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

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

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2568-2568 ◽  
Author(s):  
Nagdeep Giri ◽  
Anna Plotka ◽  
Yali Liang ◽  
Tanya Boutros ◽  
Grace Ni ◽  
...  
Keyword(s):  
Liver Function ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Hepatic Impairment ◽  
Hepatic Function ◽  
Moderate Hepatic Impairment ◽  
Open Label ◽  
Post Dose ◽  
Normal Hepatic Function ◽  
Mild Impairment

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]

scholarly journals Pharmacokinetics and safety of rucaparib in patients with advanced solid tumors and hepatic impairment

2021 ◽  
Author(s):  
Nikolay Grechko ◽  
Viera Skarbova ◽  
Monika Tomaszewska-Kiecana ◽  
Rodryg Ramlau ◽  
Piotr Centkowski ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Hepatic Impairment ◽  
Geometric Mean ◽  
Hepatic Function ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Moderate Hepatic Impairment ◽  
Advanced Solid Tumors ◽  
Castration Resistant Prostate Cancer ◽  
Normal Hepatic Function

Abstract Purpose The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors. Methods Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg. Concentrations of rucaparib and its metabolite M324 in plasma and urine were measured. Pharmacokinetic parameters were compared between hepatic function groups, and safety and tolerability were assessed. Results Sixteen patients were enrolled (n = 8 per group). Rucaparib maximum concentration (Cmax) was similar, while the area under the concentration–time curve from time 0 to infinity (AUC0–inf) was mildly higher in the moderate hepatic impairment group than in the normal control group (geometric mean ratio, 1.446 [90% CI 0.668–3.131]); similar trends were observed for M324. Eight (50%) patients experienced ≥ 1 treatment-emergent adverse event (TEAE); 2 had normal hepatic function and 6 had moderate hepatic impairment. Conclusion Patients with moderate hepatic impairment showed mildly increased AUC0–inf for rucaparib compared to patients with normal hepatic function. Although more patients with moderate hepatic impairment experienced TEAEs, only 2 TEAEs were considered treatment related. These results suggest no starting dose adjustment is necessary for patients with moderate hepatic impairment; however, close safety monitoring is warranted.

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

Liver Cancer ◽  
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

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> 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 (<i>n</i> = 123), patients with mild impairment (<i>n</i> = 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 (<i>n</i> = 27) had a GMR of 0.88. Patients in Asia ([<i>n</i> = 162] vs. outside [<i>n</i> = 161]) had a GMR of 1.25 for cycle 1 atezolizumab AUC. Compared with GO30140 patients who had normal hepatic function (NCI-ODWG [<i>n</i> = 61]), patients with mild impairment (<i>n</i> = 92) had a GMR of 0.97 for cycle 1 peak bevacizumab concentrations; those with moderate impairment (<i>n</i> = 9) had a GMR of 0.94. Patients in Asia (<i>n</i> = 111) versus outside Asia (<i>n</i> = 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. <b><i>Conclusions:</i></b> 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.

scholarly journals Dotinurad: a clinical pharmacokinetic study of a novel, selective urate reabsorption inhibitor in subjects with hepatic impairment

2019 ◽  
Vol 24 (S1) ◽  
pp. 25-35 ◽  
Author(s):  
Yuji Kumagai ◽  
Masashi Sakaki ◽  
Kenichi Furihata ◽  
Takayoshi Ito ◽  
Kazuaki Inoue ◽  
...  
Keyword(s):  
Uric Acid ◽  
Serum Uric Acid ◽  
Hepatic Impairment ◽  
Hepatic Function ◽  
Moderate Hepatic Impairment ◽  
Severe Hepatic Impairment ◽  
Single Dose Study ◽  
Normal Hepatic Function ◽  
Function Group ◽  
Urate Reabsorption

Abstract Background Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1 (URAT1). We compared the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with hepatic impairment and normal hepatic function. Methods This was a multicenter, open-label, single dose study. A total of 24 subjects were divided into four groups: the normal hepatic function group and the mild, moderate, and severe hepatic impairment groups. The primary endpoints were changes in plasma dotinurad levels and PK parameters. Results The geometric mean ratio of the maximum plasma concentration (Cmax) [two-sided 90% confidence interval (CI)] of dotinurad in in the mild, moderate, and severe hepatic impairment groups relative to that in the normal hepatic function group was 0.840 (0.674–1.047), 0.798 (0.653–0.976), and 0.747 (0.570–0.979), respectively, showing a lower Cmax in the moderate and severe hepatic impairment groups. Following adjustment for body weight, only the moderate hepatic impairment group had a lower Cmax than the normal hepatic function group. No meaningful differences in other PK parameters were observed between the groups. Regarding the PD of dotinurad, the changes in serum uric acid levels after dosing were similar in all groups. As for safety, no noteworthy concerns were raised in relation to any group. Conclusion The study revealed no clinically meaningful influence of hepatic impairment on the PK, PD, or safety of dotinurad. These findings indicate possibility that dotinurad can be used without dose adjustment in patients with hepatic impairment.

Pharmacokinetics of Nilotinib in Subjects with Normal or Impaired Hepatic Function.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2379-2379 ◽  
Author(s):  
Jaymes Holland ◽  
Chiaki Tanaka ◽  
Wei Zhou ◽  
Venkat Sethuraman ◽  
Douglas M. Heuman ◽  
...  
Keyword(s):  
Back Pain ◽  
Adverse Events ◽  
Serum Concentration ◽  
Hepatic Impairment ◽  
Hepatic Function ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Moderate Hepatic Impairment ◽  
Serum Samples ◽  
Normal Hepatic Function

Abstract Nilotinib, a selective and potent inhibitor of Bcr-Abl tyrosine kinase, has demonstrated activity at 400 mg twice daily dosing against imatinib-resistant forms of Bcr-Abl in patients with CML or Ph+ALL in an open label phase I/II study. In this patient population, elevated liver transaminases levels over baseline, which may be related to a combination of past medical history and the hepatotoxic effects of previous medications, are frequently observed but are generally mild and self-limiting. Nilotinib is metabolized in the liver by CYP3A4, and the metabolites are excreted exclusively via the bile into feces. This study was designed to assess pharmacokinetics of nilotinib across a broad spectrum of hepatic impairment in comparison to a control group with normal hepatic function in order to provide guidance for the safe use of the drug in patients with hepatic impairment. Hepatic impairment was categorized using the three Child-Pugh categories (mild, moderate, and severe). The demographics of the impaired and control group were similar with respect to ethnicity, age (years) impaired (47–64) control (48–62), BMI (kg/m2) impaired (23.6–34.7) control (22.8–32.0), and weight (kg) impaired (73.9–103.9) control (73.3–109.5). Serum samples for determination of nilotinib serum concentration by liquid chromatography tandem mass spectrometry were collected up to 120 hours following a single oral 200 mg dose of nilotinib after an overnight fast. Pharmacokinetic parameters were derived from the individual serum concentration-time data by non-compartmental methods. Pre-dose (nilotinib-free) serum samples were obtained to determine ex vivo nilotinib serum protein binding. The results from 14 subjects (6 subjects in each of the mildly and moderately impaired groups and 8 in the control group) in this ongoing study are reported here. Nilotinib exposure at 200 mg dose was similar in patients from a previous clinical study and subjects in the control group of this study. Nilotinib AUC was increased on average by 18% in the mild impairment group, and 23% in the moderate impairment group as compared to the control group. A total of 6 grade 1 and 2 adverse events were reported comprising of back pain, worsening abdominal pain, headache, nausea, heart burn, and indigestion. One adverse event (grade 2 worsening back pain) was reported in the control group. No laboratory or cardiac monitoring findings were considered as adverse events during the treatment period. The currently available results suggest that the pharmacokinetic profile of nilotinib is comparable between subjects with normal hepatic function and subjects with mild or moderate hepatic impairment.

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

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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