Posaconazole Trough Research Articles

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.

Elevated posaconazole trough concentrations are not associated with increased risk for posaconazole toxicity in lung transplant recipients.

Posaconazole is used for prophylaxis and treatment of invasive fungal infections in lung transplant recipients (LTR). Previous studies have not described the relationship between elevated posaconazole trough concentrations and adverse drug reactions in this population. This IRB-approved, retrospective cohort study at NewYork-Presbyterian Hospital included LTR who had posaconazole trough concentrations measured. The primary aim of this study was to evaluate elevated posaconazole trough concentrations and changes in liver function tests as well as QTc interval. A secondary aim of this study was to identify patient factors associated with elevated posaconazole trough levels. A total of 109 LTR were included. The average age was 58.1years (IQR, 48-65), the majority were male (56%). A total of 932 trough levels were assessed with a median number of 8 (IQR, 5-15) levels per patient. The median posaconazole trough concentration was 1.7mg/L (IQR, 1.1-2.5). Hepatotoxicity, as defined by common terminology criteria for adverse events (CTCAE), was observed in 73.4% of subjects, with the majority classified as grade 1 (67.5%). However, there was no correlation between elevated posaconazole levels and aspartate aminotransferase (r=.03), alanine aminotransferase (r=.04), alkaline phosphatase (r=.04), and total bilirubin (r=.02). There was also no correlation between posaconazole trough concentrations and QTc interval (r=.03). This analysis demonstrates that no correlation exists between whole blood posaconazole levels and hepatotoxicity or QTc prolongation. Based on these results, posaconazole dose reductions may not be warranted for posaconazole levels that are significantly above the therapeutic target to avert risk for hepatotoxicity or QTc prolongation.

P269 Managing prosthetic valve endocarditis due to Sarocladium kiliense: Finding a way through uncertainties

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PM ObjectiveTo discuss the challenges in a case of recurrent/refractory prosthetic valve endocarditis due to Sarocladium kiliense.Methods and ResultsTimeline of events (Fig. 1).AUC/MIC is associated with efficacy. Recent clinical studies have incorporated the MIC into targets for TDM, wherein Trough/MIC target of 2-5 may be usedR.In this caseVoriconazole trough—3.1/MIC-0.25 = 12.5Usual posaconazole trough—1.2/MIC 0.5 = 2.4, which is at the lower limit of the PKPD indexHence voriconazole was used.Drug interactions of voriconazole with acenocoumarol, clopidogrel were considered.Beta D-Glucan was used to assess infection of the newly implanted valve as well as improvement and need for continuing treatment.Since it is difficult to be certain of a cure, the patient was advised voriconazole as lifelong chronic suppressive therapy with periodic follow-up.R: reference available.ConclusionsThe patient's status of the third mitral prosthetic valve necessitated all efforts to avoid further surgery. Therefore, the most efficacious agent had to be selected based on PK PD considerations and the likelihood of major long-term adverse effects.Careful management of DDI was needed.BDG may help to assess recurrence and response to treatment.

Breakthrough Penile Mucormycosis in a Patient With Acute Myelogenous Leukemia on Posaconazole Prophylaxis

Abstract In patients with acute myelogenous leukemia, posaconazole prophylaxis has been shown to prevent deep invasive fungal infections, including mucormycosis. In the present case, posaconazole prophylaxis was initiated in a 58-year-old man undergoing induction chemotherapy for acute myelogenous leukemia. Three weeks after initiating chemotherapy, he developed a tender violaceous macule on the shaft of his penis. The initial differential included fixed drug eruption versus pyoderma gangrenosum. However, punch biopsy ultimately showed mucormycosis, and cultures grew Rhizopus species, despite therapeutic posaconazole trough. He was treated with intravenous amphotericin B and required right orchiectomy, penectomy, and hyperbaric oxygen therapy. Oral posaconazole was reinstituted after completion of amphotericin B course, and at 4 months follow-up, his penectomy site was fully healed. As demonstrated by the present case, not all mucormycoses are prevented by posaconazole prophylaxis. A high index of suspicion and early biopsy for prompt diagnosis are of critical importance in improving outcomes.

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.

Pseudocanariomyces americanus, gen. nov., sp. nov., A New Thielavia-Like Species in the Chaetomiaceae: Identification and Management of a Prosthetic Hip Infection.

This report describes the phenotypic characteristics of a novel fungal species, isolated from a prosthetic hip infection. The patient, who had undergone multiple total hip arthroplasties due to Legg-Calvé-Perthes disease, presented with continued fever and wound dehiscence. Findings upon incision and draining were notable for necrotic tissue and a sinus tract from the fluid collection. Intraoperative cultures were positive for a sterile filamentous fungus. BLASTn results following DNA sequencing placed the isolate within the family Chaetomiaceae close to the genera Madurella, Canariomyces, Stolonocarpus, Stellatospora, Ovatospora, Carteria and Melanocarpus. Phylogenetic analysis demonstrated that the isolate was a new thielavia-like species, Pseudocanariomyces americanus. Antifungal susceptibility was performed, and low minimum inhibitory concentrations were observed with amphotericin B, itraconazole, posaconazole, and voriconazole. The patient was initially treated with voriconazole but was switched to posaconazole secondary to a photosensitivity reaction. Acceptable posaconazole trough concentrations were achieved, and the patient remained stable without pain or drainage from her surgical incision.

Clinical and Pharmacological Considerations for Concomitant Administration of Posaconazole and Isavuconazole with Letermovir.

We sought in this case-control retrospective study to compare posaconazole and isavuconazole (PCZ and IVC, respectively) plasma trough concentration (Ctrough) levels in high-risk allogeneic hematopoietic cell transplant (HCT) recipients who received letermovir (LET) or not. PCZ/IVC Ctrough levels were not found to be significantly different between cases and controls, as they were 1.31 mg/liter (median) (interquartile range [IQR], 0.90) versus 1.36 mg/liter (IQR, 1.16) (P = 0.31) and 3.20 mg/liter (IQR, 2.40) versus 2.35 mg/liter (IQR, 1.50) (P = 0.17), respectively. In conclusion, we observed PCZ/IVC Ctrough levels within the expected range and no significant effect of LET coadministration.

Experience with Posaconazole Use for Fungal Prophylaxis Immediately Post Heart Transplant

Purpose Fungal infections, specifically mucormycosis, are associated with high morbidity and mortality in the immunocompromised host. Noting a recent elevation in our rates of fungal infections, we sought to avoid mucormycosis and other post-Orthotopic Heart Transplant (OHT) fungal infections through the implementation of a systematic antifungal prophylaxis protocol. Methods Posaconazole was selected as the antifungal of choice, given provided mucormycosis coverage not provided by other azoles. We developed a Posaconazole Prophylaxis Protocol (PPP) consisting of post-operative day 1 initiation of posaconazole for a 3-month duration with a goal posaconazole trough level 1000-2000 ng/mL. At time of posaconazole discontinuation, a 2-fold dose escalation of tacrolimus dosing was implemented and bi-weekly tacrolimus levels drawn for 2 weeks to ensure goal calcineurin inhibitor levels. If strong cyp3A4 interactions or prolonged QTc prohibited posaconazole, isavuconazole was used. If early cessation of posaconazole-therapy was necessary, surveillance chest imaging was obtained with chest CT scans. Results In the 13-month period following initiation of our PPP 50 patients underwent OHT. All but one (49/50) patients received therapeutic posaconazole or in the case of drug-drug interactions, isavuconazole. 2/50 were transitioned to isavuconazole due to QT prolongation. 5/50 had posaconazole interruption with the most common reason being liver enzyme elevation (4/50). 45/50 tolerated the 3-month period on systemic azole prophylaxis. During this period there were no systemic fungal infections. Conclusion Our initial 13-month experience with a systematic 3-month antifungal prophylaxis protocol appears to be feasible, safe, and associated with uniform prevention of mucormycosis and other fungal infections that have previously proven to be highly morbid in our OHT recipients.

Tacrolimus Dosage Adjustments after Posaconazole Discontinuation in Lung Transplant Recipients

Purpose Posaconazole is commonly used in lung transplant recipients (LTRs) as prophylaxis against invasive fungal infections. Due to CYP3A4 drug interactions, tacrolimus (TAC) dose adjustments are required after discontinuing posaconazole. Current data has assessed tacrolimus dose adjustments only with posaconazole initiation. This study's purpose was to assess TAC dose adjustment requirements following posaconazole discontinuation in LTRs. Methods This was a single-center, retrospective review of LTRs between Jan and Dec 2019. The primary outcome was the change in TAC dose‐corrected trough concentration (∆C/D) from pre- to post-posaconazole discontinuation. Secondary outcomes included the time to first therapeutic TAC level post-posaconazole discontinuation and the number of TAC dose changes to achieve the first therapeutic TAC level after stopping posaconazole. Results 19 LTRs were included, the majority of which were Caucasian and CYP3A5 poor metabolizers [Table 1]. The median (IQR) TAC ∆C/D was 3.1 (2.3-4.4). Following posaconazole discontinuation, the median (IQR) time to the first therapeutic TAC level was 19 (14-26) days, and a median (IQR) of 3 (1-4) dose changes were required to achieve the first therapeutic TAC level. There was a trend towards the one CYP3A5 extensive metabolizer having a higher TAC ∆C/D (11.2), compared with poor (3.1) and intermediate metabolizers (3.3), although non-significant (p=0.25). Baseline posaconazole trough level did not impact the TAC ∆C/D (p=0.57). Similarly, baseline TAC trough level did not impact the time to first therapeutic TAC level post-posaconazole discontinuation (p=0.42). Conclusion In this cohort, LTRs required a 3-fold increase in TAC dose to obtain a trough level within goal after posaconazole discontinuation. Further studies are warranted to assess the impact of posaconazole discontinuation on TAC dose adjustments in various CYP3A5 pharmacogenomic phenotypes, cystic fibrosis LTRs, and those receiving TAC extended-release.

Characterization of Therapeutic Drug Monitoring Practices of Voriconazole and Posaconazole at a Pediatric Hospital.

To characterize the voriconazole and posaconazole serum trough ordering practices in patients receiving prophylactic and treatment antifungal therapy. A retrospective chart review over a 6-year period of pediatric patients who received voriconazole and/or posaconazole for >24 hours. A total of 113 patients were included in this study and of these patients, 105 received voriconazole and 16 received posaconazole during the study period. Additionally, 167 trough levels were assessed in this study. Only 50% and 54% of levels were considered within goal recommendations for voriconazole and posaconazole, respectively. The median dose required to achieve goal trough concentration was dependent on drug, indication, and dosage form. Lastly, the most common adverse drug reactions (ADRs) were hepatoxicity, QTc prolongation, and CNS changes, which were in concordance with ADRs documented in the clinical trials for voriconazole and posaconazole. Approximately 20% of patients receiving either voriconazole or posaconazole died during the study period and the median trough in both groups was subtherapeutic. Increased monitoring of trough concentrations may be warranted to prevent death or breakthrough invasive fungal infections. Further studies are warranted for assessing the relationship between trough concentrations and treatment outcomes as well as relationship between dosing and achieving goal trough concentrations.

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.

1737. Impact of Therapeutic Drug Monitoring (TDM) of Azole Prophylaxis in Lung Transplant Recipients on the Development of Positive Fungal Events

BackgroundThe utility and clinical impact of therapeutic drug monitoring (TDM) of prophylactic azole antifungals in lung transplant recipients is not well described. The objective of this study was to investigate the impact of TDM of azole prophylaxis in lung transplant recipients on the development of positive fungal events.MethodsA retrospective analysis was performed on 47 lung transplant recipients between 2013 and 2018 at Northwestern Memorial Hospital. A positive fungal event was defined as fungal species on BAL culture and/or positive BAL Aspergillus galactomannan (GM) with an index value ≥1.0. Study groups were defined based on attainment of therapeutic trough levels after initiation of oral therapy (therapeutic if posaconazole level ≥0.7 μg/mL or voriconazole ≥1–5.5 μg/mL, subtherapeutic if ≥2 consecutive levels of posaconazole <0.7 μg/mL or voriconazole <1 μg/mL after initial dose increase).ResultsThere were no differences in baseline characteristics (Figure 1). There were a total of 11 fungal events with 3 (12.0%) occurring in the therapeutic cohort and 8 (36.4%) in those subtherapeutic (P = 0.08). In the 5 patients with a positive GM, the mean index was 2.02 ± 0.95. 7/30 (23.3%) of patients on posaconazole had a fungal event, with 2/7 (28.6%) requiring treatment at the time of event. For patients on voriconazole, 4/17 (23.5%) had a fungal event, with 1/4 (25.0%) requiring treatment. Mean time to fungal event was 164.5 ± 8.9 days vs. 135.9 ± 13.7 days in the therapeutic and subtherapeutic group, respectively (P = 0.05).All patients on posaconazole suspension who experienced a fungal event were subtherapeutic (3/3, 100%) compared with the majority of patients on posaconazole delayed release (DR) tablets who achieved therapeutic levels (17/22, 77.3%). Mean posaconazole trough level observed in the patients receiving DR tablet was 2.15 ± 0.95 μg/mL.ConclusionThere was an association between two consecutive subtherapeutic azole prophylaxis levels and positive fungal events indicating a role for TDM in lung transplant recipients. Time to fungal event post-transplant was shorter in subtherapeutic patients. As anticipated, the use of posaconazole suspension resulted in subtherapeutic levels. This study presents an opportunity for further research of the impact of TDM on clinical outcomes to optimize patient care. Disclosures All authors: No reported disclosures.

Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations.

The delayed-release tablet formulation of posaconazole (POS-tab) results in higher plasma POS trough concentrations (Cmin) than the oral suspension (POS-susp), which raises the question of the utility of therapeutic drug monitoring (TDM). We aimed to compare the variability of the POS Cmin for the two formulations and identify determinants of the POS-tab Cmin and its variability. Demographic, biological, and clinical data from 77 allogeneic hematopoietic stem cell transplant patients (874 Cmin) treated with POS-tab (n = 41), POS-susp (n = 29), or both (n = 7) from January 2015 to December 2016 were collected retrospectively. Interpatient and within-subject coefficients of variation (CVs) of the Cmin adjusted to dose (D) were calculated for each formulation. Between-group comparisons were performed using a linear mixed effects model. The POS Cmin was higher for the tablet than for the suspension (median [25th-75th percentile]: 1.8 [1.2-2.4] mg/liter versus 1.2 [0.7-1.6] mg/liter, P < 0.0001). Interpatient CVs for the tablet and suspension were 60.8 versus 63.5% (P = 0.7), whereas within-subject CVs were 39.7 and 44.9%, respectively (P = 0.3). Univariate analysis showed that age and treatment by POS-tab were significantly and positively associated with the POS Cmin, whereas diarrhea was associated with a diminished POS Cmin Multivariate analysis identified treatment with POS-tab and diarrhea as independent factors of the POS Cmin, with a trend toward a lower impact of diarrhea during treatment with POS-tab (P = 0.07). Despite increased POS exposure with the tablet formulation, the variability of the POS Cmin was not significantly lower than that of the suspension. This suggests that TDM may still be useful to optimize tablet POS therapy.

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.

Evaluation of Intravenous Posaconazole Dosing and Pharmacokinetic Target Attainment in Pediatric Patients.

Limited data exist on intravenous (IV) posaconazole dosing and the risk for hepatotoxicity it confers to children. In this study, we evaluated dosing and resulting trough levels in 10 pediatric patients on IV posaconazole. A therapeutic level in these patients was achieved 95% of the time. We found a median minimum effective dose of 6.55 mg/kg of body weight. No correlation was found between the duration or posaconazole trough level and an increased alanine transaminase level.

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.

Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose.

Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent. This study aimed to (i) describe the pharmacokinetics of posaconazole tablets in a real-life cohort of patients with hematological malignancies and (ii) perform Monte Carlo simulations to assess the possibility that the daily dose can be reduced while keeping a sufficient exposure. Forty-nine consecutive inpatients were prospectively included in the study. Posaconazole trough concentrations (TC) were measured once a week, and biological and demographic data were collected. The concentrations were analyzed by compartmental modeling, and Monte Carlo simulations were performed using estimated parameters to assess the rate of attainment of the target TC after dose reduction. The pharmacokinetics of posaconazole were well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were as follows: the absorption constant (ka ) was 0.588 h-1 (fixed), the volume of distribution (V/F) was 420 liters (28.2%), and clearance (CL/F) was 7.3 liters/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady state of ≥1.5 μg/ml and maintained a TC above 1 μg/ml after a reduction of the dose to 200 mg daily. A third of these patients eligible for a dose reduction had TC of ≥1.5 μg/ml as soon as 48 h of treatment. Though posaconazole tablets were less impacted by bioavailability issues than the oral suspension, the pharmacokinetics of posaconazole tablets remain highly variable. Simulations showed that approximately half of the patients would benefit from a reduction of the dose from 300 mg to 200 mg while keeping the TC above the minimal recommended target of 0.7 μg/ml, resulting in a 33% savings in the cost of this very expensive drug.

Risk factors for suboptimal drug concentration of posaconazole oral suspension in patients with hematologic malignancy

Absorption of posaconazole oral suspension is influenced by several factors including diet, medications, and mucosal integrity. However, there are few prospective data about which is the most important modifiable factor in routine clinical practice. We prospectively analyzed clinical risk factors associated with low posaconazole trough concentrations in 114patients receiving anticancer chemotherapy due to acute myeloid leukemia or myelodysplastic syndrome who received posaconazole oral suspension. In multivariate analyses, risk factors for drug level<500ng/mL included low calorie intake, mucositis≥grade2, H2 blocker famotidine and proton-pump inhibitor. The only significant risk factor for drug level<700ng/mL was famotidine use (adjusted relative risk, 3.18; 95% confidence interval, 1.07-9.11; P=0.038). In conclusion, medication of H2 blocker famotidine should be cautious in patients with hematologic malignancy receiving posaconazole suspension.

Risk factors for subtherapeutic levels of posaconazole tablet.

Posaconazole is the prophylactic antifungal of choice for patients with haematological malignancies at high risk of invasive fungal infections (IFIs). Studies have demonstrated that subtherapeutic concentrations of posaconazole are associated with breakthrough fungal infections and specific risk factors for subtherapeutic troughs associated with the suspension formulation have been identified. However, these risk factors have not been evaluated in a large patient population with the recently approved tablet formulation. To determine the risk factors for subtherapeutic posaconazole troughs associated with the tablet formulation in patients receiving posaconazole as IFI prophylaxis. From 1 February 2013 to 31 March 2015 all posaconazole serum trough concentrations were evaluated. A total of 157 patients receiving posaconazole tablet for prophylaxis during induction therapy for haematological malignancies and allogeneic stem cell transplant recipients with graft-versus-host disease were included for analysis. Overall, 28 patients (18%) had subtherapeutic troughs (<700 ng/mL). Patients were more likely to have subtherapeutic troughs if they had diarrhoea (n = 24; 83%) (P < 0.001), were receiving a proton pump inhibitor (n = 27; 93%) (P = 0.016) and weighed >90 kg (n = 14; 48%) (P = 0.047). While the posaconazole tablet has provided more consistent therapeutic concentrations when compared with the suspension there may still be a role for therapeutic drug monitoring (TDM). These results may guide us to a specific population in which TDM is necessary to identify subtherapeutic troughs.