AbstractVoriconazole is the cornerstone of the treatment and prevention of fungal infections. While there is a good correlation between CYP2C19 genotype and voriconazole exposure during prophylactic treatment, no correlation was found in patients with invasive aspergillosis. Proinflammatory cytokines result in inhibition of CYP2C19 enzyme activity (and may result in phenoconversion). Here we investigated the relationship between inflammation, CYP2C19 genotype‐predicted‐phenotype, and CYP2C19 activity in patients receiving voriconazole. Data were obtained from two prospective studies investigating voriconazole treatment (NCT02074462 and NCT00893555). Dose‐corrected voriconazole plasma concentration and C‐reactive protein (CRP) were used as proxies for CYP2C19 activity and inflammation, respectively. After data extraction and synthesis, data from 39 patients with paired voriconazole and CRP measurements were available. The distribution of CYP2C19 genotype‐predicted metabolizer phenotypes was 31% intermediate (IM), 41% normal (NM), and 28% rapid metabolizer (RM). During inflammation, dose‐corrected voriconazole levels were increased by 245%, 278%, and 486% for CYP2C19 NMs IMs and RMs, respectively. Patients with moderate or high CRP levels (>50 mg/L) were phenoconverted to a lower metabolizer phenotype irrespective of their CYP2C19 genotype. In a subgroup analysis of eight patients with longitudinal data available with and without inflammation, the pattern of the dose‐corrected voriconazole and CRP measurements were similar, with CYP2C19 activity following decreasing or increasing CRP levels. In conclusion, voriconazole plasma concentrations increase during inflammation due to downregulation of CYP2C19 activity. While this effect appears largest for CYP2C19 RMs, no clinically relevant differences were observed between the CYP2C19 genotypes.

ABSTRACT:Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, β2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308μg/L vs 146μg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to β2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.

Context AdvSM is a rare clonal hematologic neoplasm driven by KIT D816V in ~95% of cases. Subtypes are aggressive SM (ASM), SM with associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL). Avapritinib, a highly selective KIT D816V inhibitor, showed deep and durable responses in adults with AdvSM in phase 1 and 2 studies regardless of subtype or prior systemic therapy (PST), leading to approval in the USA and Europe. Objective Present 3-year follow-up from PATHFINDER (NCT03580655). Design Open-label, single-arm, phase 2. Patients Adults with centrally confirmed AdvSM. Interventions Avapritinib 200 or 100 mg once daily. Main outcome measures Overall response rate (ORR, primary outcome), duration of response (DOR), progression-free survival (PFS), overall survival (OS), disease burden measures, and safety. Results As of September 15, 2023, 107 patients (20% ASM, 66% SM-AHN, and 14% MCL) received avapritinib 200 mg (n=105) or 100 mg (n=2). Median age was 68 years, 58% were male, and 26% had Eastern Cooperative Oncology Group performance status 2-3; 64% had ≥1 PST. Median ORR in the 83 response-evaluable patients (REP) was 73%, 87% in treatment-naive, and 66% in PST. Responses were similar across subtypes. High complete remission/complete remission with partial hematologic recovery rate (29%) was observed in REP and was double in treatment-naive (43%) vs PST patients (21%). 14% of patients had progressive disease, most in the AHN component. Median treatment duration was 33.2 months. Median DOR and PFS were not reached (NR) in REP. Median OS was NR regardless of subtype or PST. Bone marrow mast cell aggregate clearance was seen in 71%, 63% had <1% KIT D816V variant allele fraction, 65% had <20 ng/mL serum tryptase, and 80% developed nonpalpable spleens. Treatment-related adverse events (TRAEs, [≥25% of N=107]) were (any grade; grade ≥3) periorbital edema (41%; 6%), thrombocytopenia (40%; 18%), peripheral edema (38%; 2%), and anemia (32%; 13%). Dose reductions, interruptions, and discontinuations due to TRAEs occurred in 76%, 63%, and 13%. No additional intracranial bleeding events since previous data cutoff or treatment-related deaths occurred. Conclusions Avapritinib showed continued deep and durable responses with a favorable benefit-risk profile regardless of AdvSM subtype or prior therapy.

Background Hereditary alpha tryptasemia (H alpha T) has significant prevalence and potential morbidity in the general population. However, it remains largely undiagnosed in routine clinical diagnostics due to low availability of efficient assessment methods. To address this issue, we developed a reliable and efficient single-well multiplex digital droplet PCR assay.Methods The assay was based on the reconstruction of the TPSAB1 gene through quantification of the ratio of alpha- and beta-tryptase copy number variants (CNV) in a single-well measurement. We performed analytical validation by determining CNV measurement clustering around the expected copy numbers in 281 cases and determined the diagnostic accuracy of basal serum tryptase (BST) to predict H alpha T and H alpha T subtypes in 141 symptomatic patients.Results The assay determined alpha- and beta-tryptase CNVs with an overall accuracy, expressed as a 99% prediction interval, of 0.03 +/- 0.27 copy numbers. The optimal BST cutoff level to predict H alpha T in symptomatic patients, who had no other explanation for relatively high tryptase levels (i.e., no diagnosis of systemic mastocytosis, myeloid neoplasm, or end-stage renal failure), was 9.2 ng/mL (sensitivity: 98.1%; specificity: 96.6%). H alpha T showed a linear gene-dose effect, with an average gene-dose increase of 7.5 ng/mL per extra alpha-tryptase gene.Conclusion Our single-well multiplex digital droplet PCR assay accurately determined H alpha T and could be implemented as a state-of-the-art routine diagnostic test. The assay demonstrated a strong correlation with BST and the optimal threshold for identifying H alpha T in symptomatic patients with unexplained high tryptase concentrations was at a BST level of 9.2 ng/mL.

Topic: 16. Myeloproliferative neoplasms - Clinical Background: AdvSM, a clonal mast cell (MC) disease, is driven by the KIT D816V mutation in ~95% of cases. Avapritinib, a highly selective KIT D816V inhibitor, demonstrated rapid, deep, and durable responses in patients with AdvSM in the phase 1 EXPLORER (NCT02561988) study and in an interim analysis of the phase 2 PATHFINDER (NCT03580655) study. Responses were observed regardless of prior therapy or disease subtype (aggressive SM [ASM], SM with an associated hematological neoplasm [SM-AHN], or MC leukemia [MCL]). Data from these studies led to approval of avapritinib to treat adult patients with AdvSM in the USA and in Europe after ≥1 prior systemic therapy. Avapritinib is not recommended for patients with a platelet count <50×109/L. Aims: We present efficacy and safety analyses with a 2-year follow-up. Methods: Adult patients with centrally confirmed AdvSM treated with avapritinib were included in these analyses. Primary endpoint was centrally-adjudicated overall response rate (ORR), per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (mIWG) response criteria. Secondary endpoints were time to response (TTR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), mean change from baseline objective disease burden measures (bone marrow [BM] MC burden, serum tryptase level, blood KIT D816V variant allele fraction [VAF], spleen volume), and safety. Results: As of September 9, 2022, 107 patients with AdvSM (20% ASM, 66% SM-AHN, and 14% MCL) had initiated avapritinib 200 mg (n=105) or 100 mg (n=2) once daily; 36% were treatment-naïve, and 64% had received ≥1 prior systemic therapy. Median age (range) was 68 years (31–88), 58% were male, and 26% had ECOG performance status 2–3. In 83 mIWG response-evaluable patients, ORR (95% CI) was 73% (63–83), with 27% achieving complete remission (CR) or CR with partial hematologic recovery. In the largest subtype group, SM-AHN, ORR was 75% (61–85) overall, 91% (71–99) in treatment-naïve patients, and 64% (45–80) in those previously treated. Two patients had disease progression as best response. Median TTR (range) was 2.3 months (0.3–15) across subtypes. Median DOR, PFS, and OS were not reached; 24-month DOR, PFS, and OS rates (95% CI) were 89% (81–97), 76% (66–85), and 79% (70–87). Benefit was observed regardless of prior therapy or subtype (Table). Reductions of ≥50% in BM MC burden (88%, n=92/105), serum tryptase (92%, n=98/107), KIT D816V VAF (81%, n=87/107), and ≥35% reduction in spleen volume (70%, n=73/105) were observed. 70% (n=72/107) of patients had total clearance of MC aggregates, 61% (n=65/107) had serum tryptase <20 ng/mL, 58% (n=62/107) had KIT D816V VAF <1%, and 74% (n=40/54) with palpable spleens became non-palpable. The most frequent (≥25% of n=107) treatment-related adverse events (TRAEs) were (any grade, grade ≥3) thrombocytopenia (39%, 18%), periorbital edema (39%, 6%), peripheral edema (38%, 2%), and anemia (29%, 13%). Treatment-related cognitive effects occurred in 24% of patients, mostly Grade 1–2 (n=22/26) and managed with dose modification. Intracranial bleeds (ICBs) occurred in 2.8%; all discontinued treatment and events resolved. Incidence of ICBs, as well as general safety, was consistent with previous reports. There were no treatment-related deaths. Dose reductions, interruptions, and discontinuations due to TRAEs occurred in 75%, 64%, and 10% of patients. Summary/Conclusion: In patients with AdvSM, avapritinib continues to provide robust efficacy with a favorable benefit-risk profile, regardless of prior therapy or disease subtype.Keywords: Tyrosine kinase inhibitor, c-kit, Systemic mastocytosis

Gastrointestinal mucositis could potentially compromise drug absorption due to functional loss of mucosa and other pathophysiological changes in the gastrointestinal microenvironment. Little is known about this effect on commonly used anti-infectives. This study aimed to explore the association between different stages of gastrointestinal mucositis, drug exposure, and gut microbiota. A prospective, observational pilot study was performed in HSCT patients aged ≥ 18 years receiving anti-infectives orally. Left-over blood samples and fecal swabs were collected from routine clinical care until 14 days after HSCT to analyze drug and citrulline concentrations and to determine the composition of the gut microbiota. 21 patients with a median age of 58 (interquartile range 54–64) years were included with 252 citrulline, 155 ciprofloxacin, 139 fluconazole, and 76 acyclovir concentrations and 48 fecal swabs obtained. Severe gastrointestinal mucositis was observed in all patients. Due to limited data correlation analysis was not done for valacyclovir and fluconazole, however we did observe a weak correlation between ciprofloxacin and citrulline concentrations. This could suggest that underexposure of ciprofloxacin can occur during severe mucositis. A follow-up study using frequent sampling rather than the use of left-over would be required to investigate the relationship between gastrointestinal mucositis, drug exposure, and gut microbiome.

Le pronostic des patients (pts) atteints de AdvSM est péjoratif. Dans l’étude de phase 1 EXPLORER, ava, un inhibiteur puissant et sélectif de KIT D816 V, a induit des réponses rapides et durables chez les pts atteints d’AdvSM, indépendamment de tout traitement antérieur. PATHFINDER (NCT03580655) est une étude de phase 2 ouverte, à un seul bras, portant sur l’ava chez des pts atteints d’AdvSM. Étaient inclus les pts (≥ 18 ans) ayant une AdvSM, confirmée de manière centralisée. L’analyse intermédiaire a été réalisée auprès de 32 pts évaluables pour le critère principal, le taux de réponse global (ORR ; selon les critères mIWG-MRT-ECNM, hypothèse nulle 28 % selon l’efficacité antérieure de la midostaurine, un inhibiteur moins puissant et sélectif). La variation moyenne du score total des symptômes (TSS) et la sécurité représentaient les critères d’évaluation secondaires. Sur 62 pts qui ont commencé le traitement par ava par voie orale principalement à 200 mg une fois par jour, 52 (84 %) sont restés sous traitement. 31 % avaient un ECOG PS 2-3 et 68 % avaient déjà reçu un traitement systémique (55 % avec la midostaurine). Le critère d’évaluation principal a été atteint avec un ORR de 75 % (IC 95 % 57-89) chez 32 pts évaluables ORR (p = 1,6 × 10−9, suivi médian 10,4 mois), dont 6 (19 %) ayant obtenu une rémission clinique complète avec récupération hématologique partielle. Les ORR étaient respectivement de 82 % (14/17) et 67 % (10/15) chez les pts avec et sans midostaurine préalable. Le délai médian de réponse était de 2 mois (0,3-12). La survie globale médiane (OS) dans la population évaluable pour l’ORR n’a pas été atteinte ; l’OS estimée à 12 mois était de 86 %. À l’inclusion le TSS moyen était de 18,3 (n = 56), des améliorations rapides ont été maintenues jusqu’au cycle 11 (réduction moyenne de 36 %, p < 0,001), avec une diminution moyenne de 9,8 points (n = 22). Les effets indésirables (EI ; tout grade, grade ≥ 3) fréquents (≥ 25 %) ont été les œdèmes périphériques (50 %, 3 %) et périorbitaires (35 %, 3 %), la thrombocytopénie (32 %, 8 %) et l’anémie (29 %, 16 %). Dans l’ensemble, 3 (5 %) pts ont arrêté le traitement en raison d’un EI lié au traitement et 3 (5 %) pts en raison de la progression de la maladie, dont 1 pt ayant une transformation en leucémie myéloïde aiguë. Un hématome sous-dural de grade 4 est survenu chez un (2 %) pt présentant une thrombocytopénie sévère au départ. Ultérieurement les pts présentant une thrombocytopénie sévère (plaquettes < 50 × 109/L) n’ont plus été inclus dans l’étude. L’ava à la dose initiale de 200 mg par jour a induit des réponses rapides et durables et a amélioré de manière significative les symptômes chez les pts atteints d’AdvSM. Ava a été globalement bien toléré et peu de pts ont interrompu le traitement en raison d’EI.

Anatomy-based imaging methods are the usual imaging methods used in assessing invasive fungal infections (IFIs). [18F]FDG PET/CT has also been used in the evaluation of IFIs. We assessed the added value of [18F]FDG PET/CT when added to the most frequently used anatomy-based studies in the evaluation of IFIs. The study was conducted in two University Medical Centers in the Netherlands. Reports of [18F]FDG PET/CT and anatomy-based imaging performed within two weeks of the [18F]FDG PET/CT scan were retrieved, and the presence and sites of IFI lesions were documented for each procedure. We included 155 [18F]FDG PET/CT scans performed in 73 patients. A total of 216 anatomy-based studies including 80 chest X-rays, 89 computed tomography studies, 14 magnetic resonance imaging studies, and 33 ultrasound imaging studies were studied. The anatomy-based studies were concordant with the [18F]FDG PET/CT for 94.4% of the scans performed. [18F]FDG PET/CT detected IFI lesions outside of the areas imaged by the anatomy-based studies in 48.6% of the scans. In 74% of the patients, [18F]FDG PET/CT added value in the management of the IFIs.

Abstract Introduction: Systemic mastocytosis is a clonal, hematologic neoplasm driven by KIT D816V mutation in >90% of cases, with limited treatment options. In a phase I study, ava, a potent inhibitor of KIT D816V, induced durable responses which deepened over time in pts with AdvSM, regardless of prior therapy or AdvSM subtype. PATHFINDER (NCT03580655) is a pivotal open-label, single-arm phase II study of ava in pts with AdvSM. Methods: Pts were aged ≥18 years with centrally confirmed diagnosis of an AdvSM subtype. Primary endpoint was overall response rate (ORR) by modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis criteria. This pre-specified interim analysis included 32 response-evaluable pts. Secondary endpoints included mean baseline change in AdvSM-Symptom Assessment Form Total Symptom Score (TSS) (Gotlib J et al. ASH 2018) and safety. Results: At June 23, 2020, 62 pts with AdvSM received ava primarily at 200 mg orally once daily (QD). Median age was 69 years (range 31-88), 31% had ECOG PS 2-3, and 68% had prior systemic treatment (55% with midostaurin). At 10.4 months median follow-up, 52/62 (84%) pts remained on treatment. ORR was 75% (95% CI 57-89; P=1.6×10-9) in 32 response-evaluable pts. Complete remission with full or partial hematologic recovery occurred in 19% of pts. Median time to response was 2 months; responses deepened over time. Median overall survival (OS) was not reached; estimated 12-month OS was 87%. There were ≥50% reductions from baseline serum tryptase (87%; n=54), marrow mast cell aggregates (71%; n=44), and KIT D816V allele fraction (53%; n=33). Mean TSS at baseline (n=56) was 18.3; fatigue, spots, itching, flushing, and abdominal pain were the most severe symptoms. Mean change in TSS was -7.7 (1-sided P<0.001) after 6 months of treatment (n=36). Common (≥25%) adverse events (AEs; all grade, Grade ≥3) were peripheral (50%, 3%) and periorbital (35%, 3%) edema, thrombocytopenia (32%, 8%), and anemia (29%,16%). Overall, 5% of pts discontinued due to a treatment-related AE and 5% due to disease progression. There were 3 (5%) deaths, all unrelated to treatment. Seven (11%) pts had cognitive effect AEs (all Grade 1-2). One pt with pre-treatment severe thrombocytopenia (platelets <50×109/L) had Grade 4 subdural hematoma. Subsequent pts with pre-treatment severe thrombocytopenia were excluded, platelet monitoring was intensified, and dose interruption for severe thrombocytopenia was recommended; no intracranial bleeding events occurred in 57 pts without pre-treatment severe thrombocytopenia. Conclusions: The pivotal PATHFINDER study showed that ava 200 mg QD induced rapid responses, which deepened over the course of treatment, and improved symptoms in pts with AdvSM. Ava was generally well tolerated with a manageable safety profile, including effective thrombocytopenia risk mitigation. Citation Format: Daniel J. DeAngelo, Andreas Reiter, Deepti Radia, Michael W. Deininger, Tracy I. George, Jens Panse, Alessandro M. Vannucchi, Madlen Jentzsch, Iván Alvarez-Twose, Andrzej Mital, Olivier Hermine, Ingunn Dybedal, Elizabeth O. Hexner, Lisa K. Hicks, Lambert Span, Ruben Mesa, Prithviraj Bose, Kristen M. Pettit, Mark L. Heaney, Stephen Oh, Jayita Sen, Hui-Min Lin, Brenton G. Mar, Jason Gotlib. PATHFINDER: Interim analysis of avapritinib (ava) in patients (pts) with advanced systemic mastocytosis (AdvSM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT023.

Advanced systemic mastocytosis (AdvSM) is a rare, KIT D816V-driven hematologic neoplasm characterized by mast cell infiltration and shortened survival. We report the results of a prespecified interim analysis of an ongoing pivotal single-arm phase 2 trial (no. NCT03580655 ) of avapritinib, a potent, selective KIT D816V inhibitor administered primarily at a once-daily starting dose of 200 mg in patients with AdvSM ( n = 62). The primary endpoint was overall response rate (ORR). Secondary endpoints included mean baseline change in AdvSM–Symptom Assessment Form Total Symptom Score and quality of life, time to response, duration of response, progression-free survival, overall survival, changes in measures of disease burden and safety. The primary endpoint was successfully met ( P = 1.6 × 10 -9 ), with an ORR of 75% (95% confidence interval 57–89) in 32 response-evaluable patients with AdvSM who had sufficient follow-up for response assessment, including 19% with complete remission with full or partial hematologic recovery. Reductions of ≥50% from baseline in serum tryptase (93%), bone marrow mast cells (88%) and KIT D816V variant allele fraction (60%) were observed. The most frequent grade ≥3 adverse events were neutropenia (24%), thrombocytopenia (16%) and anemia (16%). Avapritinib demonstrated a high rate of clinical, morphological and molecular responses and was generally well tolerated in patients with AdvSM.

Background: The use of (val)ganciclovir is complicated by toxicity, slow response to treatment and acquired resistance. Objectives: To evaluate a routine therapeutic drug monitoring (TDM) programme for ganciclovir in a transplant patient population. Methods: An observational study was performed in transplant recipients from June 2018 to February 2020. Dose adjustments were advised by the TDM pharmacist as part of clinical care. For prophylaxis, a trough concentration (C-min) of 1-2 mg/L and an AUC(24h) of >50 mg.h/L were aimed for. For treatment, a C-min of 2-4 mg/L and an AUC(24h) of 80-120 mg.h/L were aimed for. Results: Ninety-five solid organ and stem cell transplant patients were enrolled. Overall, 450 serum concentrations were measured; with a median of 3 (IQR 2-6) per patient. The median C-min and AUC(24h) in the treatment and prophylaxis groups were 2.0 mg/L and 90 mg.h/L and 0.9 mg/L and 67 mg.h/L, respectively. Significant introand inter-patient patient variability was observed. The majority of patients with an estimated glomerular filtration rate of more than 120 mL/min/1.73 m(2) and patients on continuous veno-venous haemofiltration showed underexposure. The highest C-min and AUC(24h) values were associated with the increase in Liver function markers and decline in WBC count as compared with baseline. Conclusions: This study revealed that a standard weight and kidney function-based dosing regimen resulted in highly variable ganciclovir C-min and under- and over-exposure were observed in patients on dialysis and in patients with increased renal function. Clearly there is a need to explore the impact of concentration-guided dose adjustments in a prospective study.

ObjectivesInfections remain a threat for solid organ and stem cell transplant recipients. Antimicrobial prophylaxis and pre-emptive therapy have improved survival of these patients; however, the failure rates of prophylaxis are not negligible. The aim of this systematic review is to explore the reasons behind failure of antimicrobial prophylaxis and pre-emptive therapy.SettingThis systematic review included prospective randomised controlled trials and prospective single-arm studies.ParticipantsThe studies included were on prophylaxis and pre-emptive therapy of opportunistic infections in transplant recipients. Studies were included from databases MEDLINE, CENTRAL and Embase published until October first 2018.Primary and secondary outcome measuresPrimary outcome measures were breakthrough infections, adverse events leading to stopping of treatment, switching medication or dose reduction. Secondary outcome measures were acquired resistance to antimicrobials, antifungals or antivirals and death.ResultsFrom 3317 identified records, 30 records from 24 studies with 2851 patients were included in the systematic review. Seventeen focused on prophylactic and pre-emptive treatment of cytomegalovirus and seven studies on invasive fungal infection. The main reasons for failure of prophylaxis and pre-emptive therapy were adverse events and breakthrough infections, which were described in 54% (13 studies) and 38% (9 studies) of the included studies, respectively. In 25%, six of the studies, a detailed description of patients who experienced failure of prophylaxis or pre-emptive therapy was unclear or lacking.ConclusionsOur results show that although failure is reported in the studies, the level of detail prohibits a detailed analysis of failure of prophylaxis and pre-emptive therapy. Clearly reporting on patients with a negative outcome should be improved. We have provided guidance on how to detect failure early in a clinical setting in accordance to the results from this systematic review.PROSPERO registration numberCRD42017077606.

Posaconazole 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 (<0.7mg/L for prophylaxis or<1.5mg/L for treatment) or high (>3.75mg/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 1.7mg/L (IQR 0.8-2.7) for prophylaxis and 1.76mg/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.

Abstract Background Oral valganciclovir and intravenous ganciclovir are used for prophylaxis, treatment, and pre-emptive treatment of cytomegalovirus and human herpesvirus 6. It is important to estimate the exposure to these antivirals, as deviating levels can cause adverse events or induce acquired drug resistance, which can both lead to treatment failure. Therapeutic drug monitoring (TDM) is a good tool to estimate drug exposure in these patients. With this observational study we aimed to evaluate which patients would benefit most from TDM. Methods An observational study was performed in adult solid-organ and stem cell transplant recipients on routine (val)ganciclovir (dosed according to renal function, weight and indication). As valganciclovir is a prodrug of ganciclovir, only the latter was measured. Ganciclovir trough (Ctrough) and peak (Cpeak) concentrations were measured with a validated LC-MS/MS assay. The target concentrations defined for the study were 1–2 mg/L and 2–4 mg/L for prophylaxis and treatment, respectively, and over 5 mg/L toxic. Results From June 2018 to April 2019, 66 patients were included. Within this timeframe, 236 Ctrough and 52 Cpeak were measured with median of 4 samples per patient. The median Ctrough was 1.1 mg/L and 2.3 mg/L for prophylaxis and treatment, respectively. Over 50% of the concentrations were out of the therapeutic window. The median creatinine for all measurements was 100 µmol/L. Observational analysis showed patients with kidney failure and on continuous renal replacement therapy (CVVH) had more concentrations measured out of the predefined range (Figures 1 and 2). For one individual with augmented renal clearance we observed significantly lower concentrations during routine dosing. 6 toxic concentrations were measured (5 subjects); creatinine concentrations ranged 71–527 µmol/L in these individuals. A preliminary linear-mixed model analysis did not show drug formulation, age or gender as a significant predictor for ganciclovir concentrations. Conclusion We believe that patients with decreased renal function, on CVVH or showing changes in renal function might benefit from TDM to guide therapy. TDM of ganciclovir for patients without renal failure remains debatable. Further studies with specific patient groups are needed to confirm these results. Disclosures All authors: No reported disclosures.

During inflammation, several cytochrome P450 enzymes are downregulated. Recently it was shown that voriconazole metabolism is reduced during inflammation. Posaconazole, another triazole with broadspectrum 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 < 0.0 0 01). 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. © 2019 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )