the pharmacodynamics (urinary glucose excretion [UGE]). Methods In an open-label, parallel-group study, 17 subjects (9 with moderate hepatic impairment [Child-Pugh Class B, score 7–9] and 8 healthy) received a single oral dose of 40 mg tofogliflozin. Plasma and urine concentrations of tofogliflozin were determined. Accumulated UGE, adverse events, and physiological and laboratory test data were monitored. Results Geometric mean ratio (GMR; geometric mean value for subjects with moderate hepatic impairment / geometric mean value for healthy subjects) of Cmax was 1.47 and GMR of AUCinf was 1.70. Moderate hepatic impairment had only a little effect on tmax and CLR but it prolonged MRT. The levels of cumulative UGE were similar between the 2 groups. No clinically significant adverse events, laboratory test values, or physiological test values were observed in any subject. Conclusions Moderate hepatic impairment increased Cmax and AUCinf of tofogliflozin by 47% and 70%, respectively. This increase in tofogliflozin exposure did not increase UGE in hepatically impaired subjects. A single oral dose of 40 mg tofogliflozin was well tolerated, supporting dose adjustment is unnecessary even in moderately hepatically impaired subjects.

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