982. Effect of Hepatic Impairment on the Safety and Pharmacokinetics of Rezafungin

Abstract Background Rezafungin (RZF) is a novel echinocandin antifungal being developed for treatment of candidemia and invasive candidiasis, and for prevention of invasive fungal diseases among immunosuppressed patients. In the Phase 2 and Phase 3 treatment trials of rezafungin compared with caspofungin (STRIVE [NCT02734862] and ReSTORE [NCT03667690], respectively), patients with severe hepatic impairment (HI) were not included due to lack of caspofungin data in this population. Rezafungin was previously evaluated in patients with moderate hepatic impairment. Here we report an open-label, single-dose study on rezafungin in patients with HI (Child-Pugh class C). Methods To investigate the safety, tolerability, and pharmacokinetics (PK) of RZF in subjects with HI and healthy subjects (HS), 8 subjects with HI and 8 HS matched for age, sex, and body mass index (BMI) were enrolled and received a single 400-mg intravenous 1-hour infusion of RZF. Plasma PK sampling was performed at various time points through 336 hours postdose. RZF PK parameters were derived using non-compartmental analysis. Safety was assessed throughout the study. Results The majority of the HI subjects were White (87.5%) and male (75%) while equal distribution between White and Black or African American was observed among HS (50%) and 75% were male. The mean age of HI subjects was 58 years (range, 41–68 years) and 56.6 years (range, 50–61 years) for the HS. Mean BMI was 29.7 kg/m2 (range, 24.5–34.3 kg/m2) for HI subjects and 29.7 kg/m2 (range, 25.4–34.2 kg/m2) for the HS. RZF exposure (Cmax and AUC) in subjects with HI was ~30% lower than that in HS (Table 1), while half-life was generally similar (HI: 121 h, HS:124 h; Figure 1). Three HI subjects had one adverse event (AE) each (bronchitis, worsening hepatic encephalopathy, hyponatremia), all moderate in severity; one HS had 1 AE of infusion site infiltration mild in severity. No AEs were considered related to RZF, and all were resolved or resolving by the end of the study. Table 1. Plasma Rezafungin PK Parameter Estimates in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400 mg IV Infusion of Rezafungin Figure 1. Mean (+SD) Plasma Rezafungin Concentration-Time Profiles in Subjects with Severe Hepatic Impairment or Normal Hepatic Function After a Single 400-mg IV Infusion of Rezafungin (Semi-Logarithmic Scale) Conclusion RZF was well tolerated in HI subjects and showed modestly reduced exposure that was within the range observed in matched HS. These findings support no RZF dose adjustment in subjects with severe hepatic impairment. Disclosures Voon Ong, PhD, Cidara Therapeutics (Employee, Shareholder) Taylor Sandison, MD, MPH, Cidara Therapeutics (Employee, Shareholder) Rebeca M. Melara, M.S., Altasciences (contract research organization) (Employee) Thomas C. Marbury, MD, Orlando Clinical Research Center (Employee, Other Financial or Material Support, Equity owner of Orlando Clinical Research Center) Alena Jandourek, MD, Cidara therapeutics (Consultant) Shawn Flanagan, PhD, Cidara Therapeutics (Employee, Shareholder)

Download Full-text

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

Clinical and Experimental Nephrology ◽

10.1007/s10157-019-01816-4 ◽

2019 ◽

Vol 24 (S1) ◽

pp. 25-35 ◽

Cited By ~ 1

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.

Download Full-text

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

Download Full-text

A Study to Evaluate Pharmacokinetics (PK) and Safety of Oral TAK-788 in Participants With Moderate or Severe Hepatic Impairment (HI) and Normal Hepatic Function

Case Medical Research ◽

10.31525/ct1-nct04056468 ◽

2019 ◽

Author(s):

Keyword(s):

Hepatic Impairment ◽

Hepatic Function ◽

Severe Hepatic Impairment ◽

Normal Hepatic Function

Download Full-text

Pharmacokinetics of Fosamprenavir plus Ritonavir in Human Immunodeficiency Virus Type 1-Infected Adult Subjects with Hepatic Impairment

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00632-09 ◽

2009 ◽

Vol 53 (12) ◽

pp. 5185-5196 ◽

Cited By ~ 13

Author(s):

María J. Pérez-Elías ◽

María Larrousse Morellon ◽

Enrique Ortega ◽

José Hernández-Quero ◽

Maribel Rodríguez-Torres ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Hepatic Impairment ◽

Hepatic Function ◽

Lower Plasma ◽

Severe Hepatic Impairment ◽

Once Daily ◽

Dosing Interval ◽

Normal Hepatic Function ◽

Immunodeficiency Virus

ABSTRACT The effect of hepatic impairment on fosamprenavir/ritonavir pharmacokinetics was investigated. Sixty human immunodeficiency virus type 1-infected subjects, including 13, 20, and 10 subjects with mild, moderate, and severe hepatic impairment, respectively, and a comparator group of 17 subjects with normal hepatic function, were enrolled. Subjects with normal hepatic function received fosamprenavir at 700 mg plus ritonavir at 100 mg twice daily, whereas subjects with hepatic impairment received adjusted doses in anticipation of increased exposures. For subjects with mild hepatic impairment, the studied regimen of fosamprenavir 700 mg twice daily plus ritonavir 100 mg once daily delivered 17% higher values for the maximum plasma amprenavir concentration at the steady state (C max), 22% higher values for the area under the plasma concentration versus time curve over the dosing interval at the steady state [AUC(0- τ)], similar values for the concentration at the end of the dosing interval (C τ), and 114% higher unbound C τ values. For subjects with moderate hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 27% lower plasma amprenavir C max values, 27% lower AUC(0-24) values, 57% lower C τ values, and 21% higher unbound amprenavir C τ values. For subjects with severe hepatic impairment, the studied dosage regimen of fosamprenavir at 300 mg twice daily plus ritonavir at 100 mg once daily delivered 19% lower plasma amprenavir C max values, 23% lower AUC(0-24) values, 38% lower C τ values, and similar unbound amprenavir C τ values. With a reduced ritonavir dosing frequency of 100 mg once daily, the plasma ritonavir AUC(0-24) values were 39% lower, similar, and 40% higher for subjects with mild, moderate, and severe hepatic impairment, respectively. The results of the study support the use of reduced fosamprenavir/ritonavir doses or dosing frequencies in the treatment of patients with hepatic impairment. No significant safety issues were identified; however, plasma amprenavir and ritonavir exposures were more variable in subjects with hepatic impairment, and those patients should be closely monitored for safety and virologic response.

Download Full-text

A Study of Apalutamide in Participants With Severe Hepatic Impairment Compared With Participants With Normal Hepatic Function

Case Medical Research ◽

10.31525/ct1-nct04154774 ◽

2019 ◽

Author(s):

Keyword(s):

Hepatic Impairment ◽

Hepatic Function ◽

Severe Hepatic Impairment ◽

Normal Hepatic Function

Download Full-text

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]

Download Full-text