Therapeutic Drug Monitoring Of Posaconazole Research Articles

Population Pharmacokinetic Modeling of Posaconazole in Japanese Patients Receiving Fungal Prophylaxis.

Posaconazole is a vital drug to treat and prevent invasive fungal infections. Several factors, such as sex, body weight, total serum proteins, dietary intake, and severe mucositis, affect posaconazole pharmacokinetics (PKs). However, the relevance of other factors that affect the PKs of posaconazole in hematopoietic stem cell transplantation (HSCT) is unknown. This study explored factors influencing the PKs of posaconazole in HSCT recipients and nontransplant patients with hematological diseases. The authors conducted a single-institution, retrospective study. Forty-two Japanese inpatients receiving oral posaconazole tablets as prophylaxis for fungal infections were enrolled in this study. A one-compartment model with first-order absorption was used as the structural pharmacokinetic model. A population PK (PopPK) analysis was performed using a nonlinear mixed-effects modeling program, using a first-order conditional estimation method with interactions. Perl-speaks-NONMEM and R were used to evaluate the goodness of fit and visualize the output. In 29% of the enrolled patients, the serum concentration of posaconazole was <0.5 mcg/mL, considered the effective range. PopPK analysis revealed that the patient had undergone HSCT within 1 year, diarrhea occurred more than 5 times a day, and aspartate aminotransferase were covariates that influenced apparent clearance (CL/F). The CL/F of posaconazole was 1.43-fold higher after HSCT and 1.26-fold higher during diarrhea. PopPK analysis revealed that HSCT, diarrhea, and aspartate aminotransferase were factors associated with the CL/F of posaconazole. The trough concentration of posaconazole may be below the therapeutic range in a few patients with diarrhea and/or after HSCT. As invasive fungal infections in patients with hematologic diseases can be life-threatening, therapeutic drug monitoring of posaconazole is strongly recommended, and patients should be carefully monitored.

Real-world Experience of Posaconazole Therapeutic Drug Monitoring in Oncology Patients: Clinical Implications of Hypoalbuminemia as a Predictor of Subtherapeutic Posaconazole Levels.

Posaconazole maintains broad antifungal activity and is employed for prevention and treatment of invasive fungal infections in oncology patients. Older formulations required therapeutic drug monitoring, and specific plasma drug levels have been recommended. This study evaluated factors associated with subtherapeutic concentrations with the newer delayed-release tablet formulation. In this retrospective, single-center cohort study at a national comprehensive cancer center, all oncology patients receiving delayed-release posaconazole at standard dosing of 300 mg orally per day from 06/2021 to 07/2023 with plasma drug concentration evaluation were identified. Demographic, clinical, and laboratory data were evaluated to identify risk factors associated with subtherapeutic drug levels at targets of ≥1.25 µg/mL and ≥1.8 µg/mL. Of 110 patients identified, 98 met criteria for inclusion in the study. The median time from initiation of posaconazole to drug level assessment was 13 days, and the median concentration was 1.29 µg/mL. Of the 22 patients receiving posaconazole for prophylaxis, 5 (22.7%) failed to achieve concentrations ≥0.7 µg/mL, and of 76 patients receiving posaconazole for treatment, 38 (50%) failed to achieve concentrations of ≥1.25 µg/mL. In multivariable analysis, albumin of ≤3 g/dL and ideal body weight ≥60 kg were found to be associated with subtherapeutic levels. For a higher target of ≥1.8 µg/mL, only albumin ≤3 g/dL was associated with subtherapeutic levels for the variables evaluated. A higher initial dosing strategy and therapeutic drug monitoring for oncology patients with albumin ≤3 g/dL receiving posaconazole, particularly for the treatment of invasive fungal infection, could be considered.

974. Real World Experience of Posaconazole Therapeutic Drug Monitoring in Oncology Patients: Clinical Implications of Hypoalbuminemia as a Predictor of Subtherapeutic Posaconazole Levels

Abstract Background Posaconazole (POS) is utilized for prophylaxis or treatment of invasive fungal infections (IFI) in patients with malignancies or following stem cell transplant (SCT). Subtherapeutic levels may be associated with breakthrough infection and therapeutic drug monitoring (TDM) is recommended. Timely measurements are not available at most institutions. We sought to identify factors associated with subtherapeutic POS levels in high-risk patients for IFI. Methods Patients at an NCI designated cancer center with POS level from 06/2021 to 07/2022 were evaluated for risk factors associated with subtherapeutic levels. Only patients with at least one level receiving oral delayed release tablets or IV formulations were included. Results A total of 66 patients were identified with 61 included. 46 had hematologic malignancies, 27 underwent SCT, 4 were treated with chimeric antigen receptor T cell therapy. Majority were male with a median age of 64 years old, a median BMI of 26.26 and a weight of 75.9 kilograms. POS was used for treatment of IFI in 53 patients. Median time from initiation to level was 13 days. The median level was 1.74mcg/mL. whereas for patients with a BMI above 30 (17/61), median level was 1.17mcg/mL. Hypoalbuminemia, defined as ≤ 3g/dL, was seen in 28 patients and was associated with statistically higher rates of sub-therapeutic levels for target levels reported for treatment of 1.25mcg/mL (18/28; p=0.004), 1.5mcg/mL (20/28; p=0.012) and 1.8mcg/mL (22/28; p=0.016). Only one breakthrough IFI occurred on patients receiving POS for prophylaxis compared to two patients receiving POS for treatment: both with subtherapeutic levels. Only one patient discontinued the drug due to intolerance. No discontinuations occurred due to liver toxicity or QTc prolongation. Conclusion Therapeutic levels are critical for treatment and prophylaxis of IFI in oncology patients and delays in accurate measurements are common. In our analysis, hypoalbuminemia was associated with subtherapeutic levels at standard dosing, and higher initial dosing may be considered in high-risk patients with hypoalbuminemia particularly for treatment of IFI. Disclosures All Authors: No reported disclosures

Association of adverse effects with high serum posaconazole concentrations.

Posaconazole therapeutic drug monitoring (TDM) is widely utilized to assess therapeutic efficacy and safety; however, clinical effects of very high serum concentrations are unknown. A retrospective review of 90 patients receiving posaconazole for treatment or prophylaxis of invasive fungal infections with serum concentrations ≥3000ng/mL from 1/1/2019 to 4/30/2021 evaluated the incidence and type of adverse drug reactions (ADRs). Symptomatic ADRs were very common in patients with posaconazole concentrations of ≥5000ng/mL and 3000-4999ng/mL (80% vs. 58.8%; P=0.31). Posaconazole TDM should be performed for both treatment and prophylaxis indications and dose decrease for serum concentrations >3000ng/mL should be considered.

Model Based Estimation of Posaconazole Tablet and Suspension Bioavailability in Hospitalized Children Using Real-World Therapeutic Drug Monitoring Data in Patients Receiving Intravenous and Oral Dosing.

Invasive fungal infections are a major cause of morbidity and mortality for immunocompromised patients. Posaconazole is approved for treatment and prophylaxis of invasive fungal infection in adult patients, with intravenous, oral suspension, and gastroresistant/delayed-released tablet formulations available. In Europe, until very recently, posaconazole was used off-label in children, although a new delayed-release suspension approved for pediatric use is expected to become available soon. A population pharmacokinetic model was developed which uses posaconazole therapeutic drug monitoring data following intravenous and oral dosing in hospitalized children, thus enabling estimation of pediatric suspension and tablet oral bioavailability. In total, 297 therapeutic drug monitoring plasma levels from 104 children were included in this analysis. The final model was a one-compartment model with first-order absorption and nonlinear elimination. Allometric scaling on clearance and volume of distribution was included a priori. Tablet bioavailability was estimated to be 66%. Suspension bioavailability was estimated to decrease with increasing doses, ranging from 3.8% to 32.2% in this study population. Additionally, concomitant use of proton pump-inhibitors was detected as a significant covariate, reducing suspension bioavailability by 41.0%. This is the first population pharmacokinetic study to model posaconazole data from hospitalized children following intravenous, tablet, and suspension dosing simultaneously. The incorporation of saturable posaconazole clearance into the model has been key to the credible joint estimation of tablet and suspension bioavailability. To aid rational posaconazole dosing in children, this model was used alongside published pharmacodynamic targets to predict the probability of target attainment using typical pediatric dosing regimen.

Drug-drug interaction: decreased posaconazole trough concentrations during concomitant flucloxacillin treatment.

Posaconazole is used as prophylaxis of invasive fungal disease in immune-compromised haematological patients with prolonged neutropenia after intensive chemotherapy. During routine therapeutic drug monitoring of posaconazole, we repeatedly observed low posaconazole serum concentrations in patients that were concomitantly treated with flucloxacillin. A possible interaction between flucloxacillin and posaconazole was explored in this case series. Posaconazole trough serum concentrations during and before/after flucloxacillin treatment were collected from 10 patients. With a median concentration of 0.5 mg/L (IQR 0.3-0.6), the posaconazole trough serum concentration decreased by 47% during flucloxacillin treatment compared with the concentration before/after flucloxacillin treatment (0.9 mg/L, IQR 0.6-1.3). As a result, the posaconazole target trough concentration of ≥0.7 mg/L was only achieved in five out of nine patients during flucloxacillin treatment. Careful monitoring of posaconazole serum trough concentrations is recommended when concomitant use of flucloxacillin cannot be avoided.

Subtherapeutic concentrations of posaconazole tablet: determining risk factors and effectiveness of a standardized dose adjustment in hematology inpatients

Posaconazole is indicated for antifungal prophylaxis in hematology patients at high-risk of invasive fungal infections (IFI). Consensus guidelines recommend maintaining steady-state trough concentrations above 0.7 mg/L; however, upto one-third of patients return subtherapeutic concentrations which is associated with breakthrough IFI. This retrospective observational study of 496 concentrations from 90 hematology inpatients prescribed posaconazole tablet (PCZ-tab) between May 2017 and May 2019 identified 24% (n = 121) of posaconazole concentrations were subtherapeutic after the dosage of 300 mg daily. On multivariable analyses, diarrhea (p = 0.002), male gender (p = 0.018), and concurrent regular metoclopramide (p = 0.002) were significantly associated with subtherapeutic posaconazole concentrations. Eighty-nine percent of patients (n = 16) who underwent dose adjustment to 200 mg twice daily successfully achieved target posaconazole concentrations at first steady-state measurement. This study confirms that therapeutic drug monitoring of posaconazole remains necessary as subtherapeutic posaconazole concentrations are relatively common, and that dose adjustment of 200 mg twice daily, safely enabled achievement of therapeutic concentrations.

P05 The impact of COVID-19 on antifungal stewardship in a UK tertiary teaching hospital: a review of prescribing practices and therapeutic drug monitoring of posaconazole

BackgroundPosaconazole is a triazole antifungal licensed for the prevention of invasive fungal infections (IFI) in haemato-oncology patients and treatment of IFI where first-line therapy has failed. In January 2020 COVID-19 hit the UK, with many NHS services reduced to meet the unprecedented challenges of the pandemic. We audited prescriptions and therapeutic drug monitoring (TDM) of posaconazole and compared the results with an audit conducted pre-COVID-19 to assess the impact of the pandemic on antifungal stewardship (AFS).MethodsInpatients prescribed posaconazole over two 3 month periods (1 October to 31 December 2019 and 2020) at Addenbrooke's Hospital, Cambridge, were identified using an electronic computer system and their records reviewed for demographic, diagnostic and therapeutic data. Posaconazole levels were performed at the national Mycology Reference Laboratory, Bristol, using guide levels of 0.7–3.75 mg/L (prophylaxis) and 1–3.75 mg/L (treatment). The first pre-dose level for each patient was used in analyses. Audit standards included (i) all inpatients on posaconazole to have an indication in local guidelines; (ii) to have the correct loading dose prescribed; (iii) to have a pre-dose level taken (iv) at the correct time (i.e. between Day 3–8) after commencing therapy or a dose change; (v) to have a turnaround time of ≤5 days; and (vi) to stop posaconazole appropriately.ResultsForty-two 42 inpatients received posaconazole in 2020 (49, 2019). In total, 39/42 (93%) patients had an appropriate indication [46/49, (94%), 2019]: 38/40 (95%) for prophylaxis [45/45, (100%) 2019]; 1/2 (50%) for treatment [1/1, (100%) 2019]. In 2020, 34/42 (81%) of patients received the correct loading dose [41/46 (89%), 2019). TDM was performed on 33/42 (79%) patients [46/46 (100%), 2019], 18/42 (43%) 3–8 days after starting [25/46 (54%), 2019] and 3/13 (23%) after a dose change [9/10 (90%), 2019]; 32/33 (97%) of TDM results were reported in ≤5 days [32/46 (70%), 2019]. Posaconazole was stopped in 24/26 (92%) patients who were no longer receiving immunosuppression and/or neutropenia had resolved [23/23 (100%), 2019].ConclusionsDespite the pressures of COVID-19, there were good standards of care with only slight reductions in compliance, with the exception of TDM. This may have reflected the change from face-to-face to virtual meetings with haemato-oncology, as well as representing issues of staff shortages and changes in hospital priorities. Such data have highlighted the usefulness of technology to facilitate AFS, e.g. electronic prescribing order sets, which would provide us with quality assurance in a system that will be facing ongoing pressures from the pandemic for years to come.

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.

Therapeutic drug monitoring of posaconazole for effective prophylaxis of invasive fungal infections in pediatric patients: a pilot study

Introduction: Posaconazole, a second-generation triazole agent, is a drug with wide interindividual variation in bioavailability and variability of pharmacokinetics. The European Conference on Infections in Leukemia recommends the implementation of posaconazole therapeutic drug monitoring (TDM) in children to provide certainty regarding the efficacy of treatment and to increase its safety. A concentration of posaconazole in plasma in prophylactic regimens of above 0.7 mg/L is recommended. The aim of our pilot study was to discover the most effective method of posaconazole plasma concentration measurement, and to analyze posaconazole pharmacokinetics profiles in pediatric patients on posaconazole prophylaxis. Material and methods: Children receiving oncological treatment or hematopoietic stem cell transplantation in the Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology in Wroclaw Medical University Hospital were included in the trial. Posaconazole concentration was determined at the MonitLabTM laboratory using a newly validated high-performance liquid chromatography with fluorescence detector method. Results : Initial analysis shows that the major problem in patients on antifungal prophylaxis is inadequately low plasma drug concentration. Conclusions: Clinical trials on TDM of posaconazole should be developed.

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach.

Therapeutic drug monitoring (TDM) of antifungal triazole was recommended, except for isavuconazole (ISA) whose target trough concentrations (Cmin ) need to be specified. Concerning posaconazole (POS), tablet formulation results in higher exposure but no upper Cmin threshold has been yet proposed. We aimed to investigate the pharmacokinetic-pharmacodynamic relationship of POS and ISA, using a bioassay approach as surrogate marker of antifungal activity, in order to refine the therapeutic Cmin of both antifungals. A bioassay using a cellulose disk diffusion method was performed to determine the growth inhibition zone (GIZ) of POS and ISA on Aspergillus fumigatus and Candida parapsilosis (ISA only). GIZs of plasma from patients undergoing TDM for POS (n=136) or ISA (n=40) were determined. GIZs of plasma patients and antifungal Cmin were highly correlated for ISA (A.fumigatus: ρ=0.942, P<0.0001; C.parapsilosis: ρ=0.949, P<0.0001) and POS (ρ=0.922, P<0.0001), and these relationships were represented with a Michaelis-Menten model. Based on this modeling, the recommended thresholds of 0.7, 1, and 1.25mg/L for the POS Cmin corresponded to 50.1, 55.2, and 59.1% of the maximal GIZ, respectively. We propose an upper threshold of 4.8mg/L for the POS Cmin and a lower threshold of 2.0mg/L for the Cmin of ISA, as they respectively corresponded to concentrations leading to 90% and 50% of the maximal GIZ on A.fumigatus. The determination of antifungal activity using this bioassay allowed refining target Cmin of POS and ISA, especially the upper threshold of POS (4.8mg/L) and the lower threshold of ISA (2.0mg/L).

Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations.

SummaryPosaconazole is indicated for prophylaxis and treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) of posaconazole is used to optimise drug exposure. The aim of this study was to analyse and describe the TDM practices and exposure of posaconazole tablets. Patients who received posaconazole for treatment or prophylaxis of fungal infections were included in the study. The following therapeutic window was defined: if concentration was low (<0.7 mg/L for prophylaxis or < 1.5 mg/L for treatment) or high (>3.75 mg/L), the hospital pharmacist provided the physician with dosage advice, which implementation to patient care was analysed. A longitudinal analysis was performed to analyse if different confounding variables had an effect on posaconazole concentrations. Forty‐seven patients were enrolled resulting in 217 posaconazole trough concentrations. A median of 3 (IQR 1‐7) samples was measured per patient. The median concentration was 1.7 mg/L (IQR 0.8‐2.7) for prophylaxis and 1.76 mg/L (IQR 1.3‐2.3) for treatment. Overall, 78 posaconazole concentrations were out of the therapeutic window. For 45 (54%) of these concentrations, a dosage change was recommended. In the longitudinal analysis, the laboratory markers and patient baseline variables did not have an effect on posaconazole concentrations. Adequate posaconazole exposure was shown in 64% (affected 28 patients) of the measured concentrations. TDM practice of posaconazole can be improved by increasing the implementation rate of dose recommendation by a multidisciplinary antifungal stewardship team.

Posaconazole trough concentrations are not influenced by inflammation: A prospective study

During inflammation, several cytochrome P450 enzymes are downregulated. Recently it was shown that voriconazole metabolism is reduced during inflammation. Posaconazole, another triazole with broad-spectrum antifungal activity, is metabolised only to a limited extent by cytochrome P450 enzymes and to a wider extent by phase 2 enzyme systems. The aim of this study was to investigate posaconazole concentrations during inflammation. Patients aged ≥18 years receiving posaconazole prophylaxis or treatment for fungal infections were enrolled in a prospective observational study. Samples for posaconazole and C-reactive protein (CRP) concentrations were collected routinely for each patient. Longitudinal data analysis was performed to analyse the correlation between posaconazole serum trough concentrations and CRP values, corrected for potential factors that could influence the posaconazole concentration. Between August 2015 and June 2017, 64 patients were recruited to this study. Data for 55 patients (511 posaconazole samples) were included in the final analysis. The overall median posaconazole concentration was 1.8 mg/L [interquartile range (IQR) 1-2.9 mg/L, range 0.1-7.94 mg/L] and the overall median CRP concentration was 23.5 mg/L (IQR 5-75 mg/L, range 0-457 mg/L). Longitudinal data analysis showed that only the posaconazole daily dose (in mg/kg body weight) had a significant influence on posaconazole concentration after correction for other factors (P < 0.0001). Posaconazole concentrations were not influenced by CRP concentrations (P = 0.77). Posaconazole concentrations are not influenced by inflammation, reflected by CRP concentration. Therefore, more frequent therapeutic drug monitoring of posaconazole during inflammation or after an infection subsides is not necessary.

A Novel, Rapid, and Low-Volume Assay for Therapeutic Drug Monitoring of Posaconazole and Other Long-Chain Azole-Class Antifungal Drugs.

Clinicians need a better way to accurately monitor the concentration of antimicrobials in patient samples. In this report, we describe a novel, low-sample-volume method to monitor the azole-class antifungal drug posaconazole, as well as certain other long-chain azole-class antifungal drugs in human serum samples. Posaconazole represents an important target for therapeutic drug monitoring (TDM) due to its widespread use in treating invasive fungal infections and well-recognized variability of pharmacokinetics. The current "gold standard" requires trough and peak monitoring through high-pressure liquid chromatography (HPLC) or liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Other methods include bioassays that use highly susceptible strains of fungi in culture plates or 96-well formats to monitor concentrations. Currently, no method exists that is both highly accurate in detecting free drug concentrations and is also rapid. Herein, we describe a new method using reduced graphene oxide (rGO) and a fluorescently labeled aptamer, which can accurately assess clinically relevant concentrations of posaconazole and other long-chain azole-class drugs in little more than 1 h in a total volume of 100 µl.IMPORTANCE This work describes an effective assay for TDM of long-chain azole-class antifungal drugs that can be used in diluted human serum samples. This assay will provide a quick, cost-effective method for monitoring concentrations of drugs such as posaconazole that exhibit well-documented pharmacokinetic variability. Our rGO-aptamer assay has the potential to improve health care for those struggling to treat fungal infections in rural or resource-limited setting.

Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis

BackgroundPosaconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of posaconazole TDM and the target of posaconazole plasma concentration for clinical successful prophylaxis remain uncertain and controversial. The aim of this study was to evaluate posaconazole exposure-response relationship and determine an optimum posaconazole concentration for prophylaxis against invasive fungal infections (IFIs).MethodsBibliographic databases were searched (from inception to September 2017) to select studies including the clinical outcomes below and above concentration cut-off value of 0.5 mg/L and 0.7 mg/L. The reliability of the results were evaluated with trial sequential analysis (TSA).ResultsTwenty-eight studies with 1930 patients included were analyzed. The results of our pooled analysis demonstrated that patients with posaconazole plasma concentrations over 0.5 mg/L were twice more likely to achieve successful responses compared with those with lower concentrations (odds ratio, OR = 1.98, 95% confidence interval, CI 1.09–3.58, P = 0.02) while the threshold, 0.7 mg/L showed no significant difference (OR = 1.84, 95% CI 0.94–3.63, P = 0.08). The TSA results showed that there was sufficient information to support these findings.ConclusionsAn optimal posaconazole concentration target of 0.5 mg/L is suggested to ensure the clinical prophylactic efficacy and may help reduce the dosage and dose-dependent toxicity comparing with the target of 0.7 mg/L.

Early Therapeutic Drug Monitoring of Posaconazole Oral Suspension in Patients With Hematologic Malignancies.

Therapeutic drug monitoring (TDM) of posaconazole is usually performed 1 week after starting the drug because of its long half-life. However, previous studies showed that measuring the posaconazole plasma concentration (PPC) on day 3 is effective for predicting steady-state levels. The purpose of this study was to evaluate the relevance of early TDM (day 3) of posaconazole for achieving an optimal PPC. This prospective study was conducted from September 2014 to August 2016. A total of 148 patients with acute myeloid leukemia or myelodysplastic syndromes received a 200 mg posaconazole oral suspension 3 times daily for fungal prophylaxis. During the period from September 2014 to December 2015 (control group), no dose adjustment was performed on day 3. During the period from January 2016 to Aug 2016 (early TDM group), the frequency of posaconazole 200-mg administration was increased to 4 times daily in patients whose PPC on day 3 was <400 ng/mL. The cutoff value for optimal PPC on day 8 was defined as 500 ng/mL. In 21 of 107 patients (20%) in the control group, PPC was <400 ng/mL on day 3. In 15 (71%) of these 21 patients, the PPC was suboptimal on day 8. In the early TDM group, the PPC was <400 ng/mL on day 3 in 4 of 41 patients (10%). After increasing the posaconazole administration frequency in these 4 patients, PPC was suboptimal on day 8 in 1 patient (25%). In both groups, 104 patients had a PPC of ≥500 ng/mL on day 3, but 7% (7/104) of these had a suboptimal level on day 8. Early TDM on day 3 for posaconazole suspension may help more patients achieve optimal drug levels on day 8, although TDM on day 8 is needed even in patients with optimal levels on day 3.

Single-centre study of therapeutic drug monitoring of posaconazole in lung transplant recipients: factors affecting trough plasma concentrations.

This study describes therapeutic drug monitoring (TDM) of posaconazole suspension and modified release (MR) tablets in lung transplant (LTx) recipients and evaluates factors that may affect posaconazole trough plasma concentration (Cmin). A single-centre, retrospective study evaluating posaconazole Cmin in LTx recipients receiving posaconazole suspension or MR tablets between January 2014 and December 2016. Forty-seven LTx patients received posaconazole suspension, and 78 received the MR tablet formulation; a total of 421 and 617 Cmin measurements were made, respectively. Posaconazole was concurrently administered with proton pump inhibitor in ≥ 90% of patients. The median (IQR) of initial posaconazole Cmin following 300 mg daily of posaconazole tablet was significantly higher than that of 800 mg daily of posaconazole suspension [1.65 (0.97-2.13) mg/L versus 0.81 (0.48-1.15) mg/L, P < 0.01]. Variability in posaconazole Cmin was apparent regardless of the formulations prescribed and dose adjustments were routinely undertaken to maintain therapeutic Cmin. A clear dose-response relationship was observed in patients receiving posaconazole MR tablets. Non-specific adverse events (fatigue, tremor, lethargy, sweating, nausea/vomiting and weight loss) were reported in 3/78 (4%) patients receiving posaconazole MR tablets. Posaconazole Cmin in these three patients was determined to be 9.6, 6.2 and 2.3 mg/L. The current study has provided clinically important insights into the TDM of posaconazole in LTx recipients. Routine TDM should be undertaken in LTx recipients receiving posaconazole suspension and/or MR tablets.

Evaluation of Posaconazole Pharmacokinetics in Adult Patients with Invasive Fungal Infection.

Mortality and morbidity due to invasive fungal infections have increased over the years. Posaconazole is a second-generation triazole agent with an extended spectrum of activity, which shows a high interindividual variability in its plasma levels, rendering dosing in many patients inconsistent or inadequate. Hence, posaconazole therapeutic drug monitoring, which is easily available in clinical practice, may improve treatment success and safety. The aim of the study was to describe posaconazole pharmacokinetics, and to evaluate the utility of therapeutic drug monitoring for therapy and prophylaxis in a cohort of adult patients. A fully validated chromatographic method was used to quantify posaconazole concentration in plasma collected from adult patients at the end of the dosing interval. Associations between variables were tested using the Pearson test. The Mann-Whitney test was used to probe the influence of categorical variables on continuous ones. A high inter-individual variability was shown. Of the 172 enrolled patients, among those receiving the drug by the oral route (N = 170), gender significantly influenced drug exposure: males showed greater posaconazole concentration than females (p = 0.028). This study highlights the importance of therapeutic drug monitoring in those with invasive fungal infections and its significant clinical implications; moreover we propose, for the first time, the possible influence of gender on posaconazole exposure.

Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses.

Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infections (IFIs) in patients with hematological malignancy. Delayed-release tablet and intravenous formulations of posaconazole have recently become available, but clinical data are limited. We sought to examine the real-world pharmacokinetics and prophylactic effectiveness of the new formulations of posaconazole given as prophylaxis for patients with hematological malignancy. A retrospective cohort of all consecutive adult inpatients with hematological malignancy who received ≥3 days of tablet or intravenous posaconazole therapy for primary IFI prophylaxis at the M. D. Anderson Cancer Center between 1 December 2013 and 31 December 2015 was established. Clinical information was collected and correlated with low posaconazole serum levels (<700 ng/ml). Rates of IFIs and safety events were assessed. A total of 1,321 courses of posaconazole were administered at the M. D. Anderson Cancer Center during the study period, of which 343 courses were assessed for prophylactic safety and effectiveness. Seventy-nine patients (23%) had posaconazole serum level measurements available for interpretation. Acute myeloid leukemia was the primary malignancy (62%), with 20% of all patients having previously received a stem cell transplant. The median posaconazole level was 1,380 ng/ml (interquartile range, 864 to 1,860 ng/ml). Low posaconazole levels (<700 ng/ml) were observed for 14 patients (18%). Proven or probable breakthrough IFIs occurred in 8 patients (2%); posaconazole therapeutic drug monitoring (TDM) was performed for 6 of those patients, all with levels above 700 ng/ml. Overall, 19% of patients experienced grade 3 or 4 liver injury, manifesting primarily as hyperbilirubinemia and being correlated with serum levels of >1,830 ng/ml. Although hepatotoxicity in a small percentage of patients is of concern, posaconazole tablets appeared to be generally safe and effective. As all breakthrough IFIs for which TDM was performed occurred in patients with levels of >700 ng/ml, and a posaconazole level of >1,830 ng/ml was correlated with grade 3 or 4 liver toxicity, further studies are needed to assess the role of TDM.

Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations.

Therapeutic drug monitoring (TDM) may be required to achieve optimal clinical outcomes in the setting of significant pharmacokinetic variability, a situation that applies to a number of anti-mould therapies. The majority of patients receiving itraconazole should routinely be managed with TDM. Voriconazole exhibits highly variable inter-individual pharmacokinetics, and a trough concentration of 1.0-5.5 mg/L is widely accepted although it is derived from relatively low-quality evidence. The case for TDM of posaconazole is currently in a state of flux following the introduction of a newer tablet formulation with improved oral bioavailability, but it may be indicated when used for either prophylaxis or treatment of established disease. The novel broad-spectrum azole drug isavuconazole does not currently appear to require TDM but 'real-world' data are awaited and TDM could be considered in selected clinical cases. For both polyene and echinocandin agents, there are insufficient data regarding the relationship between serum concentrations and therapeutic outcomes to support the routine use of TDM. A number of practical challenges to the implementation of TDM in the treatment of invasive mould infections remain unsolved. The delivery of TDM as a future standard of care will require real-time measurement of drug concentrations at the bedside and algorithms for dosage adjustment. Finally, measures of pharmacodynamic effect are required to deliver therapy that is truly individualized.