Posaconazole Oral Suspension Research Articles

Individualized regimen of Posaconazole oral suspension in Chinese HSCT patients based on population pharmacokinetic model

To establish a population pharmacokinetic (PopPK) model of posaconazole suspension in Chinese hematopoietic stem cell transplantation (HSCT) patients and to recommend an optimal dosing regimen. A single-center, retrospective, model-based study was conducted in 62 Chinese patients, including 103 with posaconazole plasma concentrations. PopPK analysis using NONMEM software. A one-compartment model of first-order elimination and absorption was in good agreement with the experimental data. Analysis of covariance showed that body weight (WT), creatinine clearance (CCR), and proton pump inhibitor (PPI) had a significant effect on the pharmacokinetics of posaconazole. The dose simulation results show that patients with CCR ≥ 90 mL/min require at least 3 mg/kg TID and 7 mg/kg BID dosing regimens for prevention and treatment, respectively. However, when combined with PPI, at least 5 mg/kg BID and 5 mg/kg TID dosing regimens are required for prevention and treatment, respectively. Regardless of whether it is used in combination with PPI or not, patients with a CCR of 60–90 mL/min can achieve PTA goals by using a 4 mg/kg BID and 4 mg/kg TID regimen for prevention and treatment, respectively. A dosing regimen of 3 mg/kg BID in patients with a CCR of 30–60 mL/min is sufficient to meet the PTA goal of prophylaxis, and the dose needs to be elevated to 4 mg/kg BID for the treatment of fungal infections, and there is no need to change the dose according to the coadministration of PPI. When the patient's CCR is less than 30 mL/min, whether or not combined with PPI, the administration regimen of 2 mg/kg BID and 3 mg/kg BID can meet the PTA goals for prevention and treatment, respectively.

Real-world safety study of posaconazole oral suspension in children under 13 years of age

Real-world safety study of posaconazole oral suspension in children under 13 years of age

The Therapeutic Efficacy and Blood Drug Concentration of Posaconazole Enteric-Coated Tablets in Preventing Pulmonary Invasive Fungal Disease after HSCT

Introduction The risk of fungal infection in patients after HSCT is high. Prophylactic use of antifungal drugs can significantly reduce the occurrence of invasive fungal disease (IFD) and potential IFD-related mortality. Posaconazole oral suspension shows good preventive effects for patients with neutropenia and severe GVHD . However, there is still a lack of prospective research confirming the effectiveness of posaconazole enteric-coated tablets in preventing fungal infections in HSCT patients. Methods This study is a prospective, non-randomized, single-arm study. 143 patients who received hematopoietic stem cell transplantation at the Transplantation Center of Blood Diseases Hospital, the Chinese Academy of Medical Sciences from December, 2020 to May, 2022 were included. Posaconazole enteric-coated tablets were administered orally at a dose of 300mg QD (double dose for the first day) for the prevention of pulmonary invasive fungal disease from the first day to the 90th day after transplantation. The study collected baseline data, serum posaconazole concentrations, UGT1A4*3 genotype of the involved patients and observed whether pulmonary invasive fungal disease occurred. Retrospective data on the use of other antifungal drugs for the prevention of pulmonary invasive fungal disease at the center were collected as a control group for comparison. After applying propensity score matching at a ratio of 1:2, a comparative analysis was conducted on 140 cases in the posaconazole enteric-coated tablets group and 280 cases in the non-posaconazole group. Results Among the 143 patients who were included in the clinical trial and treated with posaconazole enteric-coated tablets alone for the prevention of fungal infection from day 1 to day 90 after hematopoietic stem cell transplantation, 4 cases developed invasive pulmonary fungal infection, including 1 case of mold and 3 cases of undefined pathogens, with a breakthrough rate of 2.80%, significantly lower than the historical control group breakthrough rate of 7.86% in the non-posaconazole group (P=0.014). In the 90 days after transplantation, a total of 246 measurements of posaconazole blood concentration were performed in the 143 patients in the clinical trial group. The average blood drug concentrations on the 4th, 8th, 15th, 22nd, and 30th day were 930.97 ng/ml, 1143.97 ng/ml, 1569.8 ng/ml, 1652.57 ng/ml, and 1644.75 ng/ml respectively. The blood drug concentration of posaconazole enteric-coated tablets tended to stabilize since the 15th day after treatment. In the 37 patients who tested the UGT1A4*3 genotype, there was no significant correlation between UGT1A4*3 gene polymorphism and posaconazole blood drug concentration. In terms of adverse reactions, the incidence of liver adverse events in this clinical study was 1.4%. Except for a slight increase in ALT after the 14-day medication (18.29 U/L vs. 26.22 U/L, P<0.001), there were no differences in other liver and kidney function laboratory test before and after treatment. Conclusion Posaconazole enteric-coated tablets is a highly safe prophylactic drug for invasive pulmonary fungal infections after HSCT, and its efficacy is superior to other antifungal prophylaxis regimens. Posaconazole enteric-coated tablet blood drug concentration in transplant patients gradually rose over time and tended to stabilize after 15 days of medication. The UGT1A4*3 gene polymorphism has no effect on the blood drug concentration of posaconazole enteric-coated tablets. Keywords Posaconazole enteric-coated tablets, hematopoietic stem cell transplantation, pulmonary invasive fungal disease

Successful enteral administration of crushed posaconazole delayed-release tablets in children.

Erratic absorption of posaconazole oral suspension necessitates frequent dosing and administration with meals or supplements. Alternative enteral formulations are desirable for patients intolerant to enteral nutrition. Crushed posaconazole delayed-release tablets (POS-DRT) show promise in adults; limited evidence exists in children. We used crushed POS-DRT in 10 encounters with nine pediatric patients, achieving target POS concentrations in 90% of encounters. This highlights crushed POS-DRT as a potential enteral option for pediatric antifungal prophylaxis and treatment.

Meta-pharmacokinetic analysis of posaconazole following dosing of oral suspension, delayed-release tablet, and intravenous infusion in patients vs. healthy volunteers: Impact of clinical characteristics and race

ObjectivesTo investigate the potential impact of clinical characteristics and the Chinese race on posaconazole pharmacokinetics in patients using an integrated population pharmacokinetic model for posaconazole oral suspension (SUS), delayed-release tablet (DR-tablet), and intravenous (IV) infusion that was developed in healthy volunteers (HV). Methods1046 concentrations from 105 prospectively studied Caucasian patients receiving either of the three posaconazole formulations were pooled with 3898 concentrations from 182 HV. Clinical characteristics were tested for significance. The impact of Chinese race was assessed using 292 opportunistic samples from 80 Chinese patients receiving SUS. ResultsBioavailability of SUS (Fsus) in patients decreased from 38.2% to 24.6% when the dose was increased from 100 mg to 600 mg. Bioavailability of DR-tablet (Ftab) was 59% regardless of dose. Mucositis, diarrhoea, administration through a nasogastric tube, and concomitant use of proton pump inhibitors or metoclopramide reduced Fsus by 61%, 36%, 44%, 48%, and 29%, respectively, putting patients with these characteristics at increased risk of inadequate exposure. Clearance decreased from 7.0 to 5.1 L/h once albumin levels were <30 g/L. Patients showed an 84.4% larger peripheral volume of distribution (Vp) and 67.5% lower intercompartmental clearance (Q) compared with HV. No racial difference could be identified. ConclusionsPharmacokinetics of posaconazole in patients differ considerably to those in HV, with altered Fsus that is also impacted by clinical covariates, an Ftab similar to fasted conditions in HV, and altered parameters for clearance, Vp, and Q. There was no evidence to indicate that Chinese patients require a different dose to Caucasian patients.

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

COVID-19-Associated Rhino-Mucormycosis and Pulmonary Aspergillosis Infection

In the current pandemic, the incidence of fungal infections-associated COVID-19 is surging. Diabetes mellitus, overzealous steroid, and antibiotic use for COVID-19 management may cause or exacerbate the fungal disease. In paranasal sinus (PNS), ethmoids followed by the maxillary sinus are commonly involved with the risk of intra-orbital or/and intracranial involvement is quite common. In lungs, COVID-19 infection has higher mortality rate, if there is an associated fungal infection. Aspergillus fumigates is the most common fungus that cause lung infection and present as discrete lesion different from COVID-19 manifestation. Two cases of COVID-associated fungal infections, i.e., rhino-mucormycosis and pulmonary aspergillosis are described here. In the first case, computed tomography (CT) of PNS was done for the complaints of mild right-sided facial swelling and mild restriction of the eye globe on day 27 of illness. CT showed hyperdense content involving the right-sided nasal sinus with the remodeling of bones with erosion and thinning of the inferior and medial orbital wall with the extension of soft tissue into the extraorbital space. The patient was treated with Amphotericin B and posaconazole oral suspension as the first-line antifungal monotherapy. In the second case, on complaints of cough with expectoration on the 20th day of illness, X-ray chest and CT chest were done which confirmed a thick-walled cavity in the right lung and other post COVID features. The tracheal aspirate culture was suggestive of Aspergillus fumigatus and Aspergillus antigen galactomannan was found positive in the fluid. The patient was treated for the same with antifungal therapy. Hence it is important to pay attention to the high probability of fungal infections in COVID-19 patients. The association of coronavirus with mucormycosis of the PNSs and aspergillosis of the lung must be given outmost consideration. Noncontrast CT of the PNSs is usually the first investigation of choice for PNS involvement, and CT chest help in the diagnosis of pulmonary fungal infection. Uncontrolled diabetes and use of steroids are two of the main factors for aggravating factors. Both early surgical intervention and anti-fungal treatment should be sought for the management.

Antifungal prophylactic effectiveness and intrapulmonary concentrations of voriconazole versus posaconazole in lung transplant recipients.

Invasive fungal diseases (IFDs) are one of the leading causes of death in lung transplant recipients. This study aimed to compare the antifungal prophylactic effectiveness, intrapulmonary and plasma levels of voriconazole with posaconazole in lung transplant recipients. This retrospective cohort study analyzed adult recipients who underwent lung transplantation between June 2017 and December 2020. Voriconazole oral tablets or posaconazole oral suspension was used for prophylaxis against posttransplant IFD. Drug concentrations in bronchoalveolar lavage fluid (BALF) and plasma were measured by using liquid chromatography-mass spectrometry. The 182 recipients included 142 in the voriconazole group and 40 in the posaconazole group. The trough plasma levels were comparable between voriconazole and posaconazole (1.65 ± 0.09 vs. 1.69 ± 0.03 μg/ml, P = 0.55). However, the BALF levels were significantly higher for posaconazole than voriconazole (17.47 ± 11.51 vs. 0.56 ± 0.49 μg/ml, P < 0.001). There was no significant difference in the total incidence of breakthrough IFDs between the voriconazole and posaconazole groups (10.6% vs. 7.5%, P = 0.77). The intrapulmonary concentrations of posaconazole were significantly higher than voriconazole. The two agents had comparable antifungal prophylactic effectiveness.

Posaconazole and Its Pharmacologic and clinical Uses: An Antifungal Drugs

Posaconazole (PCZ) is a new broad-spectrum azole antifungal drug, that is accepted for theprevention of persistent aspergillosis and candidiasis in addition to the cure of oropharyngealcandidiasis. There is proof of efficacy in the treatment and prevention of rarer, difficult to treatfungal diseases. PCZ oral suspension has revealed limitations with fasting state absorption,raised gastrointestinal pH and high motility. Oral use of PCZ in divided doses increases thebioavailability. The recently approved sustained-release oral tablet and interavenous solutionsprovide a smart treatment option. PCZ has fungicidal activities against Aspergillus fumigatus,Blastomyces dermatitidis, Crytopcoccus neoformans, some Candida species,and Trichosporonandfungistaticactivities against Candida, Coccidioides, some Fusarium species, Scedosporium,Histoplasma, and Zygomycetes. PCZ has synergistic effects with caspofungin or amphotericin Bagainst A. fumigatus, C. glabrata and C. neoformans. The absorption of PCZ is enhanced whengiven with food, nutritional supplements, and carbonated beverages. PCZ is highly proteinbound (&gt;95%) and main elimination route is fecal. PCZ is an inhibitor of the CYP3A4 enzyme.Common adverse effects are headache, fatigue, nausea, vomiting and elevated hepatic enzymes.Oral suspension is suggested in immuno compromised patients with functional gastrointestinal tract who not responds to conventional antifungal therapies. Interavenous injection isalso available for individuals who are unable to take oral drugs. On the basis of clinical studies,PCZ is a valuable drug for the treatment of life-threatening fungal infections. This review willexamine the progress history of PCZ and emphasize the most recent progresses.

Cost-Effectiveness of Posaconazole vs. First-Generation Triazoles for the Prevention of Invasive Fungal Infections Among High-Risk Patients With Hematological Malignancies in China.

BackgroundPosaconazole is confirmed to be more effective for preventing invasive fungal infections (IFIs) than first-generation triazoles (fluconazole and itraconazole), but its economic value has not been comprehensively evaluated in China. This study compared the cost-effectiveness of these two antifungal prophylaxis regimens in hematological-malignancy patients at high risk for IFIs from the Chinese healthcare perspective.MethodsA hybrid decision tree and Markov model were built using published data to estimate the total costs and quality-adjusted life-years (QALYs) of antifungal prophylaxis with posaconazole oral suspension and first-generation triazoles. Regimens with an incremental cost-effectiveness ratio (ICER) lower than the threshold of willingness to pay (WTP) were considered cost-effective. One-way and probabilistic sensitivity analyses were performed to assess model robustness. The regional imbalance of economic development and the tablet formulation of posaconazole were considered in the scenario analyses.ResultsIn the base-case analysis, posaconazole oral suspension provided an additional 0.109 QALYs at an incremental cost of $954.7, yielding an ICER of $8,784.4/QALY, below the national WTP threshold of $31,315/QALY. One-way and probabilistic sensitivity analyses showed that the results were robust. Scenario analyses showed that the base-case ICER was consistently below the WTP thresholds of all 31 Chinese provinces, with the likelihood of posaconazole being cost-effectiveness ranging from 78.1 to 99.0%. When the posaconazole oral suspension was replaced by the tablet formulation, the ICER increased to $29,214.1/QALY, still below the national WTP threshold and WTP thresholds of 12 provinces.ConclusionsPosaconazole oral suspension is a highly cost-effective regimen for preventing IFI in high-risk hematological-malignancy patients from the Chinese healthcare perspective. Posaconazole tablets may also be considered in some high-income regions of China.

Posaconazole oral suspension for secondary antifungal prophylaxis in allogeneic stem cell transplantation recipients: a retrospective study

BackgroundThere is no consensus on the optimal secondary antifungal prophylaxis (SAP) regimen in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to evaluate the efficacy and safety of posaconazole oral suspension as secondary prophylaxis of invasive fungal disease (IFD) for allo-HSCT patients.MethodsWe retrospectively reviewed clinical data from prior IFD patients who received posaconazole oral suspension as systemic antifungal prophylaxis between June 2016 and January 2021 and have a follow-up period of 1 year after HSCT. The clinical outcomes of patients with a prior history of IFD (n = 30) and those without (n = 93) were compared.ResultsThe 1-year cumulative incidence of prophylaxis failure was 58.3% in the group with prior history of IFD and 41.6% in the group without a prior history of IFD (p = 0.459). The cumulative incidence of proven, probable or possible IFD within 1 year after allo-HSCT was 23.1% in the group with prior history of IFD and 14.1% in the group without prior history of IFD (p = 0.230). There was no significant difference between the cumulative incidence of proven or probable IFD within 1-year after allo-HSCT in the group with a prior history of IFD and the group without (p = 0.807). Multivariate logistic regression revealed cytomegalovirus disease as risk factor for post-transplantation IFD occurrence in posaconazole oral suspension prophylaxis. There was not a significant difference in overall survival between the patients with IFD history and those without (P = 0.559).ConclusionsOur study support that allo-HSCT recipients with a prior history of IFD and normal GI absorption can choose posaconazole oral suspension as a safe and effective SAP option.

Successful treatment of pulmonary mucormycosis caused by Rhizopus microsporus with posaconazole

BackgroundMucormycosis is a rare fungal infection occurring chiefly in the lung or the rhino-orbital-cerebral compartment, particularly in patients with immunodeficiency or diabetes mellitus. Among Mucorales fungi, Rhizopus spp. are the most common cause of mucormycosis.Case presentationWe report a case of pulmonary mucormycosis caused by Rhizopus microsporus in a young patient with diabetes but no other apparent risk factors. The diagnosis mainly relied on clinical manifestation, positive pulmonary tissue biopsy, and fungal culture. The patient was successfully treated with posaconazole oral suspension and remains asymptomatic at one-year follow-up.ConclusionsPulmonary mucormycosis is a life-threatening condition and posaconazole is an effective treatment for pulmonary mucormycosis caused by Rhizopus microspores.

A Population Pharmacokinetic Modeling and Simulation Study of Posaconazole Oral Suspension in Immunocompromised Pediatric Patients: A Short Communication.

Posaconazole oral suspension emerged as a promising candidate for prophylaxis of invasive fungal infections in immunocompromised children. Its pharmacodynamic advantages include a broad-spectrum activity and a favorable safety profile; however, they are overshadowed by its large pharmacokinetic (PK) variability, which might cause subtherapeutic exposure. The aim of this study was to develop a population (pop) PK model based on rich sampling data to better understand the PK of posaconazole oral suspension in pediatric patients. Data were obtained from a prospective interventional study involving hospitalized pediatric patients with a hematologic malignancy and prophylactically treated with posaconazole oral suspension. After constructing the popPK model, the probability of target attainment (PTA; 100% T ≥ 0.7 mg/L) for prophylaxis under fixed, body weight-based, and body surface area-based dosing was evaluated using Monte Carlo simulation. Fourteen patients contributed 112 posaconazole plasma concentrations. The PK of posaconazole was adequately described by a 1-compartment model with lag time 2.71 hours [13%]; nonlinear bioavailability ED50 99.1 mg/m2 (fixed); first-order absorption rate constant 0.325 hour-1 [27%]; apparent volume of distribution 1150 L [34%]; and apparent clearance 15.4 L/h [24%] (∼70-kg individual). The bioavailability decreased in the presence of diarrhea and co-treatment with a proton pump inhibitor (PPI). The unexplained interindividual variability in posaconazole PK remained large. The PTA was <85%, irrespective of the simulated dosing strategy. Patients without diarrhea and not administered a PPI had the highest PTA (85% under the fixed 300-mg dosing 4 times per day). Therapeutic drug monitoring is recommended during prophylactic posaconazole therapy in immunocompromised pediatric patients. Large-scale comparative studies are needed to characterize the PK variability between different posaconazole formulations in this cohort.

Evaluation of posaconazole plasma concentrations achieved with the delayed-release tablets in Korean high-risk patients with haematologic malignancy.

Posaconazole (PCZ) is a triazole approved for prophylaxis of invasive fungal infections. Herein, the impact of clinical variables on PCZ plasma concentrations (PPCs) attained with PCZ delayed-release tablet (DRT) was investigated and compared with a historical cohort treated with PCZ oral suspension (OS). Steady-state PCZ PPCs in 513 patients with haematologic malignancy treated with PCZ-DRT were assessed and impact of variables were analysed. Also, a comparison with matched historical cohort treated with PCZ-OS was made. The median PPC in the PCZ-DRT group was 1,308.9ng/mL (range: 29.8-10455.9). Use of proton pump inhibitor (1181 vs 1344ng/mL, P=.0337) in the AML/myelodysplastic syndrome remission induction group, diarrhoea (867 vs 1543ng/mL, P=.0325) and gastrointestinal graft-versus-host disease (870 vs 1713ng/mL, P=.0178) in the HSCT group were associated with lower PPCs. There was lack of evidence that hepatotoxicity was related with PCZ-DRT. Higher prevalence of UGT1A4*3 allele (33.0%) was noted compared to allele frequency in Koreans in those with PPCs<500mg/mL. The median PPC in the PCZ-DRT group was significantly higher than that in the PCZ-OS group (1308.9 vs 713.0ng/mL, P<.0001). Significantly less patients had PPCs<700ng/mL in the PCZ-DRT group compared to the PCZ-OS group (18.7% vs 48.0%, P<.0001). Our study demonstrates that PCZ-DRT has enhanced absorption and bioavailability than PCZ-OS in real-world clinical settings. In addition, specific factors associated with lower PPCs should prompt consideration of therapeutic drug monitoring in patients treated with PCZ-DRT.

Using State Transition Models to Explore How the Prevalence of Subtherapeutic Posaconazole Exposures Impacts the Clinical Utility of Therapeutic Drug Monitoring for Posaconazole Tablets and Oral Suspension.

Therapeutic drug monitoring (TDM) has been recommended in guidelines for patients receiving posaconazole oral suspension, but its utility in patients receiving posaconazole tablet, which has an improved bioavailability, remains unclear. We used state transition models with first-order Monte Carlo microsimulation to re-examine the posaconazole exposure-response relationships reported in two Phase III clinical trials (prophylaxis with posaconazole oral suspension - Models 1 & 2) and a third multicenter observational TDM study (Model 3). We simulated the impact of TDM-guided interventions to improve initial average posaconazole concentrations (Cavg) to reduce clinical failure (in Models 1 & 2) and breakthrough invasive fungal disease (bIFD) in Model 3. Simulations were then repeated using posaconazole tablet Cavg distributions in place of the oral suspension formulation. In all three models with posaconazole oral suspension, TDM interventions associated with maximal improvement in posaconazole Cavg reduced absolute rates of subtherapeutic exposures (Cavg < 700 ng/mL) by 25-49%. Predicted reductions in absolute clinical failure rates were 11% in Model 1 and 6.5% in Model 2, and a 12.6% reduction in bIFD in Model 3. With the tablet formulation, maximally-effective TDM interventions reduced subtherapeutic exposures by approximately 5% in all three models and absolute clinical failure rates by 3.9% in Model 1, and 1.6% in Model 2; and a 1.6% reduction in bIFD in Model 3. Our modeling suggests that routine TDM during prophylaxis with posaconazole tablets may have limited clinical utility unless populations with higher prevalence (>10%) of subtherapeutic exposures can be identified based on clinical risk factors.

Antifungal prophylaxis with posaconazole tablet and oral suspension in patients with haematologic malignancy: Therapeutic drug monitoring, efficacy and risk factors for the suboptimal level.

Posaconazole is used to prevent invasive fungal infections (IFIs) in patients with haematologic malignancy. In this study, we compared plasma posaconazole concentrations (PPCs) and the incidence of breakthrough IFIs between patients with haematologic malignancy receiving posaconazole oral suspension vs tablet. We retrospectively collected data on adult patients with haematologic malignancies who received posaconazole prophylaxis during chemotherapy from April 2014 through May 2018. A total of 242 cases with PPCs, 88 in the oral suspension group and 154 in the tablet group, were included in this study. Patients receiving tablets achieved a significantly higher mean PPC than did those on oral suspension (1.631±0.878μg/mL in the tablet group vs. 0.879±0.585μg/mL in the oral suspension group). One hundred and thirty-seven of 154 patients (89.0%) receiving tablets had PPCs of 0.7μg/mL or more, while only 41 of 88 patients (46.6%) receiving oral suspension attained an optimal level (P<.001). The incidence of breakthrough IFIs was significantly higher in the oral suspension group compared with in the tablet group (14.8% of oral suspension vs. 4.5% of tablet; P=.005). In the analysis including patients receiving posaconazole tablets, hypoalbuminemia (< 3.5g/dL) was found to be a risk factor associated with suboptimal levels (odds ratio: 8.872; 95% confidence interval: 3.011 - 26.141; P<.001). Suboptimal PPCs in the tablet group were less common than those in the oral suspension group. Therapeutic drug monitoring may be still necessary even in patients receiving posaconazole tablets, especially in those with hypoalbuminemia.

2119. Matched-Paired Analysis of Patients Treated for Invasive Mucormycosis—Standard Treatment vs. Posaconazole New Formulations (MoveOn)

BackgroundCurrent first-line (first) antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B (AMB). Salvage (SAL) treatment options are limited and often based on posaconazole oral suspension (POSsusp). However, with the approval of posaconazole new formulations (POSnew), patients could benefit from improved pharmacokinetics, safety and tolerability. Our aim was to assess the effectiveness of POSnew as first-line and SAL treatments for IM.MethodsWe performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. 1st-POSnew and 1st-AMB+POSnew cases were matched with 1st-AMB-based treatment controls, and SAL-POSnew cases were matched with SAL-POSsusp controls. Each case was matched with up to three controls based on severity, hematological/oncological malignancy, surgery and/or renal dysfunction.ResultsFive patients receiving first-line POSnew alone, 18 receiving first-line POSnew combined with AMB, and 22 receiving salvage POSnew were identified. By day 42, favorable response was reported for 80.0% (n = 4/5) of patients receiving first-line POSnew, for 27.8% (n = 5/18) receiving first-line POSnew plus AMB, and for 50.0% (n = 11/22) receiving salvage POSnew. Day-42 all-cause mortality of patients receiving POSnew was lower compared with mortality in their respective controls (20.0% (n = 1/5) in 1st-POSnew vs. 53.3% (n = 8/15) in 1st-AMB; 33.3% (n = 6/18) in 1st-AMB+POSnew vs. 52.0% (n = 26/50) in 1st-AMB; 0.0% (n = 0/22) in SAL-POSnew vs. 4.4% (n = 2/45) in SAL-POSsusp).ConclusionIn the observed patients, POSnew was effective in terms of treatment response and-associated mortality of IM. POSnew may be an alternative for the treatment of IM.Disclosures All authors: No reported disclosures.

Factors Influencing the Safety and Efficiency of Antifungal Prophylaxis with Posaconazole in Children with Hematological Diseases: From Genetics to Polypharmacotherapy

The aim of this study was to determine the impact of ABCB1 polymorphism, BMI, age and drug co-administration on safety and efficiency of posaconazole (PCZ) oral suspension treatment in children with hematological diseases. Seventy children were included in the study. ABCB1 polymorphism in fifty-eight children was determined using a PCR–RFLP method. A protocol with data on the health condition, treatment and adverse events (AE), as well as a survey on treatment tolerance for the legal guardians was evaluated. Liver function tests were observed for the first 20 days, and AE during the complete medication period. For statistical analysis a χ2 test with Yates’s correction, a Pearson’s or Spearman’s correlation test was performed (p < 0.05). Genetic testing showed 24% CC, 46% CT and 30% of TT variants. PCZ prophylaxis failed in twenty cases, where change in prophylactic treatment was needed. Fifty-two children suffered from at least one mild to moderate adverse event. Sixty-five legal guardians completed the survey, most of them reported the treatment to be well tolerated. ABCB1 polymorphism had no impact on AE occurrence and posaconazole prophylaxis efficiency. Age influenced the number of gastrointestinal (p = 0.02), visual (p = 0.05), neurological (p = 0.01), dermatological (p = 0.002) and flu-like (p = 0.02) complications. AST (p = 0.03) and LDH (p = 0.008) activity presented age dependency. The concomitant use of proton pump inhibitors (PPI) had impact on liver health parameters elevation (p = 0.009) and circulatory system complications (p = 0.008). High incidence of mild to moderate AE, and other factors influencing PCZ pharmacokinetics (PPI co-administration, obesity), suggest a need for careful pediatric onco-hematology patient evaluation.

Posaconazole oral suspension as salvage therapy for invasive fungal disease in patients with hematological diseases.

Aim: Posaconazole (POS) is an extended-spectrum triazole approved for treatment of refractory invasive fungal disease. Outcome analysis of POS salvage therapy is of great clinical significance. Methods: We retrospectively reviewed data for 113 patients who received POS oral suspension as salvage therapy between December 2013 and May 2018. Results: Cumulative success rate at 12weeks was 53.1% (60/113) with a rapid increase within the first 3-4weeks and a plateau at 6weeks after POS initiation. Multivariate logistic regression analysis showed that disseminated infection, prolonged neutropenia, severe graft-versus-host disease and high-dose steroid use were independent risk factors of response. Conclusion: POS oral suspension is effective as a salvage therapy for invasive fungal disease.

Contemporary management and clinical outcomes of mucormycosis: A systematic review and meta-analysis of case reports

With the advent of newer antifungals, optimum treatment of mucormycosis remains to be fully elucidated. This study systematically evaluated the contemporary management and outcomes of mucormycosis. Mucormycosis cases in patients aged ≥18 years published between January 2000 and January 2017 were identified through Ovid MEDLINE and Embase. Of the 3619 articles identified, 600 (851 individual patient cases) were included in the review. Of the 851 patient cases, antifungal treatment details were available for 785. Intravenous (i.v.) amphotericin B formulations remained the most commonly prescribed first-line antifungals (760/785; 96.8%): 88.2% (670/760) were initiated as monotherapy and 11.8% (90/760) as combination antifungal therapy. Posaconazole oral suspension monotherapy was prescribed as an initial antifungal in 11 cases. It was also administered as maintenance or salvage therapy in 39 and 25 cases, respectively. Itraconazole capsule monotherapy (n = 10) was prescribed primarily for cutaneous disease in patients not receiving any immunosuppressive therapy. All-cause 90-day mortality was 41.0% (349/851). Initial treatment with combination antifungals did not reduce 90-day mortality compared with i.v. conventional amphotericin B or i.v. liposomal amphotericin B monotherapy [35/90 (38.9%) vs. 146/369 (39.6%) vs. 91/258 (35.3%), respectively; P = 0.541]. Concomitant surgical and antifungal therapy was associated with significantly lower 90-day mortality compared with treatment with antifungals alone (OR = 0.23, 95% CI 0.13-0.41; P < 0.001). The findings suggest that first-line antifungals with good efficacy remain an urgent unmet need. Whilst surgery is fundamental to improving survival, the clinical utility of combination antifungal therapy or posaconazole monotherapy requires further investigation.