micafungin and Chemical-and-Drug-Induced-Liver-Injury

Topics: Chemical and Drug Induced Liver Injury; Databases, Factual; Drug Labeling; Humans; Pharmaceutical Preparations; Risk

Micafungin was commercialized in Japan in 2002 and has been used in more than 750,000 patients. As a member of the candin family, the drug's clinical and analytical tolerability is very good, both in adults and in children, including neonates. In this latter population, micafungin is the most frequently used candin. The most common adverse effects are nausea and elevated transaminase levels. Preclinical studies showed the development of benign liver tumors in rats treated with extremely high doses of the drug for prolonged periods. These data were not reproduced in other species and no cases have been reported in humans.

Topics: Adult; Animals; Antifungal Agents; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Echinocandins; Female; Gastrointestinal Diseases; Hepatocytes; Humans; Infant, Newborn; Lipopeptides; Liver Function Tests; Liver Neoplasms, Experimental; Male; Meta-Analysis as Topic; Micafungin; Mice; Multicenter Studies as Topic; Mycoses; Rabbits; Rats; Species Specificity

Antifungal prophylaxis is the first option to fight against fungal infection in high-risk hematological patients (remission of induction of acute myeloblastic leukemia/myelodysplastic syndrome, allogeneic hematopoietic stem cell transplantation). Fluconazole prophylaxis is not effective in preventing infection with moulds, mainly invasive aspergillosis, and consequently the triazole currently recommended in high-risk hematological patients is posaconazole. Nevertheless, given that posaconazole can only be administered orally, alternative prophylaxis may be required. Antifungal prophylaxis with micafungin is an attractive option. At a dose of 50 mg/day (1 mg/kg if weight is ≤ 40 kg) micafungin is approved for the prophylaxis of candidiasis in hematopoietic stem cell transplant recipients. Higher doses have been evaluated in adults (100 mg/day, 150 mg/day) and in children (3 mg/kg/day) with good efficacy and safety. Because of this agent's spectrum of activity, which includes both Candida and Aspergillus, together with its favorable pharmacokinetic profile regarding to the absence of significant drug interactions, this agent is appropriate in hematopoietic stem cell transplant recipients and in hematological patients following therapeutic protocols with vinca alkaloids. The optimal and most cost-effective dose for prophylaxis, as well as alternative regimens to daily intravenous administration, which would allow the use of this drug beyond conventional hospitalization (day care hospital, domiciliary transplantation therapy), remain to be determined.

Topics: Adult; Ambulatory Care; Antifungal Agents; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Dose-Response Relationship, Drug; Echinocandins; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Kidney Diseases; Lipopeptides; Male; Meta-Analysis as Topic; Micafungin; Mycoses; Postoperative Complications; Practice Guidelines as Topic; Triazoles

This study was conducted as a prospective, multicenter trial to evaluate the efficacy and safety of micafungin as an empirical therapy for suspected invasive fungal infections (IFIs), including febrile neutropenia (FN), and to evaluate the usefulness of β-D: -glucan (BG) and Aspergillus galactomannan (GM) antigen in patients with hematologic diseases. A total of 121 patients were enrolled and assessed for safety, and 119 were examined for clinical efficacy. The main underlying diseases were acute myeloid leukemia (38.0%), acute lymphoblastic leukemia (18.2%), and malignant lymphoma (18.2%). The median initial daily dose and duration of micafungin treatment were 150 mg/day and 13 days, respectively. The overall response rate for suspected IFIs (n = 119), based on four composite endpoints, including baseline IFI, breakthrough IFIs (proven and probable), survival, and premature discontinuation, was 79.0%. In addition, the response rate for FN (n = 81), based on these four endpoints as well as defervescence during neutropenia, was 39.5%. Breakthrough IFIs (proven, probable, and possible) occurred in five patients during micafungin treatment. All of these patients were positive for either BG or GM before the breakthrough IFIs. The incidence of adverse events (AEs) associated with micafungin was 10.7% and most were mild. The majority of AEs were liver dysfunction. These results indicate the effectiveness and safety of micafungin as an empirical therapy for suspected IFIs, including FN, and the usefulness of monitoring both BG and GM to detect breakthrough IFIs.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antifungal Agents; Antigens, Bacterial; Aspergillosis; beta-Glucans; Candidiasis, Invasive; Chemical and Drug Induced Liver Injury; Early Diagnosis; Echinocandins; Female; Galactose; Hematologic Neoplasms; Humans; Leukemia, Myeloid, Acute; Lipopeptides; Lymphoma; Male; Mannans; Micafungin; Middle Aged; Mycoses; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Young Adult

Disseminated fungal infection is a major cause of morbidity and mortality in children undergoing hematopoietic stem cell transplantation (HSCT). Prophylaxis with amphotericin B can be limited by renal toxicity. Oral triazoles can be limited by poor absorption, large interindividual pharmacokinetic (PK) variability, and hepatic toxicity, leading to interruptions in therapy and breakthrough infections. Intravenous (i.v.) micafungin has potential advantages, because of its better safety profile, specifically in terms of hepatic and renal toxicity, and lack of drug-drug interactions with common medications used in the HSCT setting. We hypothesized that higher dose micafungin (3 mg/kg) every other day will provide drug exposure similar to standard dosing (1 mg/kg) given daily, and improve patient compliance in very young children in whom oral medications can be challenging, at reduced administration costs. Both animal and adult patient data support the use of this approach. Fifteen children (M/F = 11/4, aged < or =10 years; mean: 3.9 years, range: 0.6-10 years) with various hematologic, metabolic, and immune deficiency disorders undergoing HSCT received a single dose of micafungin (3 mg/kg) i.v. over 1 hour. Dose selection was based on published PK data in pediatric patients, and exploration of different dosing regimens using Monte Carlo PK/PD simulation. Blood samples were drawn around this dose and PK analysis was conducted using standard noncompartmental methods. Micafungin at 3 mg/kg dose was well tolerated in all patients. Measurable plasma concentrations were present in all cases at 48 hours. Half-life and clearance observed were comparable to previous pediatric PK data, with clearance being higher than adults as expected. Volume of distribution was higher in our patients compared to published pediatric data, likely because of a larger proportion of very young children in our study cohort. After correction for protein binding, concentrations at the end of the dosing interval during maintenance treatment remain above the minimum inhibitory concentration (MIC) of highly susceptible fungal pathogens. These data suggest that alternate day micafungin dosing, as described here, may provide an attractive alternative for antifungal prophylaxis in HSCT patients and merits further evaluation.

Topics: Antifungal Agents; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Drug Administration Schedule; Echinocandins; Female; Half-Life; Hematopoietic Stem Cell Transplantation; Humans; Hypocalcemia; Hypokalemia; Infant; Lipopeptides; Male; Micafungin; Microbial Sensitivity Tests; Mycoses; Postoperative Complications; Premedication; Prospective Studies

Topics: Chemical and Drug Induced Liver Injury; Humans; Micafungin; Risk Factors

Topics: Chemical and Drug Induced Liver Injury; Humans; Micafungin; Risk Factors

Topics: Algorithms; Antifungal Agents; Chemical and Drug Induced Liver Injury; Duration of Therapy; Female; Humans; Liver Function Tests; Micafungin; Middle Aged; Retrospective Studies

Although echinocandins are generally well tolerated, there is little information on the frequency with which renal and hepatic adverse effects occur during use of micafungin or other parenteral antifungal (PAF) agents in clinical practice.. MYCOS is a multicentre cohort study of adult and paediatric patients who received micafungin or other PAFs between 2005 and 2012 at seven tertiary care hospitals from six centres in the USA. PAF cohort controls were selected through propensity score (PS) matching to micafungin recipients using clinical characteristics, other treatments, procedures and hospital service where PAF treatment was initiated. Analysis was restricted to patients without chronic liver and kidney conditions at the time of cohort entry. Treatment-emergent hepatic and renal injury was documented by changes in liver enzymes or estimated glomerular filtration rate through 30 days following completion of PAF treatment. Comparisons were quantified using the HR from a proportional hazards analysis.. There were 2970 micafungin recipients PS matched to 6726 recipients of comparator PAFs. Balance was achieved in all baseline covariates between treatment groups. There were similar rates of hepatic injury (micafungin, 13 events per 100 patients and other PAF, 12 per 100; HR = 0.99; 95% CI 0.86-1.14) and lower rates of renal injury (micafungin, 63 events per 100 patients and other PAF, 65 per 100; HR = 0.93; 95% CI 0.87-0.99) for micafungin recipients versus PAF comparators.. For a wide spectrum of underlying conditions, we observed no increase in liver injury by micafungin and possibly a reduced risk of renal dysfunction in comparison with other PAF medications.

Topics: Acute Kidney Injury; Adult; Antifungal Agents; Chemical and Drug Induced Liver Injury; Cohort Studies; Echinocandins; Electronic Health Records; Female; Hospitalization; Humans; Infusions, Parenteral; Lipopeptides; Male; Micafungin; Mycoses; Proportional Hazards Models; Risk Factors; Tertiary Care Centers; United States

This study was conducted as a retrospective, observational, exploratory cohort study with the aim of elucidating the safety profile of micafungin at doses exceeding 150 mg daily. We identified adult patients with hematological diseases who had received micafungin therapy for ≥ 7 consecutive days. Twenty-six patients administered micafungin at 300 mg daily (high-dose group) were compared with 58 patients administered micafungin at 150 mg daily (standard-dose group). The most frequent adverse events (AEs) were hepatotoxicity, hypertension and diarrhea. AEs were recorded in 42 (72%) and 19 (73%) patients in the standard-dose and high-dose groups, respectively (p = 1.00). Hepatobiliary AEs were noted in 28 (48%) and 15 (58%) patients, respectively (p = 0.48). Serious AEs and resultant treatment discontinuation were infrequent. Our results suggest that micafungin was safe and well tolerated at 300 mg daily.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Chemical and Drug Induced Liver Injury; Diarrhea; Dose-Response Relationship, Drug; Echinocandins; Female; Hematologic Diseases; Humans; Hypertension; Lipopeptides; Male; Micafungin; Middle Aged; Mycoses; Retrospective Studies; Treatment Outcome; Young Adult

Optical spectrophotometric methods are used to detect both plasma-free hemoglobin and antifactor Xa level, so hyperbilirubinemia can interfere with the measurement of both the monitoring laboratory tests for extracorporeal membrane oxygenation (ECMO) due to similar absorbance wavelengths. We present a seven-year-old child with acute respiratory failure on venovenous ECMO who developed an acute increase in plasma-free hemoglobin and undetectable antifactor Xa level due to acute hyperbilirubinemia from hepatic dysfunction related to antifungal therapy.

Topics: Antifungal Agents; Chemical and Drug Induced Liver Injury; Child; Echinocandins; Extracorporeal Membrane Oxygenation; Factor Xa Inhibitors; Hemoglobins; Humans; Hyperbilirubinemia; Lipopeptides; Lung Diseases, Interstitial; Male; Micafungin; Spectrophotometry

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Aspergillosis has been the prevailing deep-seated mycosis in Japan since the 1990s. Although micafungin (MCFG) has been approved in Japan for the management of patients with such infections caused by Candida and Aspergillus species, there are relatively few reports on its use in patients with chronic pulmonary aspergillosis (CPA). Therefore, we conducted a prospective observational study to evaluate the efficacy and safety of the use of MCFG in Japanese patients with CPA. The efficacy of the antifungal was assessed on the basis of improvements in clinical symptoms and radiological findings. In addition, adverse events, including abnormal laboratory findings were determined. The overall clinical efficacy rate was 68.4% (26/38 patients), which is comparable to the results obtained in clinical trials for marketing approval conducted in Japan. Although adverse drug reactions were observed in six patients (15.8%), they were not serious. The most common of these reactions was abnormal liver functions. No relationship between the incidence of adverse drug reactions and age of the patients, MCFG dose, or duration of treatment was observed. Consequently, MCFG has favorable efficacy and safety profiles in Japanese CPA patients with various backgrounds.

Topics: Adult; Aged; Aged, 80 and over; Antifungal Agents; Chemical and Drug Induced Liver Injury; Chronic Disease; Echinocandins; Female; Humans; Japan; Lipopeptides; Male; Micafungin; Middle Aged; Prospective Studies; Pulmonary Aspergillosis; Treatment Outcome

Drug-induced liver injury is one of the main causes of drug attrition. The ability to predict the liver effects of drug candidates from their chemical structures is critical to help guide experimental drug discovery projects toward safer medicines. In this study, we have compiled a data set of 951 compounds reported to produce a wide range of effects in the liver in different species, comprising humans, rodents, and nonrodents. The liver effects for this data set were obtained as assertional metadata, generated from MEDLINE abstracts using a unique combination of lexical and linguistic methods and ontological rules. We have analyzed this data set using conventional cheminformatics approaches and addressed several questions pertaining to cross-species concordance of liver effects, chemical determinants of liver effects in humans, and the prediction of whether a given compound is likely to cause a liver effect in humans. We found that the concordance of liver effects was relatively low (ca. 39-44%) between different species, raising the possibility that species specificity could depend on specific features of chemical structure. Compounds were clustered by their chemical similarity, and similar compounds were examined for the expected similarity of their species-dependent liver effect profiles. In most cases, similar profiles were observed for members of the same cluster, but some compounds appeared as outliers. The outliers were the subject of focused assertion regeneration from MEDLINE as well as other data sources. In some cases, additional biological assertions were identified, which were in line with expectations based on compounds' chemical similarities. The assertions were further converted to binary annotations of underlying chemicals (i.e., liver effect vs no liver effect), and binary quantitative structure-activity relationship (QSAR) models were generated to predict whether a compound would be expected to produce liver effects in humans. Despite the apparent heterogeneity of data, models have shown good predictive power assessed by external 5-fold cross-validation procedures. The external predictive power of binary QSAR models was further confirmed by their application to compounds that were retrieved or studied after the model was developed. To the best of our knowledge, this is the first study for chemical toxicity prediction that applied QSAR modeling and other cheminformatics techniques to observational data generated by the means of automate

Topics: Animals; Chemical and Drug Induced Liver Injury; Cluster Analysis; Databases, Factual; Humans; MEDLINE; Mice; Models, Chemical; Molecular Conformation; Quantitative Structure-Activity Relationship

Micafungin is an echinocandin-class antifungal agent licensed for treatment of invasive disease in adults. The optimal dosing regimens have not been established for infants. We describe a premature infant who developed hepatitis and cholestasis during micafungin therapy initiated for protracted candidemia. Practitioners should be aware of this potential adverse effect if using micafungin in young patients.

Topics: AIDS-Related Opportunistic Infections; Alanine Transaminase; Amphotericin B; Antifungal Agents; Aspartate Aminotransferases; Candidiasis; Chemical and Drug Induced Liver Injury; Cholestasis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Echinocandins; Female; Fungemia; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Lipopeptides; Liver Function Tests; Micafungin