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

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)

Case Report: Fatal Viscerotropic Disease in a Young Woman Following Yellow Fever Vaccination

Yellow fever is a viral hemorrhagic disease, and vaccination is the most effective way to minimize the impact of the disease. Serious adverse events after yellow fever vaccination are rare. We report the case of a young woman with an unusual presentation of yellow fever 17DD vaccine-associated acute viscerotropic disease, with severe hepatic impairment following a long incubation period. She died more than a month after yellow fever vaccination.

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

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.

A Physiologically Based Pharmacokinetic Analysis To Predict the Pharmacokinetics of Intravenous Isavuconazole in Patients with or without Hepatic Impairment

ABSTRACT Isavuconazole (ISA) is an azole antifungal used in the treatment of invasive aspergillosis and mucormycosis. Patients with mild or moderate hepatic impairment have lower clearance (CL) than the healthy population. Currently, there are no data on ISA in patients with severe hepatic impairment (Child-Pugh class C). The purposes of this study were to build a physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics (PK) of intravenous ISA and to predict changes in ISA disposition in different patient populations and in patients with hepatic impairment so as to guide personalized dosing. By incorporating the systemic and drug-specific parameters of ISA, the model was initially developed in a healthy population and was validated with 10 independent PK profiles obtained from healthy subjects and from patients with normal liver function. The results showed satisfactory predictive capacity; most of the relative predictive errors were within ±30% for the area under the concentration-time curve (AUC) and the maximum concentration of the drug in serum (Cmax). The observed concentration-time profiles of ISA in plasma were well described by the model-predicted profiles. The model adequately predicted the reduced CL of ISA in patients with mild or moderate hepatic impairment. Furthermore, the model predicted a decrease in CL of about 60% in patients with severe hepatic impairment. Therefore, we recommend reducing the dose by 50% in patients with severe hepatic impairment. The model also predicted differences in the PK of ISA between Caucasian and Asian populations, with a Chinese/Caucasian CL ratio of 0.67. The PBPK model of ISA that was developed provides a reasonable approach for optimizing the dosage regimen in different ethnic populations and in patients with severe hepatic impairment.

An Open-Label Study of the Impact of Hepatic Impairment on the Pharmacokinetics and Safety of Single Oral and Intravenous Doses of Omadacycline

ABSTRACT Omadacycline is a once-daily oral or intravenous (i.v.) aminomethylcycline antibiotic approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline pharmacokinetics were characterized in 18 patients with hepatic impairment and 12 matched healthy subjects. Patients with hepatic impairment received i.v. omadacycline at 100 mg (mild hepatic impairment) or 50 mg (moderate and severe hepatic impairment) and oral omadacycline at 300 mg (mild hepatic impairment) or 150 mg (moderate hepatic impairment); oral omadacycline was not evaluated in those with severe hepatic impairment. Safety monitoring included the collection of adverse events (AEs), performance of laboratory tests, determination of vital signs, and performance of electrocardiograms. Omadacycline exposures were similar in patients with hepatic impairment and healthy subjects following i.v. or oral administration, with the geometric mean ratios for the area under the concentration-time curve and the maximum drug concentration ranging from 0.79 to 1.42. Omadacycline was safe and well tolerated. Overall, 13/30 (43.3%) participants experienced an AE; those occurring in more than 1 participant included headache (13.3%), nausea (6.7%), infusion-site pain (6.7%), contusion (6.7%), and dizziness (6.7%), with no differences based on the degree of hepatic impairment or the route of administration. Asymptomatic increases in heart rate were observed; none was considered an AE. These findings suggest that no omadacycline dose adjustment is warranted in patients with hepatic impairment.

A Review of Newly Approved Antibiotic Treatment for Community-Acquired Bacterial Pneumonia: Lefamulin

Lefamulin is a novel systemic, semi-synthetic pleuromutilin class of antimicrobials that has been shown to be effective against common respiratory pathogens associated with community-acquired bacterial pneumonia (CABP). CABP, a common infection among older people, leads to an increase in hospitalizations and mortality. Therefore, the use of lefamulin could be beneficial for CABP treatment in patients who are 65 years of age or older.<br/> The Food and Drug Administration (FDA) approved lefamulin for the treatment of CABP, which is available in both intravenous and oral formulations. This medication offers the benefit of not having any cross-resistance to other antibiotics and is highly concentrated in lung tissues. Lefamulin is unique because it has an induced-fit mechanism of action which inhibits bacterial protein synthesis. The clinical efficacy of lefamulin has demonstrated noninferiority to current standard-of-care for CABP, and patients, generally, have tolerated it well in clinical trials.<br/> Lefamulin does not require dosage adjustment in renal impairment. However, the drug does requires dosage adjustment in severe hepatic impairment, based on Child-Pugh scores and clinical consideration in patients with severe hepatic impairment based on Child-Pugh scores. Though the benefit of adding lefamulin to a formulary is still in question; its potential to be a beneficial treatment for CABP is encouraging.