Posaconazole Delayed-release Tablets Research Articles

2546. Administration of Crushed Posaconazole Delayed Release Tablets Failed to Achieve Therapeutic Levels

Abstract Background Posaconazole (POS) delayed release tablets (DRTs) are utilized for prophylaxis or treatment of invasive fungal infections. Other POS formulations are limited by impaired absorption, lack of indication for adult patients, and need for intravenous (IV) access. Small retrospective case series have demonstrated success with administration of crushed POS DRTs via enteral feeding tubes (EFTs). In October 2022, UNC Health permitted administration of POS DRTs via EFTs. This study aims to evaluate POS levels in patients that received crushed POS DRTs via EFTs. Methods This single-center, retrospective cohort study included patients that received crushed POS DRTs via EFTs with concurrent POS therapeutic drug monitoring (TDM). The primary outcome was achievement of serum POS level per indication of prophylaxis ( > 700 ng/mL) or treatment ( > 1000 ng/mL). The secondary outcome was the proportion of patients whose therapy was altered in response to POS level. Results A total of 10 patients were included (Table 1), with both prophylaxis (40%) and treatment (60%) indications. Most were initiated on oral or IV POS (80%). Crushed POS DRTs were administered via nasogastric (70%), post-pyloric (20%), and nasoduodenal (10%) routes. Therapeutic levels with crushed POS DRTs occurred in three patients (30%) and only two patients (20%) maintained therapeutic levels (Figure 1). Of the patients that transitioned from IV or oral POS to crushed POS DRT that maintained the same POS dose, 75% experienced a decrease in their serum POS level. Based on the initial crushed POS DRT level, three patients transitioned to IV or oral POS and 3 had their crushed POS DRT dose modified. Conclusion Crushed POS DRTs administered via EFTs failed to achieve therapeutic POS levels in 70% of patients. Caution should be used when implementing crushed POS DRTs and internal data should be reviewed if already implemented. Study limitations include small sample size, single-center design, and limited attempts to titrate crushed POS DRT regimens. Future studies should assess the clinical utility of crushed POS DRTs and explore the impact of standardized nursing administration, drug-drug interactions, and enteral feeding interactions/routes on crushed POS DRT pharmacokinetics. Disclosures All Authors: No reported disclosures

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.

Breakthrough invasive fungal infection in patients with myeloid malignancy receiving posaconazole tablet prophylaxis: clinical features, risk factors, and posaconazole profiles.

Posaconazole (PSC) delayed-release tablet prophylaxis is the standard of care for preventing invasive fungal infection (IFI) in patients with acute myeloid leukemia undergoing myelosuppressive chemotherapy. The clinical features, risk factors, and PSC profiles of breakthrough IFI (bIFI) in patients receiving PSC tablet prophylaxis were investigated. A single-center retrospective cohort study was conducted, including adult patients with myeloid malignancy who received prophylactic PSC tablets while undergoing chemotherapy from June 2016 to June 2021. Logistic regression analysis was used to identify risk factors for breakthrough IFI. A receiver operating characteristic curve was used to predict the relationship between PSC trough level at steady-state and breakthrough IFI. A total of 434 patients with myeloid malignancy who received PSC tablets were screened. Ten patients with bIFI were compared with 208 non-IFI patients. There were four proven and six probable IFI cases, nine due to Aspergillus and one due to Fusarium species. The bIFI patients had higher in-hospital mortality (30.0%) than the non-IFI patients (1.9%; P<0.001). History of allogeneic hematopoietic stem cell transplantation (OR 6.27; 95% CI 1.63-24.09), prolonged neutropenia≥28 days (OR 4.33; 95% CI 1.20-15.70), and low plasma PSC concentration<0.7μg/mL (OR 16.33; 95% CI 4.15-64.26) were risk factors for bIFI. The optimal cut-off value of plasma PSC concentration predicting bIFI was 0.765μg/mL (sensitivity, 60.0%; specificity, 91.3%; area under the curve, 0.746). bIFI was not uncommon in patients with myeloid malignancy receiving PSC tablets prophylaxis and associated with poor outcomes. Therapeutic drug monitoring may still be necessary, even in patients receiving PSC tablets.

(199) Serum Concentrations of Crushed Posaconazole Delayed Release Tablets in Lung Transplant Recipients

(199) Serum Concentrations of Crushed Posaconazole Delayed Release Tablets in Lung Transplant Recipients

What Is New in Pulmonary Mucormycosis?

Mucormycosis is a rare but life-threatening fungal infection due to molds of the order Mucorales. The incidence has been increasing over recent decades. Worldwide, pulmonary mucormycosis (PM) presents in the lungs, which are the third main location for the infection after the rhino-orbito-cerebral (ROC) areas and the skin. The main risk factors for PM include hematological malignancies and solid organ transplantation, whereas ROC infections classically are classically favored by diabetes mellitus. The differences between the ROC and pulmonary locations are possibly explained by the activation of different mammalian receptors-GRP78 in nasal epithelial cells and integrin β1 in alveolar epithelial cells-in response to Mucorales. Alveolar macrophages and neutrophils play a key role in the host defense against Mucorales. The diagnosis of PM relies on CT scans, cultures, PCR tests, and histology. The reversed halo sign is an early, but very suggestive, sign of PM in neutropenic patients. Recently, the serum PCR test showed a very encouraging performance for the diagnosis and follow-up of mucormycosis. Liposomal amphotericin B is the drug of choice for first-line therapy, together with correction of underlying disease and surgery when feasible. After a stable or partial response, the step-down treatment includes oral isavuconazole or posaconazole delayed release tablets until a complete response is achieved. Secondary prophylaxis should be discussed when there is any risk of relapse, such as the persistence of neutropenia or the prolonged use of high-dose immunosuppressive therapy. Despite these novelties, the mortality rate from PM remains higher than 50%. Therefore, future research must define the place for combination therapy and adjunctive treatments, while the development of new treatments is necessary.

Effect of Isavuconazonium Sulfate and Posaconazole Delayed Release Tablets on Tacrolimus Dose-to-Concentration Ratios.

Limited evidence exists on the effect of isavuconazonium sulfate and posaconazole delayed release tablets on tacrolimus dose-to-concentration ratios in lung transplant recipients. The purpose of this evaluation was to assess the impact of novel triazoles on tacrolimus dose-to-concentration ratios. This retrospective review included lung transplant recipient ≥18 years of age from January 1, 2017 to October 1, 2020 who received either posaconazole delayed release tablets or isavuconazonium sulfate for. A paired analysis evaluated outcomes pre-triazole and post-triazole initiation. Forty-one patients met evaluation criteria for inclusion. A total of 34 of 41 patients received posaconazole delayed release tablets. Of these patients, 22 of 34 were transitioned from previous triazole to posaconazole delayed release tablets and experienced a 47% reduction in tacrolimus dose-to-concentration ratio. Twelve patients were newly initiated on posaconazole delayed release tablets and experienced a 50% reduction in tacrolimus dose-to-concentration ratios. Although not statistically significant, a 30% reduction in tacrolimus dose-to-concentration ratio was observed when transitioning to isavuconazonium sulfate from previous triazole therapy. Limited data exists to provide guidance on tacrolimus dose adjustments with initiation and conversion of novel triazoles, however, this evaluation provides more knowledge on the drug interaction with novel triazoles and tacrolimus.

Therapeutic drug monitoring of posaconazole delayed release tablet while managing COVID-19-associated mucormycosis in a real-life setting.

Along with COVID-19 pandemic, India has faced an outbreak of COVID-19-associated mucormycosis (CAM). Due to restricted availability of amphotericin B during this outbreak, clinicians were forced to use posaconazole or isavuconazole preparations as first-line or alternate therapy in many patients. We planned an early monitoring of posaconazole trough level while using delayed release (DR) tablet as first-line or alternate therapy. Primary objective of the study was to determine percentage of patients achieving arbitrarily decided therapeutic posaconazole levels (≥1.2μg/ml) after using standard dosages of posaconazole. Secondary objective was to identify potential factors associated with sub-therapeutic posaconazole levels. We performed retrospective chart review of the hospitalised patients, who received posaconazole DR tablet as first-line or alternate therapy to treat CAM during outbreak period (March 1 to May 31, 2021). High-performance liquid chromatographic (HPLC) method was used to measure trough level of posaconazole. Posaconazole serum levels of 29 patients were analysed, who received posaconazole DR tablet. Majority (n=23) were male with the median (range) age 53 (24-86) years. The mean (SD) posaconazole level was 1.66 (0.76)μg/ml. Sub-therapeutic posaconazole trough level was observed in 7 (24.1%) patients. Relatively younger patients were associated with lower posaconazole level (p=.046). Except two patients, all the patients tolerated posaconazole well. The study supports the posaconazole trough level measurement on day 4 while using posaconazole DR tablet as first-line or alternate therapy to treat mucormycosis during limited supply of amphotericin B.

941. Isavuconazole Prophylaxis Against Invasive Fungal Infection: A Pooled Analysis with a Comparison of Posaconazole Delayed-release Tablet Prophylaxis

BackgroundThere are limited data regarding the use of isavuconazole as primary antifungal prophylaxis against invasive fungal infection (IFI) among immunocompromised patients. Therefore, the purpose of this study was to assess efficacy and breakthrough IFIs of isavuconazole prophylaxis by a pooled analysis of the reported cases of isavuconazole prophylaxis with a comparison of cases of posaconazole delayed-release tablet prophylaxis.MethodsPubmed was searched for English-written articles published up to April 2021. Studies that reported cases of primary antifungal prophylaxis with isavuconazole or posaconazole delayed-release tablet in adults ≥ 18 years were reviewed. Breakthrough IFI was defined as the occurrence of proven or probable IFI while on prophylaxis.ResultsFor overall isavuconazole prophylaxis, a total of 818 courses of prophylaxis was identified from 12 studies. Breakthrough IFIs were noted in 41 patients. The median duration of isavuconazole prophylaxis of these patients before the diagnosis of IFI was 17 days. The most common breakthrough IFI was candidiasis (34.1%), followed by aspergillosis (24.4%) and mucormycosis (12.2%). Sixteen patients died (39.0%). Among patients with hematologic malignancies or hematopoietic stem cell transplantation, isavuconazole prophylaxis (404 courses) was compared with posaconazole delayed-release tablet prophylaxis (1952 courses). The incidence rate of breakthrough IFIs was higher in the cohort of isavuconazole prophylaxis (24 patients of 404 courses) than in the cohort of posaconazole delayed-release tablet prophylaxis (44 patients of 1952 courses). Aspergillosis (40.9%) was the most common breakthrough IFI in the cohort of isavuconazole prophylaxis among patients with hematologic malignancies or hematopoietic stem cell transplantation, followed by candidiasis (27.3%) and mucormycosis (18.2%).ConclusionAlthough isavuconazole is licensed to treat aspergillosis and mucormycosis, breakthrough IFIs including aspergillosis, mucormycosis, and candidiasis may occur while on isavuconazole prophylaxis. Therefore, further studies are needed to define the benefits and risks of isavuconazole prophylaxis.Disclosures All Authors: No reported disclosures

Supratherapeutic Posaconazole Concentration in a Pediatric Transplant Patient With Confirmed Rhizopus Infection.

There are a limited number of studies that guide dosing of posaconazole delayed-release (DR) tablets for the pediatric population. Current FDA-approved doses are only recommended for patients 13 years and older. For younger patients, providers are faced with the challenge of recommending posaconazole doses extrapolated from adult studies or choosing an alternative agent. We report on a case of a 10-year-old patient who experienced a supratherapeutic trough serum concentration and transaminitis after receiving the extrapolated adult dosage of posaconazole DR tablets (300 mg twice daily for the first day, followed by 300 mg daily) for 7 days. In the end, the patient required a smaller dose of 200 mg daily to achieve the desired trough target concentration for the treatment of a Rhizopus neck infection. Our findings highlight the need for additional studies to determine the optimal dosing of posaconazole DR tablets for children.

Development of posaconazole delayed-release tablets by high shear melt granulation technique

Development of posaconazole delayed-release tablets by high shear melt granulation technique

755. Posaconazole versus voriconazole as antifungal prophylaxis for invasive fungal diseases in patients with hematological malignancies

BackgroundThe incidence of Invasive Fungal Diseases (IFDs) has dramatically increased in patients with hematologic malignancies due to prolonged neutropenia. IFDs are associated with significant morbidity and mortality. Due to these risks, international guidelines have recommended antifungal prophylaxis for Acute Myeloid Leukemia (AML) and Myelodysplastic syndromes (MDS) patients. Posaconazole has been recommended as the prophylactic agent of choice. Also, voriconazole has been recommended by guidelines with different levels of recommendations. Data on a direct comparison between Posaconazole delayed-release tablets (DR) and Voriconazole for IFD prophylaxis are lacking. Therefore, we aim to compare the efficacy and safety of the fungal prophylaxis; voriconazole versus posaconazole in AML/MDS patients at Princess Nourah Oncology Center, JeddahMethodsRetrospective chart review study for eligible patients from January 2017 to February 2019 to identify the breakthrough IFD rates and assess the frequency of adverse events within AML/MDS patients at PNOC, Saudi ArabiaResultsA total of 48 patients (130 chemo cycles) were included in the study: 50 using posaconazole (DR) and 80 using oral voriconazole as antifungal prophylaxis. The incidence rates of IFD in the posaconazole group was 8 % (4/50) of those 2 were probable, and 2 were possible infections while 6.26 % (5/80) of patients in the voriconazole group have developed IFD of them 4 had a possible infection, and one had a probable infection (p=0.7325). A higher percentage of patients in the voriconazole group discontinued prophylaxis due to adverse events (5 patients vs. 2 patients). Use of voriconazole as antifungal prophylaxis for 15 days in 130 cycles in 48 AML/MDS patients would cost 175,500 SR in comparison to the cost of the posaconazole for the same duration of 1,350,130 SR. So, use of voriconazole would save 1.13 million SR and is more cost effective when used as antifungal prophylaxis in AML/MDS patients in comparison to posaconazole although later is category 1 recommended antifungal prophylaxis in international guidelinesConclusionOur study has shown that both posaconazole and voriconazole have comparable efficacy and safety in the prevention of IFD in AML and MDS receiving chemotherapy but voriconazole is more cost effectiveDisclosures All Authors: No reported disclosures

Posaconazole delayed-release tablets in paediatric haematology-oncology patients.

To date, there are few studies that describe pharmacokinetics, safety and efficacy of posaconazole delayed-release tablet (DRT) formulation in the paediatric population. We evaluated retrospectively posaconazole plasma concentrations and safety of posaconazole DRT in paediatric haematology-oncology patients. Posaconazole DRT was assessed in 28 haematological paediatric patients with a median age 15 of years (range 5-18) and a median body weight of 50kg (range 22-83kg). Twenty-one patients received posaconazole DRT as prophylaxis and 7 patients as therapy. As prophylaxis, the median daily dose was 5.5mg/kg/day (range 2.2-22.2) with posaconazole trough level≥0.7μg/mL in 80% by first week, 62.5% by second week and 87.5% by fourth week. As therapy, the median daily dose was 4mg/kg/day (range 3.3-4.5) with trough level≥1μg/mL 100% by first week, 80% by second week and 33.4% by fourth week. Posaconazole DRT is feasible in paediatric patients capable to swallow tablets. Specific pharmacokinetic studies are needed.

Comparison of the Efficacy of Posaconazole Delayed Release Tablets and Suspension in Pediatric Hematology/Oncology Patients.

Posaconazole is effective in preventing invasive fungal infections in neutropenic pediatric patients. The oral suspension has challenges in administration and absorption that are theorized to be minimized with delayed release tablets. However, this has not been validated in the pediatric population. This study was conducted to compare the efficacy and safety of posaconazole suspension and delayed release tablets in pediatric hematology/oncology patients. A retrospective chart review in pediatric hematology/oncology patients was conducted from February 2013 to February 2017. Data collected include patient demographic data; posaconazole formulation, dose, and serum concentrations; and adverse events. Sixty-five patients with 353 serum posaconazole concentrations were included; 51.6% of concentrations drawn while patients were receiving posaconazole suspension were therapeutic, whereas 62.5% of concentrations drawn while patients were receiving posaconazole delayed release tablets were therapeutic (p = 0.035). Serum concentrations drawn while taking acid suppression (histamine receptor antagonists or proton pump inhibitors) and posaconazole suspension were less likely to be therapeutic (p < 0.0001) compared with those taken while receiving delayed release tablets. Adverse event profiles were similar between both formulations. Delayed release tablets proved more effective in achieving therapeutic serum posaconazole concentrations than posaconazole suspension, with minimal difference in adverse events, in pediatric hematology/oncology patients.

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.

Plasma exposures following posaconazole delayed-release tablets in immunocompromised children and adolescents.

Posaconazole is a recommended option for antifungal prophylaxis in paediatric patients >12 years of age. However, little is known about plasma exposures and safety following administration of the delayed-release tablets (DRTs) in children and adolescents. In a retrospective observational study, we analysed steady-state trough concentrations of posaconazole in all paediatric patients who had received the DRT formulation between May 2015 and December 2018 for antifungal prophylaxis. Dosing was guided by a published population pharmacokinetic model with weight-based dosing. Drug concentrations in plasma were measured by a validated tandem MS method. Liver function and drug discontinuations due to adverse effects were also assessed. A total of 34 patients (21 male, 13 female; median age 12 years, range 5-17 years; median body weight 43.5 kg, range 16-84 kg) undergoing treatment for haemato-oncological disorders (n=23) or immunosuppression for polyarthritis (n=1) or post-allogeneic HSCT (n=11) received posaconazole DRTs for a median of 70 days (range 9-391 days). The median first steady-state trough plasma concentration following model-derived dosing was 1607 ng/mL (range 501-8485 ng/mL) with trough concentrations being above the dosing target of ≥700 ng/mL in 32/34 patients (94%). Considering all (first and subsequent) trough concentrations, target attainment was 90% (63/70 samples). Posaconazole was well tolerated without adverse event-related discontinuations or breakthrough infections. Administration of posaconazole DRTs to paediatric patients guided by a population pharmacokinetic-derived dosing algorithm resulted in predictable and potentially effective exposures and was well tolerated over prolonged time periods.

Therapeutic drug monitoring and adverse events of delayed-release posaconazole tablets in patients with chronic pulmonary aspergillosis.

Posaconazole delayed-release tablets offer better bioavailability than the liquid suspension, but no post-marketing data are available in immunocompetent hosts such as those with chronic pulmonary aspergillosis (CPA). To explore the pharmacokinetics and adverse event (AE) profile of posaconazole tablets in patients with CPA. Patients started on posaconazole tablets at the National Aspergillosis Centre (NAC), Manchester, UK between February 2014 and October 2015 were identified from the NAC database and analysed retrospectively. The medical records were reviewed for factors that could affect posaconazole serum levels and the development of AEs. Seventy-two patients were included; 50 (69%) were male and the mean age was 48.5 ± 12 years. Therapeutic levels (≥1 mg/L) were achieved in 90% of cases on 200 mg versus 90% of cases on 300 mg daily (P = not significant). Based on multivariate analysis, female sex (P = 0.041), a 100 mg daily dose (P < 0.001), asthma (P = 0.01) and bronchiectasis (P = 0.001) were associated with subtherapeutic levels. Forty-nine (68%) patients developed AEs, mainly fatigue (37%), dyspnoea (18%) and nausea (12%). AEs were present on 115/196 (59%) occasions on 300 mg/day and on 45/115 (39%) occasions on 200 mg/day (P < 0.01). The mean level was 1.81 ± 0.96 mg/L for patients reporting no AEs and 1.90 ± 1.11 mg/L for those reporting AEs (P = not significant). Factors associated with AEs of grade ≥2 were a daily dose of 300 versus 200 mg (P = 0.001) and asthma (P = 0.008). A lower-than-recommended posaconazole tablet dose achieved therapeutic levels in most patients and was better tolerated. Males were more likely to achieve a therapeutic level. Underlying conditions affected the degree and frequency of AEs.

Co-administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed-released tablets in adult patients with haematological malignancies.

The aim of this study was to determine clinical variables associated with posaconazole exposure among adult patients with haematological malignancies who received posaconazole tablets for prophylaxis of invasive fungal infections (IFIs). The study population included adult patients with haematological malignancies who received posaconazole delayed-release tablets for prophylaxis of IFIs after induction chemotherapy for acute leukaemia or graft-versus-host-disease (GVHD) complicating hematopoietic stem cell transplantation (HSCT) in the period January 2016-December 2017. Sixty-six consecutive patients with 176 posaconazole Cmin were included for evaluation in the study. Subtherapeutic posaconazole concentrations (< 0.7mgl-1 ) were observed at least once in 33.3% of patients (22/66), and overall in 17.0% of therapeutic drug monitoring (TDM) episodes (30/176). At multilevel linear regression, use of PPIs (P=0.008), use of intermediate or high dose steroids (>0.7mgkg-1 daily) (P=0.022) and male gender (P=0.025) were significantly associated with decreased Cmin , whereas time from starting therapy (P=0.032) was associated with increased Cmin in our patient population. Posaconazole exposure during treatment with delayed-released tablet formulation may be affected by the use of PPIs and/or of intermediate or high dose steroids.

Low dose posaconazole delayed release tablets for fungal prophylaxis in lung transplant recipients.

In November 2013, posaconazole delayed release (DR) tablets were approved by the FDA with the labeled dose of 300mg daily for fungal prophylaxis. There are no studies demonstrating the appropriate dose in lung transplant recipients (LTR). We performed a 2-center retrospective cohort study of LTR taking posaconazole DR tablets for prophylaxis between January 2014 and January 2017. Mean serum trough concentrations and percentage of measurements ≥0.7mcg/mL were compared by daily dose. Forty-nine subjects with 156 steady state serum posaconazole concentrations were included. There was a significant difference in percentage of first measured concentration ≥0.7mcg/mL by initial daily dose (P=.04). The mean serum posaconazole concentration by dose was 0.9 (±0.42)mcg/mL for 100mg daily, 1.66 (±0.91)mcg/mL for 200mg daily, 2.39 (±1.49)mcg/mL for 300mg daily, and 1.75 (±0.21)mcg/mL for 400mg daily (P<.001). Mean concentrations were at goal in 63.3%, 96.9%, 94.9%, and 100% of subjects taking 100mg, 200mg, 300mg, and 400mg daily respectively (P=.04). Our results suggest that doses less than 300mg daily of posaconazole DR tablets may be adequate to achieve target serum concentrations in LTR. Larger studies are needed to confirm these findings.

Antifungal Prophylaxis with Posaconazole Delayed-Release Tablet and Oral Suspension in a Real-Life Setting: Plasma Levels, Efficacy, and Tolerability.

We continuously determined posaconazole plasma concentrations (PPCs) in 61 patients with hematological malignancies receiving posaconazole (PCZ) delayed-release tablets (DRT; 48 patients; median duration of intake, 92 days) and PCZ oral solution (OS; 13 patients; median duration of intake, 124 days). PCZ DRT and OS antifungal prophylaxis was efficient and well tolerated. Thirty-four of 48 patients (71%) receiving DRT always had PPCs of >0.7 mg/liter, while 14 of 48 patients (29%) had at least one PPC of ≤0.7 mg/liter. In patients receiving OS, 4 of 13 patients (31%) always had PPCs of >0.7 mg/liter, 6 of 13 patients (46%) had at least one PPC of ≤0.7 mg/liter, and 3 (23%) patients never reached a PPC of 0.7 mg/liter. In patients with at least one determined PPC, the mean proportion of all PPCs of >0.7 mg/liter was 91% for PCZ DRT, whereas it was 52% for PCZ OS (P = 0.001). In the per sample analysis, PPCs were significantly more likely to be >0.7 mg/liter in patients receiving DRT than in patients receiving OS (PPCs were >0.7 mg/liter in 91.4% [297/325] of patients receiving DRT versus 70.3% [85/121] of patients receiving OS; P < 0.001). Patients receiving PCZ DRT had higher proportions of PPCs of >0.7 mg/liter than patients receiving OS both in the per patient and in the per sample analyses. Two patients (3%) had side effects during PCZ prophylaxis, and one (2%) had fungal breakthrough infection. Therapeutic drug monitoring enables detection of extended periods of PPCs of ≤0.7 mg/liter (e.g., due to nonadherence or graft-versus-host disease), which may also be associated with the loss of protective intracellular PCZ concentrations, regardless of the PCZ formulation.

Posaconazole-Induced Hypertension and Hypokalemia: Mechanistic Evaluation

Background Recent studies have shown the new posaconazole delayed-release tablets have superior bioavailability compared with the liquid suspension formulation. As higher serum posaconazole concentrations have been associated with improved clinical responses, this formulation has been a welcome addition to available treatment options. However, higher serum and tissue levels are likely to reveal previously undescribed toxicity as adverse events attributed to “off-target” effects are observed.Methods We prospectively identified two patients with new onset hypertension, hypokalemia, and alkalosis after starting posaconazole tablets. Patient vital signs and laboratory values were within normal limits prior to starting posaconazole; however, following over 30 days of therapy both patients became newly hypertensive (mean systolic BP increase 59 mmHg). Serum posaconazole levels were 4.3–4.6 μg/ml. Complete suppression of renin and aldosterone, with increased 11-deoxycortisol, estradiol levels, and cortisol/cortisone ratios were observed in both patients. The TTKG in both patients was inappropriately elevated.ResultsPosaconazole-induced disruption of the steroid biosynthesis pathway in patients has not previously been described, but has been suggested by in vitro studies. Our patients’ laboratory results show clinically significant inhibition of 11β-hydroxysteroid dehydrogenase enzyme type 2 isoform (11β-HSD2) as evidenced by: the elevated 11-deoxycortisol (with subsequent suppression of renin and aldosterone), the highly elevated cortisol/cortisone ratio, and the inappropriately elevated TTKG in the setting of hypokalemia. The normal deoxycorticosterone confirms normal function of 11β-hydroxylase and the observed effects in our patients are thus downstream from this enzyme.Conclusion Our findings support in vitro predictions and highlight the clinical sequelae of posaconazole-mediated inhibition of 11β-HSD2. Additional studies are necessary to determine the frequency of posaconazole induced apparent mineralocorticoid excess syndrome and whether other azole antifungals can be associated with this phenomenon.Disclosures All authors: No reported disclosures.