Safety, tolerability, and pharmacokinetics of HRS9432(A) injection in healthy Chinese subjects: a phase-I randomized, double-blind, dose escalation, placebo-controlled study.

HRS9432(A) is a long-acting echinocandin antifungal medication primarily used to treat invasive fungal infections, particularly invasive candidiasis. The safety, tolerability, and pharmacokinetic characteristics of HRS9432(A) injection were investigated in a randomized, double-blind, placebo-controlled, single- and multiple-ascending-dose Phase I study involving 56 healthy adult subjects. Doses ranging from 200 to 1200 mg were administered. Safety was continually monitored, including adverse events, clinical laboratory examinations, vital signs, 12-lead electrocardiograms, and physical examinations, while the pharmacokinetic profile within the body was evaluated. The results indicated that concentrations of HRS9432 peaked immediately after infusion, demonstrating essentially linear pharmacokinetic characteristics within the dosage range of 200-1,200 mg. It exhibited a low clearance rate and an extended half-life, with a clearance of approximately 0.2 L/h, a volume of distribution of around 40 L, and a half-life of approximately 140h following a single dose. The accumulation index for AUC0-τ after multiple doses ranged from 1.41 to 1.75. No severe adverse events occurred during the study, and the severity of all adverse events was mild or moderate. Therefore, the intravenous administration of HRS9432(A) in healthy Chinese adult subjects, either as multiple infusions of 200 to 600 mg (once a week, four doses) or as a single infusion of 900-1,200 mg, demonstrated overall good safety and tolerability. The pharmacokinetic exhibited essentially linear characteristics in the body, supporting a weekly dosing frequency for clinical applications and providing additional options for the treatment or prevention of invasive fungal infections. CLINICAL TRIALS: This study is registered with the International Clinical Trials Registry Platform as ChiCTR2300073525.

A case of immune complex type hemolytic anemia induced by initial micafungin administration.

We report the first case of immune complex type hemolytic anemia by initial micafungin administration that was given as prophylaxis to a 42-year-old Japanese man receiving chemotherapy for primary amyloidosis. The few cases found in the literature were associated with secondary administration causing immune hemolytic attacks. Despite its rarity, the present case calls for increased awareness of micafungin-induced hemolytic anemia upon initial administration.

Risk assessment of micafungin-induced liver injury using spontaneous reporting system data and electronic medical records.

INTRODUCTION: There is limited information regarding antifungal-induced liver injuries, which have high mortality rates. Therefore, we used the Japanese Adverse Drug Event Report (JADER) database for signal detection associated with antifungal-induced liver injuries and medical records for risk assessment. METHODS: Reports of antifungal-induced liver injuries from JADER data were analyzed to calculate the reporting odds ratio (ROR) and 95% confidence interval (CI). A medical record-based study involving 109 adult patients treated with micafungin shows liver injury as the primary outcome in patients treated with micafungin. The albumin-bilirubin (ALBI) score was calculated based on albumin and total bilirubin levels. We selected five explanatory factors for multivariable logistic regression: alanine aminotransferase ≥20 IU/L, alkaline phosphatase ≥372 IU/L, aspartate aminotransferase ≥25 IU/L, ALBI score ≥ -1.290, and age ≥65 years. RESULTS: Signal detection for micafungin was observed in both, hepatocellular and cholestatic injuries, as per data from JADER. Univariate analyses performed on medical records suggest that alanine aminotransferase (p = 0.008), aspartate aminotransferase (p = 0.036), alkaline phosphatase (p = 0.045), and ALBI score (p = 0.028) may be factors associated with micafungin-induced liver injury. Based on multivariable logistic regression, the adjusted odds ratio for micafungin-induced liver injury in patients with ALBI score ≥ -1.290 was 2.78 (95% CI: 1.014-7.605, p = 0.047), suggesting that low hepatic functional reserve could be a risk factor for micafungin-induced liver injury. CONCLUSIONS: Careful monitoring of liver function may be necessary for micafungin administration in patients with low hepatic functional reserve.

Biological Properties and Analytical Methods for Micafungin: A Critical Review.

Micafungin is characterized as one of the most active available drugs for candidemia treatment; however, their use is also associated in prophylaxis protocols in cases of invasive fungal infections. The use of this drug is widely appreciated in the medical field due to be the most active echinocandin available for invasive fungal infections. In order to provide important parameters related to the chemical, physical, biological and therapeutic characteristics, this review article gathers important research results that demonstrate the biological potential of this drug, as well as to present analytical methods that can be used to determine the antifungal potential and a monitoring of administered dosages. Important studies about the methods most commonly used in biological activity evaluation and determination/quantification by analytical methods are provided in this review article. With the data provided, the scientific community will have the possibility to choose the analytical methods and biological that can be employed in clinical and scientific research to provide greater safety and reliability of the results to be found.

Efficacy and safety of micafungin in empiric and D-index-guided early antifungal therapy for febrile neutropenia; A subgroup analysis of the CEDMIC trial.

OBJECTIVES: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. METHODS: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. RESULTS: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2-79.4) and 79.6% (71.0-86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2-80.9%) and 78.0% (65.3-87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. CONCLUSIONS: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT.

Use of micafungin as antifungal prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Spain (GETH-MIC) / Profilaxis antifúngica con micafungina en pacientes que reciben un trasplante alogénico de progenitores hematopoyéticos (alo-TPH) en España (GETH-MIC)

INTRODUCTION: The fungal infections remain an important problem in the allogeneic stem cell trasnsplantation (allo-SCT) setting and thus, anti-fungal prophylaxis is commonly used. The antifungal drug should offer activity, at least against Candida and Aspergillus spp., a good safety profile and low probability interactions. Micafungin could theoretically fulfill these requisites. The aim of the study was to describe the experience with micafungin as primary prophylaxis in patients undergoing allo-SCT in a cohort of Spanish centres, and to evaluate its efficacy and tolerability in this population. MATERIAL AND METHODS: Retrospective multicentre observational study including all consecutive adult patients admitted for allo-SCT in participating centres of the Grupo Español de Trasplante Hematopoyético (GETH), from January 2010 to December 2013, who received micafungin as primary prophylaxis during the neutropenic period. RESULTS: A total of 240 patients from 13 centres were identified and 159 patients were included for the analysis. Most patients (95.6%) received 50 mg/day of micafungin. During the follow-up, 7 (4.4%) patients developed breakthrough invasive fungal disease, 1 proven and 6 probable; one patient discontinued the drug because of serious drug interactions. Prophylaxis with micafungin was considered effective in 151 (94.9%) patiens. CONCLUSIONS: According to our experience, micafungin is an appropriate alternative for antifungal prophylaxis in patients undergoing an allo-HSCT, because its efficacy, its low profile of drug interactions and side-effects

INTRODUCCIÓN: Las infecciones fúngicas siguen representando un problema en el trasplante alogénico de progenitores hematopoyéticos (alo-TPH) por lo que es habitual el uso de profilaxis antifúngica en estos PACIENTES: El tratamiento antifúngico debe presentar al menos actividad frente a Candida y Aspergillus spp, un buen perfil de seguridad y baja probabilidad de infecciones, siendo micafungina una de las opciones que podría cumplir todos estos requisitos. El objetivo del estudio fue describir la experiencia con micafungina como profilaxis primaria en pacientes sometidos a alo-TPH en una cohorte de hospitales españoles, y evaluar su eficacia y seguridad en esta población. MATERIAL Y MÉTODOS: Estudio retrospectivo multicéntrico observacional consecutivo de todos los pacientes adultos ingresados para alo-TPH en los centros del Grupo Español de Trasplante Hematopoyético (GETH) desde enero de 2010 a diciembre de 2013 y que recibieron micafungina como profilaxis primaria durante el periodo de neutropenia. RESULTADOS: Se identificaron 240 pacientes de 13 hospitales y 159 fueron incluidos para el análisis. La mayoría (95.6%) de ellos recibieron dosis de 50mg/día de micafungina. Durante el seguimiento, 7 (4.4%) pacientes desarrollaron infecciones de brecha, 1 probada y 6 probables; en un paciente se suspendió el tratamiento por interacciones medicamentosas graves. La profilaxis con micafungina se consideró efectiva en el 94,9% de los pacientes (151 de 159). CONCLUSIONES: En base a nuestros resultados, consideramos que micafungina es una buena alternativa como profilaxis antifúngica en pacientes sometidos a alo-TPH, por su eficacia, el bajo riesgo de interacciones y de efectos adversos

Use of micafungin as antifungal prophylaxis in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Spain (GETH-MIC).

OBJECTIVE: The fungal infections remain an important problem in the allogeneic stem cell trasnsplantation (allo-SCT) setting and thus, anti-fungal prophylaxis is commonly used. The antifungal drug should offer activity, at least against Candida and Aspergillus spp., a good safety profile and low probability interactions. Micafungin could theoretically fulfill these requisites. The aim of the study was to describe the experience with micafungin as primary prophylaxis in patients undergoing allo-SCT in a cohort of Spanish centres, and to evaluate its efficacy and tolerability in this population. METHODS: Retrospective multicentre observational study including all consecutive adult patients admitted for allo-SCT in participating centres of the Grupo Español de Trasplante Hematopoyético (GETH), from January 2010 to December 2013, who received micafungin as primary prophylaxis during the neutropenic period. RESULTS: A total of 240 patients from 13 centres were identified and 159 patients were included for the analysis. Most patients (95.6%) received 50 mg/day of micafungin. During the follow-up, 7 (4.4%) patients developed breakthrough invasive fungal disease, 1 proven and 6 probable; one patient discontinued the drug because of serious drug interactions. Prophylaxis with micafungin was considered effective in 151 (94.9%) patients. CONCLUSIONS: According to our experience, micafungin is an appropriate alternative for antifungal prophylaxis in patients undergoing an allo-HSCT, because its efficacy, its low profile of drug interactions and side-effects.

Long-term risk of hepatocellular carcinoma mortality in 23220 hospitalized patients treated with micafungin or other parenteral antifungals.

BACKGROUND: Liver tumours observed in rats exposed to micafungin led to a black box warning upon approval in Europe in 2008. Micafungin's risk for liver carcinogenicity in humans has not been investigated. We sought to describe the risk of fatal hepatocellular carcinoma (HCC) among persons who received micafungin and other parenteral antifungals (PAFs) with up to 12 years of follow-up. METHODS: We assembled a US multicentre cohort of hospitalized patients who received micafungin or other PAFs between 2005 and 2012. We used propensity score (PS) matching on patient characteristics from electronic medical records to compare rates of HCC mortality identified through the National Death Index though to the end of December 2016. We computed HRs and 95% CIs. RESULTS: A total of 40110 patients who received a PAF were identified; 6903 micafungin recipients (87% of those identified) were successfully matched to 16317 comparator PAF users. Ten incident HCC deaths, one in the micafungin-exposed group and nine among comparator PAF users, occurred in 71285 person-years of follow-up. The HCC mortality rate was 0.05 per 1000 person-years in micafungin patients and 0.17 per 1000 person-years in comparator PAF patients. The PS-matched HR for micafungin versus comparator PAF was 0.29 (95% CI 0.04-2.24). CONCLUSIONS: Both micafungin and comparator PAFs were associated with HCC mortality rates of <0.2 per 1000 person-years. Given the very low event rates, any potential risk for HCC should not play a role in clinical decisions regarding treatment with micafungin or other PAFs investigated in this study.

Drug-Induced Liver Injury (DILI) With Micafungin: The Importance of Causality Assessment.

Background: Micafungin is increasingly used in the treatment and prevention of candidiasis in hospitalized patients. Limited data are available from which to assess the risk of drug-induced liver injury (DILI) with micafungin. No studies, to date, have applied a standardized causality assessment method to the study of micafungin-associated DILI. Objective: This study aimed to identify the frequency and clinical pattern of DILI in micafungin-treated patients as determined using 2 standardized causality assessment algorithms. Methods: A retrospective analysis was conducted of micafungin-treated patients at a single center between May 15, 2017, and May 15, 2018. DILI was defined on the basis of liver test elevations and the presence of associated signs and symptoms. The Roussel UClaf Causality Assessment Method (RUCAM) and the Naranjo algorithm were applied to each case. Results: A total of 99 patients were assessed; 52 were excluded, with a final sample of 47 evaluable patients. The definition of DILI was met in 9 (19%) patients, with a clinical pattern consistent with cholestatic injury in 7 of 9 (78%) patients. No cases were associated with jaundice. Agreement between the 2 causality assessment methods occurred in 4 of 9 (44%) cases. Application of the RUCAM algorithm led to the exclusion of 4 cases, resulting in a final reported prevalence of micafungin-associated DILI of 10.6%. Conclusion and Relevance: Asymptomatic DILI was identified in 10.6% of micafungin-treated patients. The choice of a causality assessment nomogram substantially influenced the determination of DILI prevalence. Compared with the Naranjo algorithm, the RUCAM algorithm is recommended as a more precise tool of assessing the relationship between drug exposure and DILI.

Use of Micafungin for the Prevention and Treatment of Invasive Fungal Infections in Everyday Pediatric Care in France: Results of the MYRIADE Study.

BACKGROUND: Invasive fungal infections are responsible for significant morbidity and mortality. Safety and effectiveness of antifungal agents is a particular concern in pediatric populations, where data are often limited. Micafungin is an echinocandin with demonstrated antifungal activity against a wide spectrum of Candida spp.; this subanalysis of data from the MYRIADE study describes the use of micafungin and its therapeutic outcomes in pediatric patients, in normal clinical practice. METHODS: MYRIADE was an observational, multicenter, national, prospective, longitudinal study conducted from January 2010 to December 2012, in patients treated with micafungin using a prophylactic or curative strategy, across 17 sites [oncohematology (n = 8), neonatal intensive care units (ICUs) (n = 5) and pediatric ICUs (n = 4)]. The treatment regimen, the achievement of the therapeutic objective and the tolerance were reported. RESULTS: The study population consisted of 110 pediatric patients (31 neonates, 24 children <2 years old and 55 children ≥2 to <16 years old). The therapeutic objective was achieved in 49/64 (76.6%) oncohematology patients, 28/29 (96.6%) neonatal ICU patients and 12/14 (85.7%) pediatric ICU patients. Twenty-four (21.8%) children developed an adverse event (AE); more AEs were observed in oncohematology patients compared with ICU patients [17 (26.1%) vs. 7 (15.6%)]. Only one serious AE, reported in an oncohematology patient, was considered related to micafungin. CONCLUSIONS: In the first large observational study of micafungin treatment or prophylaxis conducted under real-world conditions in France, micafungin was effective and well tolerated for prophylaxis of invasive fungal infections in pediatric oncohematology patients and for curative purposes in pediatric and neonatal ICU patients.

Leukopenia induced by micafungin in a bottlenose dolphin (Tursiops truncatus): a case report.

A bottlenose dolphin (Tursiops truncatus) housed in the Port of Nagoya Public Aquarium (PNPA) presented with symptomatic pneumonia caused by Aspergillus fumigatus. The dolphin was treated with micafungin. On days 2 and 11 after the first administration of micafungin, results from a physical examination and laboratory test indicated a decline of body temperature (BT) and leukopenia, with lowest BT, white blood cells (WBCs), and segmented neutrophils (SEGs) of 34.2°C, 600 cells/µl, and 67 cells/µl, respectively. BT, WBCs, and SEGs returned to normal range after administration of granulocyte colony stimulating factor (G-CSF). To the best of our knowledge, this is the first report of micafungin-induced decline of BT and leukopenia that was successfully treated with G-CSF in a bottlenose dolphin.

Efficacy and Safety of Echinocandins for the Treatment of Invasive Candidiasis in Children: A Meta-analysis.

BACKGROUND: Echinocandins are recommended for the treatment of suspected or confirmed invasive candidiasis (IC) in adults. Less is known about the use of echinocandins for the management of IC in children. The aim of this study was to investigate the overall efficacy and safety of echinocandin class in neonatal and pediatric patients with IC. METHODS: PubMed, Cochrane Central, Scopus and Clinical trial registries were searched up to July 27, 2017. Eligible studies were randomized controlled trials that evaluated the efficacy and safety of any echinocandin versus agents of other antifungal classes for the treatment of IC in pediatric patients. The primary outcome was treatment success with resolution of symptoms and signs, and absence of IC. In the meta-analysis a random effects model was used, and the odds ratio (OR) and 95% confidence intervals (CIs) were calculated. RESULTS: Four randomized clinical trials (324 patients), 2 confirmed IC (micafungin vs. liposomal amphotericin B (L-AmB) and caspofungin vs. L-AmB) and 2 empirical therapy trials (caspofungin vs. deoxycholate amphotericin B and caspofungin vs. L-AmB) were included. There was no significant difference between echinocandins and comparator in terms of treatment success (OR = 1.61, 95% CI: 0.74-3.50) and incidence of treatment-related adverse events (OR = 0.70, 95% CI: 0.39-1.26). However, fewer children treated with echinocandins discontinued treatment because of adverse events than amphotericin B formulations (OR = 0.26, 95% CI: 0.08-0.82, P = 0.02). CONCLUSIONS: In the treatment of IC in children, echinocandins show non-inferior efficacy compared with amphotericin B formulations with fewer discontinuations than in comparator arm.

Micafungin-Induced Hypoglycemia in a Patient With Type 1 Diabetes: A Case Report and Review of Literature.

Objective: Patients with type 1 diabetes mellitus (T1DM) are insulin dependent. Infection increases insulin resistance and subsequently increases insulin needs. We are reporting a case of a patient with T1DM and severe infection who has reduced insulin needs after starting micafungin therapy. Participant: A 29-year-old Hispanic woman with known history of long-standing, uncontrolled T1DM presented for evaluation of worsening dysphagia and dyspnea. She was found to have cervical necrotizing fasciitis extending into the mediastinum and required several debridement surgeries along with broad-spectrum antibiotics and antifungal therapy. She had uncontrolled diabetes with a glycosylated hemoglobin of 13.4% (18.8 mM) on admission. Her insulin requirements progressively increased as a result of worsening infection, continuous tube feeds, and multiple debridement surgeries. She was started on micafungin, a potent 1,3-ß-D glucan synthase inhibitor, to broaden antimicrobial coverage when her insulin requirement decreased to zero for >48 hours. Right after discontinuation of micafungin and her switch to a different antifungal, insulin requirements increased back to her baseline needs. Results: This is a report of decreased insulin requirements in a patient with T1DM correlating with micafungin administration. The mechanism of micafungin-induced hypoglycemia is not yet established. Oral administration of linear 1,3-ß-D glucan has been documented to decrease blood glucose levels significantly by inhibition of expression of sodium-glucose transporter 1 (SGLT1) in intestinal mucosa. Conclusion: We hypothesize that micafungin may inhibit SGLT-1 function and decrease insulin requirements in patient with T1DM.

Micafungin may be safely administered as outpatient parenteral antimicrobial therapy for chronic pulmonary aspergillosis.

BACKGROUND: Intravenous micafungin has been reported as a treatment alternative in patients with chronic pulmonary aspergillosis (CPA) where long-term oral triazole therapy is unfeasible. OBJECTIVES: We evaluated the safety and efficacy of micafungin administered via the outpatient parenteral antimicrobial therapy (OPAT) service for the treatment of CPA. METHODS: We included all CPA patients who received micafungin via OPAT between April 2016 and March 2018. Data on adverse events and line-related complications, and Quality of Life (QoL) scores at the start of micafungin course and 3 months later were extracted. Improvements in QoL were defined as an improvement of ≥4 points in at least one modality (symptom, impact, activity, total) in the St George's QoL score. A stable QoL score was defined as a change in score of <4 points in either direction whilst deterioration was defined as an increase of ≥4 points. RESULTS: There were 20 OPAT episodes involving 18 patients with a median duration of micafungin therapy of 21 (range: 4-248) days. Improvement or stability in the symptoms, activity, impact and total score was seen in 14 (78%), 12 (67%), 9 (50%) and 9 (50%) of the patients, respectively. However, half of the patients reported deterioration in the impact domain and total scores. By self-assessment, patients who categorised themselves as "poor" were comparable at the start of OPAT and at 3 months (43% vs 50%, McNemar's P = 0.7). Adverse events attributable to micafungin were recorded in 3 (14.3%) episodes. CONCLUSIONS: Micafungin may be safely administered via an OPAT service. Micafungin therapy was associated with an improvement or stability in QoL scores in at least 50% of the patients across the four domains.

Effectiveness and Tolerability of Micafungin in Chinese Patients with Invasive Fungal Infections: A Retrospective, Multicenter Study.

INTRODUCTION: Invasive fungal infections (IFIs) are a significant health problem in immunocompromised patients, resulting in substantial morbidity, mortality, and healthcare costs. Micafungin is a broad-spectrum echinocandin with activity against Candida and Aspergillus spp. This was a multicenter, non-comparative, retrospective observational study that evaluated the effectiveness and tolerability of intravenously administered micafungin for treating IFIs caused by Candida and Aspergillus spp. METHODS: Adult patients in China who had received at least one dose of intravenously administered micafungin were eligible. Retrospective data (May 2008-April 2015) were extracted from patients' medical files and recorded using electronic data capture. The primary endpoint was overall success rate (patients with complete or partial response). Subgroup analyses determined effectiveness according to diagnostic certainty, fungal species, type of IFI, duration of micafungin treatment, and daily dose of micafungin. Tolerability, including the incidence of adverse events (AEs), was also assessed. RESULTS: Overall, 2555 patients who received at least one dose of micafungin were identified. The mean duration of treatment and mean daily dose were 10.2 days and 133.0 mg, respectively. The overall success rate was 60.8%; this was significantly higher in patients who received treatment for at least 1 week (range 67.9-71.6% [mean 69.2%]) compared with less than 1 week (47.8%; P < 0.0001), and those who received 50-100 mg (65.7%) compared with other daily doses (range 42.9-60.1% [mean 59.0%]; P = 0.0011). Success rates in Candida- and Aspergillus-infected patients were similar (61.9% and 56.8%, respectively). AEs and adverse drug reactions were observed in 36.2% and 4.5% of patients, respectively. The majority of AEs were mild, while discontinuation due to AEs was low (2.3%). CONCLUSION: Micafungin is effective and well tolerated for the treatment of patients with IFIs in China, as demonstrated in Candida- and Aspergillus-infected adults. Subgroup analyses highlighted the potential benefits of treating IFIs with micafungin for a minimum of 1 week. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02678598. FUNDING: Astellas Pharma Inc.

Pharmacokinetics and safety of fluconazole and micafungin in neonates with systemic candidiasis: a randomized, open-label clinical trial.

AIMS: The pharmacokinetics (PK) of fluconazole and micafungin differ in neonates compared with children and adults. Dosing instructions in product labels appear to be inconsistent with the emerging scientific evidence. Limited information is available on the safety profile of these agents in neonates. Our objective was to study the population PK and safety of both drugs, randomly administered in neonates with suspected or confirmed systemic candidiasis. METHODS: Neonates were randomized 1:1 to fluconazole (loading dose 25 mg kg-1 ; maintenance dose 12 mg kg-1 day-1 or 20 mg kg-1 day-1 , respectively, for infants <30 weeks or ≥30 weeks' corrected gestational age) or micafungin (loading dose 15 mg kg-1 day-1 ; maintenance dose 10 mg kg-1 day-1 ). PK samples were taken on treatment days 1 and 5. Population parameters were determined using NONMEM and Monte Carlo simulations performed to reach predefined targets. Clinical and laboratory data, and adverse events were collected up to 36 weeks' corrected gestational age or hospital discharge. RESULTS: Thirty-six neonates were enrolled. The median (range) gestational age was 28.2 (24.1-40.1) and 26.8 (23.5-40.0) weeks for fluconazole and micafungin, respectively. Based on 163 PK samples, the median population clearance (l h-1 kg-1 ) and volume of distribution (l kg-1 ) for fluconazole were: 0.015 [95% confidence interval (CI) 0.008, 0.039] and 0.913, and for micafungin were: 0.020 (95% CI 0.010, 0.023) and 0.354 (95% CI 0.225, 0.482), respectively. The loading dose was well tolerated. No adverse events associated with micafungin or fluconazole were reported. CONCLUSION: Based on Monte Carlo simulations, a loading dose for fluconazole and dosing higher than recommended for both drugs are required to increase the area under the plasma drug concentration-time curve target attainment rate in neonates.