Posaconazole Plasma Concentrations Research Articles

Dosing of IV posaconazole to treat critically ill patients with invasive pulmonary aspergillosis: a population pharmacokinetics modelling and simulation study.

Posaconazole is used for the prophylaxis and treatment of invasive fungal infections in critically ill patients. Standard dosing was shown to result in adequate attainment of the prophylaxis Cmin target (0.7 mg/L) but not of the treatment Cmin target (1.0 mg/L). To provide an optimized posaconazole dosing regimen for IV treatment of patients with invasive pulmonary aspergillosis in the ICU. A population pharmacokinetics (popPK) model was developed using data from the POSA-FLU PK substudy (NCT03378479). Monte Carlo simulations were performed to assess treatment Cmin and AUC0-24 PTA. PTA ≥90% was deemed clinically acceptable. PopPK modelling and simulation were performed using NONMEM 7.5. Thirty-one patients with intensive PK sampling were included in the PK substudy, contributing 532 posaconazole plasma concentrations. The popPK of IV posaconazole was best described by a two-compartment model with linear elimination. Interindividual variability was estimated on clearance and volume of distribution in central and peripheral compartments. Posaconazole peripheral volume of distribution increased with bodyweight. An optimized loading regimen of 300 mg q12h and 300 mg q8h in the first two treatment days achieved acceptable PTA by Day 3 in patients <100 kg and ≥100 kg, respectively. A maintenance regimen of 400 mg q24h ensured ≥90% Cmin PTA, whereas the standard 300 mg q24h was sufficient to achieve the AUC0-24 target throughout 14 days, irrespective of bodyweight. We have defined a convenient, optimized IV posaconazole dosing regimen that was predicted to attain the treatment target in critically ill patients with invasive aspergillosis.

Personalized Antifungal Therapy Through Model-Informed Precision Dosing of Posaconazole.

Posaconazole is a pharmacotherapeutic pillar for prophylaxis and treatment of invasive fungal diseases. Dose individualization is of utmost importance as achieving adequate antifungal exposure is associated with improved outcome. This study aimed to select and evaluate a model-informed precision dosing strategy for posaconazole. Available population pharmacokinetic models for posaconazole administered as a solid oral tablet were extracted from the literature and evaluated using data from a previously published prospective study combined with data collected during routine clinical practice. External evaluation and selection of the most accurate and precise model was based on graphical goodness-of-fit and predictive performance. Measures for bias and imprecision included mean percentage error (MPE) and normalized relative root mean squared error (NRMSE), respectively. Subsequently, the best-performing model was evaluated for its a posteriori fit-for-purpose and its suitability in a limited sampling strategy. Seven posaconazole models were evaluated using 764 posaconazole plasma concentrations from 143 patients. Multiple models showed adequate predictive performance illustrated by acceptable goodness-of-fit and MPE and NRMSE below ±10% and ±25%, respectively. In the fit-for-purpose analysis, the selected model showed adequate a posteriori predictive performance. Bias and imprecision were lowest in the presence of two prior measurements. Additionally, this model showed to be useful in a limited sampling strategy as it adequately predicted total posaconazole exposure from one (non-)trough concentration. We validated an MIPD strategy for posaconazole for its fit-for-purpose. Thereby, this study is an important first step towards MIPD-supported posaconazole dosage optimization with the goal to improve antifungal treatment in clinical practice.

Single-Dose Crossover Comparative Bioavailability Study of Two Different Posaconazole 100 mg Gastro-Resistant Tablets Under Fasted and Fed Conditions in Healthy Volunteers.

This study aimed to compare the bioavailability of two different gastro-resistant oral tablet formulations of posaconazole under fasted and fed conditions and to evaluate a potential food effect on the bioavailability of each formulation. Healthy volunteers randomly assigned to receive a test product (Posagil® 100 mg gastro-resistant tablet) or reference product (Noxafil® 100 mg gastro-resistant tablet) were included in this single-center, randomized, four-period (days 1, 15, 29 and 43), four-sequence crossover comparative bioavailability study. Data on posaconazole plasma concentrations and related pharmacokinetic profile (the maximum observed plasma concentration [Cmax] from time 0 to the time of last observed quantifiable plasma concentration [AUC0-T] and from time zero to infinity [AUC0-∞]) were recorded to evaluate efficacy of the test product in relation to the reference product under both fasted and fed conditions, based on bioequivalence (T-fasted vs. R-fasted and T-fed vs. R-fed) and food effect (T-fasted vs. T-fed and R-fasted vs. R-fed) assessments. Safety was evaluated through assessment of adverse events (AEs), standard laboratory evaluations, and vital signs. The bioequivalence criteria were met under fed conditions (T-fed vs. R-fed: geometric LSMean ratios of Cmax, AUC0-T, and AUC0-∞ of posaconazole were 97.41%, 97.45%, and 97.08%, respectively; all within the range of 80% to 125%) but not under fasted conditions. There was a food effect on the reference product (R-fed vs. R-fasted: geometric LSMean ratios of Cmax, AUC0-T, and AUC0-∞ of posaconazole were 145.32%, 138.84%, and 138.46%, respectively) but not on the test product. No safety concerns were identified. Our findings suggest that the pharmacokinetic profile of Posagil® is similar to the pharmacokinetic profile of Noxafil®. The generic Posagil® seems to have similarly high bioavailability under fed and fasted conditions, offering a higher posaconazole exposure than the original Noxafil® in the fasted state. Hence, Posagil® may be considered a value-added generic product that offers adequate posaconazole exposure under fasted state and fed state, regardless of the concomitant high-fat meal intake.

Pharmacogenetics and Pharmacokinetics of Posaconazole in Patients with Acute Myeloid Leukemia: Useful Tools for Antifungal Stewardship

DISCUSSION INTRODUCTION Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy is usually recommended [1]. Few studies described the clinical impact of suboptimal posaconazole plasma concentrations during prophylaxis, which may be associated with a higher risk of invasive fungal infections (IFI) and a strong impact on clinical outcome [2]. ENDPOINT: The primary endpoint of this study was to evaluate weekly posaconazole Cthrough plasma concentration in AML patients treated with induction chemotherapy. Since polymorphisms of genes encoding enzymes, transporters and transcription factors were also analyzed a possible association amongst plasma exposure, genetic polymorphisms, risk of breakthrough infection and clinical outcam was evaluated . MATERIALS AND METODS: This was a prospective, single center study at “City of Health and Science”, Molinette Hospital in Turin, Italy. Adult Patients with AML undergoing induction chemotherapy admitted to Haematological wards, were enrolled between March 2023 and July 2023. Antifungal prophylaxis with oral posaconazole, 300mg bid the first day and 300 mg qd thereafter was given. Biological samples (plasma for posaconazole quantificatication and whole blood for genetics) were obtained for each patient after loading dose and then posaconazole C trough were evaluated weekly (at 7, 14, 21 and 28 days). The Following genes were evaluated: UGT1A1, UGT1A3, ABCB1, ABCG2, ABCC2, ABCB11, SLCO1B1, SLCO1B3, SLC22A6, PXR, CAR, VDR, CYP27B1, CYP24A1, GC. The mortality was assessed at day 28 from hospital admission. Invasive fungal disease (IFD) was defined as the occurence of a proven or probable IFD according to the European Organization for Research and Treatment of Cancer/National insitute of Allergy and Infection Diseases Micoses Study Group Criteria (EORTC/MSG) revised definitions [3]. Furthermore, according to the clinical suspicion of breakthrough infection, the switch from prophylaxis to antifungal therapy was also recorded as well as antifungal restaging before treatment change. RESULTS: Twenty patients were included: 9 were women (45%) with a median age of 67 years old (±10.5) and a median Charlson Comorbidity Index of 5 (±1.3). Mean posaconazole C through plasma concentrations are reported in Table 1 and were in range for all the different timepoints. According to EORTC criteria, two patients (10%) had a probable IFI on day 14, and antifungal therapy with liposomal amphotericin B was started [3]. One of those patients had low C trough value at time of suspected breaktrough infection (T 14; 0.2 microg/L 9). The 28 day mortality was 10%, due to the haematological underlying disease. Regarding pharmacogenetic analysis, posaconazole C trough at day 7 and 14 was associated with ABCB1 1236 polymorphism with p=0.022 and p=0.038, respectively. Furthermore, VDR ApaI (p=0.010), VDR TaqI (p=0.023), VDR BsmI (p=0.042), ABCB11 (p=0.023) and UGT1A3 023 (p=0.023) genetic variants were reported in patients with probable IFI. There is a potential impact of the use of posaconazole plasma levels monitoring and associated pharmacogenetics to evaluate the risk of underexposure during antifungal prophylaxis, but also at antifungal restaging before treatment switch. These useful tools may help clinicians to identify patients with a higher risk for under-effective plasma concentrations of posaconazole and can be used to improve antifungal stewardship approach in this setting. The utility of such approaches should also be evaluated in azole-to-azole strategies BIBLIOGRAPHY Olivia White et al. Isavuconazonium or posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia. J Oncol Pharm Pract 2023 May 15;10781552231175825. doi: 10.1177/10781552231175825.Tang LA et al. Risk factors for subtherapeutic levels of posaconazole tablet. J Antimicrob Chemother. 2017 Oct 1;72(10):2902-2905. doi: 10.1093/jac/dkx228. PMID: 29091205Peter Donnelly et al. Revision and update of the Consensus definition of Invasive Fungal Disease from the European Organization for Research adn Treatment of Cancer and the Mycoses study Group Education and Research Consortium. Clin Infect Dis 2020 Sep 12;71(6):1367-1376. doi: 10.1093/cid/ciz1008.

The Effects of Mycophenolate Mofetil and Cyclosporine with Concomitant Posaconazole Tablets in the Early Stage of Allogeneic Hematopoietic Stem Cell Transplantation

Background： Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) mainly applied the “Beijing regimen”(cyclosporine + methotrexate + mycophenolate mofetil（MMF）). This approach significantly reduces the risk of graft-versus-host disease (GVHD), increases the risk of infection. Posaconazole can significantly reduce the incidence of invasive fungal disease (IFD) during the immunosuppressive phase. Cyclosporine and posaconazole have significant drug interactions, with MMF also have drug interactions. However, there is limited research about drug interactions of simultaneous three-drug combination. Objective： Explore the effects of MMF and cyclosporine with concomitant posaconazole in allo-HSCT patients within 30 days and the breakthrough incidence of IFD within 100 days post-transplantation. Method: A single-arm, open-label, prospective trial was conducted to evaluate posaconazole tablet (300 mg q12h oral d1,300 mg/d) as secondary antifungal prophylaxis in allo-HSCT patients (18-65 years old) with previous proven or probable IFD (ChiCTR2200059472). Posaconazole and cyclosporine were started when conditioning began, while MMF was used one day before infusion of stem cell for one month with fixed dose of 2 g/d. The plasma concentration of posaconazole and mycophenolic acid (MPA) which is the active ingredient of MMF, were monitored weekly, cyclosporine was monitored twice one week until 30 days post-transplantation. Results: Thirty patients from July 2022 to March 2023 were enrolled in the trial, included 16 males and 14 females, acute myelogenous leukemia 22, acute lymphoblastic leukemia 2, myelodysplastic syndrome 2, aplastic anemia 4. All patients underwent haploidentical HSCT. All patients had history of IFD(5 proven IFD, 13 probable IFD and 12 possible IFD). At week1, 2, 3 and 4 after conditioning, The mean plasma concentrations of posaconazole were 0.47±0.29ug/ml, 0.66±0.32ug/ml,0.72±0.40ug/ml and 0.91±0.32ug/ml（Figure 1）. The mean plasma concentrations of cyclosporine were 138.20±35.33ng/ml, 190.61±48.07ng/ml,245.46±37.31ng/ml and 253.56±45.19ng/ml（Figure 2）.The mean plasma concentrations of MPA at week 2, 3 and 4 were 0.35±0.15mg/L, 0.89±0.36mg/L and 1.18±0.58mg/L (Figure 3). After week 1, concentration of cyclosporine of 13 cases was below 150ng/ml and the dosage was increased by 25% of the original dose, at week 4, concentration of cyclosporine of 9 cases was above 250ng/ml and the dosage was decreased by 25%. After posaconazole reached steady state concentrations at week 2, while cyclosporine reached target concentrations after the dose increase, MPA did not reach target concentrations at week 2. The concentrations of MPA significant increase without changing the MMF dose and reached target concentrations at week 3 simultaneous three-drug combination. Cyclosporine concentrations increased significantly at week 4 with stable concentrations of MPA and posaconazole, and 30% of patients required dose reduction of cyclosporine. Only one patient was diagnosed as aspergillus fumigatus pneumonia through NGS of pulmonary alveolar lavage fluid. The breakthrough incidence of IFD was 3.33%. Conclusion: Different times of administration lead to different times of interaction among the three drugs. The combination of cyclosporine and MMF leads to decrease in MPA concentrations, but the concentration of MPA can rapidly increase when combined with posaconazole. When target concentration of MPA is not reached in the first week, it is recommended to suspend dose modification and TDM in the second week. However, the accumulation of cyclosporine was significant in the fourth week, and it was recommended that cyclosporine should be monitored and adjusted within three weeks after the three drugs were combined. The cumulative breakthrough incidence of 3.33% is lower than reported in literaturesuggesting that posaconazole appears to be effective for secondary prophylaxis of IFD after allo-HSCT.

Integrating Forward and Reverse Translation in PBPK Modeling to Predict Food Effect on Oral Absorption of Weakly Basic Drugs.

Ketoconazole and posaconazole are two weakly basic broad-spectrum antifungals classified as Biopharmaceutics Classification System class II drugs, indicating that they are highly permeable, but exhibit poor solubility. As a result, oral bioavailability and clinical efficacy can be impacted by the formulation performance in the gastrointestinal system. In this work, we have leveraged in vitro biopharmaceutics and clinical data available in the literature to build physiologically based pharmacokinetic (PBPK) models for ketoconazole and posaconazole, to determine the suitability of forward in vitro-in vivo translation for characterization of in vivo drug precipitation, and to predict food effect. A stepwise modeling approach was utilized to derive key parameters related to absorption, such as drug solubility, dissolution, and precipitation kinetics from in vitro data. These parameters were then integrated into PBPK models for the simulation of ketoconazole and posaconazole plasma concentrations in the fasted and fed states. Forward in vitro-in vivo translation of intestinal precipitation kinetics for both model drugs resulted in poor predictions of PK profiles. Therefore, a reverse translation approach was applied, based on limited fitting of precipitation-related parameters to clinical data. Subsequent simulations for ketoconazole and posaconazole demonstrated that fasted and fed state PK profiles for both drugs were adequately recapitulated. The two examples presented in this paper show how middle-out modeling approaches can be used to predict the magnitude and direction of food effects provided the model is verified on fasted state PK data.

Posaconazole plasma concentrations in children and adolescent

Posaconazole plasma concentrations in children and adolescent

Population pharmacokinetics of posaconazole in Chinese pediatric patients with acute leukaemia: Effect of food on bioavailability and dose optimization

This study aimed to investigate the effect of food on the pharmacokinetics of posaconazole suspension in pediatric patients with acute leukaemia and to recommend optimal dosing strategies. This single-site, prospective, open-label, observational study was conducted in 42 patients and included 186 plasma concentrations of posaconazole. Sparse data were analyzed using population pharmacokinetic modeling. Monte Carlo simulations were conducted to predict the morning trough concentrations at steady-state with the proposed dose of 2–7 mg/kg three times daily (tid) or four times daily (qid) for bodyweights of 10–36 kg. The target concentrations were 700 ng/mL for prophylaxis and 1000 ng/mL for treatment. Dosage regimens with percentage of target attainment (PTA) ≥70% were recommended. A one-compartment model with allometric scaling adequately described the pharmacokinetic profile. The apparent clearance was 9.05 L/h (95% confidence interval [CI] 7.14–11.09) and the apparent volume of distribution was 283 L (95% CI 168–491) for a typical individual of 17.5 kg. The relative bioavailability with high-fat diet was as high as 1.95-fold compared with regular food. Following the intake of regular meals, 4 mg/kg qid was adequate with a PTA ≥ 71.8% for prophylaxis. A dosage of 6 mg/kg qid under a regular diet reached a PTA ≥ 73.4% for treatment. The recommended dosage of posaconazole for prophylaxis and treatment could be predicted by the pharmacokinetic model based on bodyweight and diet type in pediatric patients.

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.

Population pharmacokinetics of a posaconazole tablet formulation in transplant adult allogeneic stem cell recipients

BackgroundPosaconazole is an antifungal agent extensively used as a prophylaxis for invasive fungal infections (IFIs) in allogeneic stem cell transplant (SCT) recipients. Low posaconazole concentrations have been associated with reduced clinical response. The aim of this study was to develop a population pharmacokinetic (popPK) model of a posaconazole tablet formulation in allogeneic SCT adult recipients for supporting model-informed precision dosing (MIPD). Materials and methodProspective observational study performed in adult allogeneic SCT recipients receiving posaconazole as prophylaxis for IFIs and followed up by a therapeutic drug monitoring (TDM) program. Posaconazole plasma concentrations were quantified using an ultra-high-performance liquid chromatography (UPLC) with UV detector. A popPK model was developed using NONMEM v.7.4.0. Deterministic and stochastic simulations were carried out with the final model to evaluate the differences across physiological variables with impact on drug exposure. ResultsA one-compartment model with sequential absorption (zero and first order) and first order elimination described adequately 55 posaconazole concentrations from 36 patients. Higher doses of posaconazole were found to be required by males and patients with lower values of total serum proteins. A nomogram to estimate the posaconazole daily dose based on pharmacokinetic/pharmacodynamic (PKPD) criterion for males and females for different values of total proteins was developed. ConclusionsGender and total serum proteins have been identified as covariates influencing posaconazole CL/F in adult allogeneic SCT recipients receiving the delay-released tablet formulation. Additional studies are required to better characterize the absorption of posaconazole and implications on dosage recommendations together with potential safety concerns.

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.

Development of UPLC-MS/MS Method for Studying the Pharmacokinetic Interaction Between Dasatinib and Posaconazole in Rats.

Background and AimDasatinib is approved for the treatment of leukaemia worldwide. Triazole agents such as posaconazole may be used for the control of secondary fungal infection with leukaemia. This work aimed to develop a bioanalytical method to study the potential interaction between dasatinib and posaconazole.MethodsAn ultrahigh-performance liquid chromatography-tandem mass spectrometry method was established to measure the plasma concentrations of dasatinib and posaconazole in rats simultaneously. Simple protein precipitation with acetonitrile was applied to extract dasatinib and posaconazole in samples. The chromatographic separation of analytes was conducted on an UPLC BEH C18 column using a mobile phase consisting of 0.1% aqueous formic acid and acetonitrile. Dasatinib and posaconazole were monitored in positive ion mode with the following mass transition pairs: m/z 488.2→401.1 for dasatinib and m/z 701.3→683.4 for posaconazole. The method was successfully applied for pharmacokinetic interaction between dasatinib and posaconazole.ResultsThe established method expressed good linearity in 1–1000 ng/mL of dasatinib and 5–5000 ng/mL of posaconazole, with limit of detection was 1 ng/mL and 5 ng/mL, respectively. Methodology validations, including accuracy, precision, matrix effect, recovery, and stability, met the US Food and Drug Administration (FDA) acceptance criteria for bioanalytical method validation. Dasatinib strongly inhibited the clearance of posaconazole in vivo, while posaconazole expressed no significant effect on the pharmacokinetics of dasatinib.ConclusionDasatinib alters the pharmacokinetics of posaconazole. Attention should be paid to the unexpected risk of adverse clinical outcomes when posaconazole is co-administered with dasatinib.

Pharmacokinetics and tolerability of intravenous posaconazole in healthy Chinese volunteers: a randomized, open-label and single-dose study.

Posaconazole is a triazole antifungal drug with strong antifungal effect. The pharmacokinetics, safety, and tolerability were evaluated following the intravenous administration of posaconazole injection. A total of 36 healthy adults were enrolled in the parallel-designed clinical trial, and the subjects received single doses of posaconazole injection (100, 200 and 300 mg). Posaconazole concentrations in plasma were determined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The levels of posaconazole in plasma increased proportionally between 100 and 300-mg dose, but AUC showed a more-than-dose-proportional increase. Besides, decreased Vd and CL were observed, along with the increased posaconazole dosage. Posaconazole was well tolerated at all dose levels, and the adverse events were not dose dependent. No clinically significant changes in electrocardiograms were observed.

Experience using intravenous posaconazole in paediatric and young adult oncology patients.

Posaconazole exhibits broad-spectrum antifungal activity. An IV formulation became available in 2014. Few studies describing the use of this formulation exist in patients under the age of 18 years. This study describes our experience using IV posaconazole in paediatric and young adult cancer patients. This single-centre retrospective chart review evaluated patients who received IV posaconazole and had at least one posaconazole plasma concentration obtained after five or more days with a consistent dosage. Relationships between doses required to achieve a plasma concentration of ≥1 µg/mL and patient age, weight and body surface area (BSA) were evaluated. The clinical record was reviewed to identify descriptions of any adverse events. Twenty-five patients were analysed, with a median age of 10.5 years (range 1.9-22.9 years; 92% were <18 years). All patients were able to achieve a posaconazole plasma concentration ≥1 µg/mL during their treatment course. The daily mg/kg/day dose required to achieve the target concentration decreased significantly with increasing age of the patient (P = 0.018). Assessment of dosage based on BSA suggested a requirement of 225 mg/m2/day across all age groups <18 years. Adverse events documented in the clinical record were consistent with those described with the oral formulations. No CNS toxicities were observed with use of IV posaconazole. Concentrations ≥1 µg/mL are achievable and a BSA-based dosing approach may allow a consistent empirical dose for patients <18 years of age. Therapeutic drug monitoring is recommended to ensure patients achieve therapeutic concentrations.

Pharmacokinetics and Pharmacodynamics of Posaconazole.

Posaconazole is typically used for preventing invasive yeast and mold infections such as invasive aspergillosis in high-risk immunocompromised patients. The oral suspension was the first released formulation and many pharmacokinetic and pharmacodynamic studies of this formulation have been published. Erratic absorption profiles associated with this formulation were widely reported. Posaconazole exposure was found to be significantly influenced by food and many gastrointestinal conditions, including pH and motility. As a result, low posaconazole plasma concentrations were obtained in large groups of patients. These issues of erratic absorption urged the development of the subsequently marketed delayed-release tablet, which proved to be associated with higher and more stable exposure profiles. Shortly thereafter, an intravenous formulation was released for patients who are not able to take oral formulations. Both new formulations require a loading dose on day 1 to achieve high posaconazole concentrations more quickly, which was not possible with the oral suspension. So far, there appears to be no evidence of increased toxicity correlated to the higher posaconazole exposure achieved with the regimen for these formulations. The higher systemic availability of posaconazole for the delayed-release tablet and intravenous formulation have resulted in these two formulations being preferable for both prophylaxis and treatment of invasive fungal disease. This review aimed to integrate the current knowledge on posaconazole pharmacokinetics, pharmacodynamics, major toxicity, existing resistance, clinical experience in special populations, and new therapeutic strategies in order to get a clear understanding of the clinical use of this drug.

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.

Evaluation of target attainment of oral posaconazole suspension in immunocompromised children.

Posaconazole is a broad-spectrum antifungal that is not licensed for use in children <13 years of age. Despite this and by necessity, it is used extensively in paediatric hospitals for prophylaxis of invasive fungal disease. To determine whether initial prophylactic dosing recommendations attain a posaconazole plasma concentration of ≥700 ng/mL in immunocompromised children <13 years of age. We performed a retrospective study of immunocompromised children <13 years of age receiving posaconazole suspension prophylaxis at a starting dose of 5 mg/kg every 8 h for ≥7 days and who had a posaconazole concentration measured after ≥7 days. Posaconazole plasma concentrations and rate of breakthrough infection were recorded. A total of 70 patients were included with a median age of 5 years (range 3 months to 12 years). The mean posaconazole plasma concentration was 783.4 ng/mL (IQR 428.3-980 ng/mL) and the percentage of patients with a posaconazole plasma concentration ≥700ng/mL was 47.9%. Patients who were on a proton pump inhibitor, a histamine H2 antagonist or metoclopramide, had mucositis or were enterally fed had a lower posaconazole plasma concentration compared with patients without these co-administered drugs/mucositis/enteral feeding (542.3 versus 1069.8 ng/mL; P<0.001). The breakthrough invasive fungal infection rate was 4.3% (3/70). The studied 5 mg/kg posaconazole suspension every 8 h resulted in target concentrations in only 47.9% of patients and further studies looking at newer posaconazole formulations are needed.

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.

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.

The Genetic Polymorphism UGT1A4*3 Is Associated with Low Posaconazole Plasma Concentrations in Hematological Malignancy Patients Receiving the Oral Suspension.

The metabolism of posaconazole is mediated mainly by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, especially UGT1A4. The aim of this study was to investigate the effects of genetic polymorphisms on the posaconazole plasma concentration (PPC). This prospective study was conducted from September 2014 to August 2016. We enrolled patients with acute myeloid leukemia or myelodysplastic syndrome treated with posaconazole oral suspension (200 mg) three times daily for fungal prophylaxis. The patients were examined for the multidrug resistance gene 1 3435C>T and 2677G>T/A variations and the UGT1A4*3 allele by direct sequencing of DNA from peripheral whole-blood samples. We defined poor absorbers to be those with PPCs of <200 ng/ml and the optimal PPC to be ≥700 ng/ml on day 8. The associations between genetic polymorphisms and the PPC were evaluated using multivariate logistic regression analysis including clinical variables. During the study period, 132 patients were enrolled. Six patients (4.5%) were defined as poor absorbers, and 49 patients (37.1%) did not reach the optimal PPC on day 8. In multivariate analysis, the independent risk factors for a poor absorber were at least one UGT1A4*3 allele (adjusted odds ratio [aOR], 18.81; 95% confidence interval [CI], 1.09 to 324.44; P = 0.043) and poor oral food intake (aOR per -100 kcal, 1.44; 95% CI, 1.04 to 1.99; P = 0.029). There was no statistically significant association between the genetic polymorphisms and achievement of the optimal PPC on day 8. The UGT1A4*3 polymorphism is an independent risk factor for being a poor absorber of posaconazole oral suspension in patients with hematological malignancies.