Exploring Indicators of Hepatotoxicity-Related Post-Marketing Regulatory Actions: A Retrospective Analysis of Drug Approval Data

<b><i>Background:</i></b> Hepatotoxicity is a major reason for medication withdrawal from the markets. Unfortunately, serious adverse hepatic effects can occur after marketing with limited indicators during clinical development. Therefore, finding possible predictors for hepatotoxicity might guide the monitoring program of various stakeholders such as drug regulatory authorities. <b><i>Objective:</i></b> To explore the potential of drugs, pre-approval regulatory factors as predictors for the occurrence of hepatotoxicity-related post-marketing regulatory actions. Pre-approval factors were specified as: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. <b><i>Methods:</i></b> Using publicly accessible FDA data, we examined clinical review documents for drugs approved in the USA during the period from 2011 to 2016 to evaluate their hepatic safety profile, identifying the 3 specified indicators for analysis. <b><i>Predictors (Covariates):</i></b> We assessed whether these medications meet: (a) Hy’s Law hepatotoxicity grade ≥3, (b) accelerated approval status, and (c) labeled hepatic adverse effects and regulatory actions at approval. <b><i>Outcome (Dependent Variable):</i></b> Post-marketing regulatory action related to hepatotoxicity including products withdrawal and updates to either warning, precaution or adverse effects sections. <b><i>Statistical Analysis:</i></b> Drugs that were approved between 2011 and 2016 were included in the analysis with follow-up time from the date of approval until end of December 2019 or the date of first post-marketing regulatory action related to hepatotoxicity, whichever occurred first. The hazard ratio (HR) was estimated using Cox-regression analysis. <b><i>Results:</i></b> A total of 192 medications were included in the study. We classified 48 drugs with grade ≥3 hepatotoxicity, 43 with accelerated approval status, and 74 with labeled information about hepatotoxicity prior to marketing. The adjusted HRs for post-marketing regulatory action for products with grade ≥3 hepatotoxicity was 0.61 (95% confidence interval [CI], 0.17–2.23), 0.92 (95% CI, 0.29–2.93) for drug approved via accelerated approval program, and 0.91 (95% CI, 0.33–2.56) for drugs with labeled hepatotoxicity information at approval time. <b><i>Conclusion:</i></b> Hy’s Law with hepatotoxicity grade ≥3, accelerated approval, and label information on hepatotoxicity were not identified as predictors for post-marketing additional regulatory actions concerning liver adverse effects. However, the evidence is inconclusive due to small sample size and potential channeling bias.

P.030 Long-term Safety and Tolerability of Atogepant 60 mg Following Once-Daily Dosing Over 1 Year for the Preventive Treatment of Migraine

Background: The goal of the study was to assess the safety and tolerability of atogepant, an oral, calcitonin gene-related peptide receptor antagonist in development for migraine preventive treatment, once daily over 1 year. Methods: Multicenter, open-label trial (NCT03700320). Adults with migraine were randomized 5:2 to atogepant or oral standard-of-care (SOC) migraine prevention. Results: 744 randomized participants (n=546 atogepant), 739 safety population participants (n=543 atogepant). Adverse events (AEs) were reported by 67.0% of atogepant participants; 18.0% had AEs considered related to atogepant. AEs reported by ≥5% of atogepant-treated participants were upper respiratory tract infection (10.3%), constipation (7.2%), nausea (6.3%), and urinary tract infection (5.2%). 4.4% of atogepant participants reported serious AEs that included various, common medical conditions; no event occurred in ≥1 participant and none were atogepant-related. Two deaths were reported in atogepant-treated participants (homicide victim; toxic shock syndrome); both were considered not treatment-related. 5.7% of atogepant participants discontinued due to AEs. Alanine aminotransferase/aspartate aminotransferase levels ≥3X upper limit of normal were reported for 2.4% of atogepant participants (n=13/531) and 3.2% of SOC participants (n=6/190). No cases of potential Hy’s Law were reported. Conclusions: Once-daily use of atogepant for preventive treatment of migraine over 1 year was safe and well-tolerated with no safety concerns identified.

Hepatic safety of repeated treatment with pyronaridine-artesunate (PA) versus artemether-lumefantrine (AL) in patients with uncomplicated malaria: A secondary analysis of the WANECAM 1 data from Bobo-Dioulasso, Burkina Faso

BackgroundThe use of pyronaridine-artesunate (PA) has been associated with scarce transaminitis in patients. This analysis aimed to evaluate the hepatic safety profile of repeated treatment with PA versus artemether-lumefantrine (AL) in patients with consecutive uncomplicated malaria episodes in Bobo-Dioulasso, Burkina Faso.MethodsWe secondarily analyzed data from a clinical trial conducted from 2012 to 2015, in which patients with uncomplicated malaria were assigned to either PA or AL arms and followed up to 42 days. Subsequent malaria episodes within a 2-years follow up period were also treated with the same ACT initially allocated. Transaminases (AST/ALT), alkaline phosphatase (ALP), total and direct bilirubin were measured at days 0 (baseline), 3, 7, 28 and on some unscheduled days if required. The proportions of non-clinical hepatic adverse events (AEs) following first and repeated treatments with PA and AL were compared within study arms. The association of these AEs with retreatment in each arm was also determined using a logistic regression models.ResultsA total of 1379 malaria episodes were included in the intention to treat analysis with 60% of all cases occurring in the AL arm. Overall, 179 non-clinical hepatic AEs were recorded in the AL arm versus 145 in the PA arm. Elevated ALT was noted in 3.05% of treated malaria episodes, elevated AST 3.34%, elevated ALP 1.81%, and elevated total and direct bilirubin with 7.90% and 7.40% respectively. Retreated participants were less likely to experience elevated ALT and AST than first episode treated participants in both arms. One case of Hy’s law condition was recorded in a first treated participant of the PA arm. Patients from the retreatment group were 76% and 84% less likely to have elevated ALT and AST respectively in the AL arm and 68% less likely to present elevated ALT in the PA arm. In contrast, they were almost 2 times more likely to experience elevated total bilirubin in both arms.ConclusionPyronaridine-artesunate and artemether-lumefantrine showed similar hepatic safety when used repeatedly in patients with uncomplicated malaria. Pyronaridine-artesunate represents therefore a suitable alternative to the current first line antimalarial drugs in use in endemic areas.Trial RegistrationPan African Clinical Trials Registry. PACTR201105000286876

A simple method to identify undiagnosed drug-induced liver injury (DILI) and its application in oncology pharmacy practice

Aims To establish a simple method to identify chemotherapy-induced liver injury among oncological patients. To evaluate current clinical approach to elevated laboratory liver test results. Methods A total of 289 patients admitted to oncology department who had systemic chemotherapy episodes for cancer treatment from 1 January 2017 to 31 December 2017 were identified. With aid of healthcare information system, Hy's law was applied to laboratory liver test results to identify potential hepatocellular drug-induced liver injury cases. Medical record review was carried out among identified patients to exclude liver dysfunction of alternative causes. Current clinical approach to elevated laboratory liver tests was evaluated through medical record review. Results Of 289 patients who were treated by systemic chemotherapies, there were 123 patients with elevated laboratory liver tests, among which 8 patients were suspected as potential Hy's law cases. After medical record review, there were two patients determined with chemotherapy-associated liver injury, caused by 5-fluorouracil, leucovorin, irinotecan, and S-1 plus paclitaxel separately. Of eight potential Hy's law cases, seven (87.5%) patients were prescribed with ≥2 kinds of liver protectants and remained treated with traditional Chinese medicine for decoction. Conclusions A reliable and simple method to identify undiagnosed drug-induced liver injury was successfully established. An annual incidence of 0.69% of chemotherapy-associated liver injury in oncology department of the setting was found.

699. Hepatobiliary Safety in Adults With Community-Acquired Bacterial Pneumonia (CABP) Treated With Lefamulin (LEF) or Moxifloxacin (MOX): Pooled Analysis of Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Study Results

Background LEF efficacy and safety were shown in 2 noninferiority trials (LEAP 1/2) vs. MOX in adults with CABP. We assessed the hepatobiliary safety of LEF based on pooled analyses of LEAP 1/2 data. Methods In LEAP 1, PORT III–V patients received LEF 150 mg IV q12h for 5–7 days or MOX 400 mg IV q24h for 7 days, with optional IV-to-oral switch (600 mg LEF q12h or 400 mg MOX q24h). In LEAP 2, PORT II–IV patients received oral LEF 600 mg q12h for 5 days or oral MOX 400mg q24h for 7 days. Exclusion criteria included infection with HBV/HCV, acute hepatitis, cirrhosis, AST or ALT >5xULN, total bilirubin >3xULN (unless Gilbert’s disease), AST or ALT >3xULN and total bilirubin >2xULN, and manifestation of end-stage liver disease. Hepatic safety was assessed from baseline (BL) and multiple post-BL blood samples using a central laboratory, TEAEs, and expert consultant adjudication. Pooled analyses included all randomized/treated patients (safety population). Results Of 1282 randomized/treated patients, 1251 had BL and post-BL hepatobiliary data (table). Post-BL distribution of ALT/AST was generally similar for both groups, although ALT >AST in the absence of muscle injury or alcohol use. Overall, rates of patients experiencing an increase in ALT/AST >3xULN, ALP >2xULN, or total bilirubin >1.5xULN were low (table). Patients with elevated vs. normal BL transaminases (TAs) were more likely to have post-BL elevations >3xULN, but the vast majority remained <5xULN. Among patients with ALT >5xULN, peak increases were generally seen in the first week after the first LEF dose and declined to within/near normal levels by late follow-up (day 28); for MOX, time to peak ALT was less consistent (figure). No LEF pt and 1 MOX pt met laboratory criteria for Hy’s Law. Elevations in TAs were reversible, with no evidence of chronic injury. The LEF injury pattern was predominantly hepatocellular (50.0%)/mixed (40.0%), with no apparent gender, age, or ethnic predominance. TEAEs in the hepatobiliary disorders system organ class were reported in 6 (0.9%) LEF patients and 6 (0.9%) MOX patients, with similar levels seen in patients with elevated BL TAs. There were no symptomatic patients, severe disease, or evidence of hypersensitivity. Conclusion Low incidences of hepatobiliary parameter elevations and TEAEs were observed, with no apparent differences between LEF and MOX. Disclosures All authors: No reported disclosures.

722. Pharmacokinetics (PK) and Safety of Lefamulin (LEF) After Single Intravenous Dose Administration in Subjects With Impaired Hepatic Function

Background Patients with chronic liver disease (CLD) have impaired immune function, are prone to community-acquired bacterial pneumonia (CABP), and experience greater morbidity/mortality and healthcare costs than CABP patients without CLD. LEF, a novel pleuromutilin antibiotic (IV/oral) with primary liver elimination, was generally well tolerated and noninferior to moxifloxacin in two phase 3 studies of adults with CABP. We investigated the PK and safety of LEF and its main metabolite, BC-8041, in subjects with hepatic impairment. Methods In this open-label study, subjects were allocated to 1 of 3 groups based on hepatic function level; Moderate (Child-Pugh score 7–9) or Severe subjects (Child-Pugh score ≥10) were matched (gender, age, and weight) to subjects in the Normal group (normal hepatic function, no liver cirrhosis). Subjects received a single 1-hour 150 mg LEF infusion. Blood and urine samples were collected predose and over a 48-hour period postdose for PK analysis; plasma and urine were assayed for LEF and BC-8041 using validated assays. Safety assessments included treatment-emergent adverse events (TEAEs), labs, vital signs, and electrocardiograms. Results 27 subjects enrolled in and completed the study (n = 11, Normal; n = 8, Moderate; n = 8, Severe). Mean LEF and BC-8041 plasma concentration profiles were comparable across all hepatic function groups through the first 12 hours following the start of infusion. Subjects with hepatic impairment had slightly slower rates of elimination in the later elimination phases. LEF and BC-8041 exposures were similar across all hepatic function groups (table), and the majority of LEF and BC-8041 were excreted nonrenally. TEAEs were reported in 2 (18.2%) subjects in the Normal group, 2 (25%) in the Moderate group, and 1 (12.5%) in the Severe group. None of the TEAEs were serious or led to study drug discontinuation. No subject met Hy’s law criteria. Within 4 hours postdose, the maximum mean change from baseline in the QTcF interval was 12.4, 19.2, and 14.1 msec in the Normal, Moderate, and Severe groups, respectively. Conclusion No dosage adjustment for LEF appears to be required when treating subjects with hepatic impairment. LEF was generally well tolerated in all subjects regardless of hepatic functional status. Disclosures All authors: No reported disclosures

Assessment of Serious Acute and Chronic Idiosyncratic Drug-Induced Liver Injury in Clinical Practice

Drug-induced liver injury (DILI) is the leading cause of acute liver failure (ALF) in developed countries. The extremely variable phenotype of DILI, both in presentation and in severity, is one of the distinctive characteristics of the disease and one of the major challenges that hepatologists face when assessing hepatotoxicity cases. A new Hy's law that more accurately predicts the risk of ALF related to DILI has been proposed and validated. Other prognostic scoring algorithms for the early identification of DILI patients who may go on to develop ALF have been developed as it is of most clinical relevance to stratify patients for closer monitoring. Recent data indicate that acute DILI often presents a more prolonged resolution or evolves into chronicity at a higher frequency than other forms of acute liver injury. Risk factors for chronicity, specific phenotypes, and histological features are discussed in this study. Biomarkers to predict DILI outcome are in need.