Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity.

Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI >30 kg/m2) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC >125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (P < .001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI >60 mL/min/1.73 m2 may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.

Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease.

SUMMARYFungal infections are on the rise, driven by a growing population at risk and climate change. Currently available antifungals include only five classes, and their utility and efficacy in antifungal treatment are limited by one or more of innate or acquired resistance in some fungi, poor penetration into "sequestered" sites, and agent-specific side effect which require frequent patient reassessment and monitoring. Agents with novel mechanisms, favorable pharmacokinetic (PK) profiles including good oral bioavailability, and fungicidal mechanism(s) are urgently needed. Here, we provide a comprehensive review of novel antifungal agents, with both improved known mechanisms of actions and new antifungal classes, currently in clinical development for treating invasive yeast, mold (filamentous fungi), Pneumocystis jirovecii infections, and dimorphic fungi (endemic mycoses). We further focus on inhaled antifungals and the role of immunotherapy in tackling fungal infections, and the specific PK/pharmacodynamic profiles, tissue distributions as well as drug-drug interactions of novel antifungals. Finally, we review antifungal resistance mechanisms, the role of use of antifungal pesticides in agriculture as drivers of drug resistance, and detail detection methods for antifungal resistance.

Evaluation of the drug-drug interaction between triazole antifungals and cystic fibrosis transmembrane conductance regulator modulators in a real-life cohort.

Limited data on the clinical management of drug-drug interactions between triazoles and Cystic Fibrosis transmembrane conductance regulator (CFTR) modulators are available. We retrospectively evaluated azole target attainment and dose adaptations in patients from two Dutch CF centres concomitantly receiving triazoles and CFTR modulators. In total, 21 patients with 59 triazole trough concentrations were evaluated. Subtherapeutic concentrations were frequently observed, especially for itraconazole and voriconazole. Of the investigated antifungal agents, posaconazole appears the most preferable option. Our results emphasize the importance of adequate management of this interaction and underpin the added value of therapeutic drug monitoring of triazoles in this population.

Fungal infections are serious complications in Cystic Fibrosis (CF) patients. We evaluated patients concomitantly receiving triazoles and CF transmembrane conductance regulator modulators: subtherapeutic triazole exposure was frequently observed. Posaconazole appears the preferable antifungal agent.

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

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Development and validation of an UPLC-MS/MS assay for the simultaneous quantification of seven commonly used antibiotics in human plasma and its application in therapeutic drug monitoring.

OBJECTIVE: To develop and validate an UPLC-MS/MS assay for simultaneous determination of the total concentration of ceftazidime, ciprofloxacin, flucloxacillin, piperacillin, tazobactam, sulfamethoxazole, N-acetyl sulfamethoxazole and trimethoprim, and the protein-unbound concentration of flucloxacillin, in human plasma to be used for research and clinical practice. METHODS: Sample pretreatment included protein precipitation with methanol. For the measurement of protein-unbound flucloxacillin, ultrafiltration was performed at physiological temperature. For all compounds, a stable isotopically labelled internal standard was used. Reliability of the results was assessed by participation in an international quality control programme. RESULTS: The assay was successfully validated according to the EMA guidelines over a concentration range of 0.5-100 mg/L for ceftazidime, 0.05-10 mg/L for ciprofloxacin, 0.4-125 mg/L for flucloxacillin, 0.2-60 mg/L for piperacillin, 0.15-30 mg/L for tazobactam, 1-200 mg/L for sulfamethoxazole and N-acetyl sulfamethoxazole, 0.05-10 mg/L for trimethoprim and 0.10-50 mg/L for unbound flucloxacillin. For measurement of total concentrations, the within- and between-day accuracy ranged from 90.0% to 109%, and 93.4% to 108%, respectively. Within- and between-day precision (variation coefficients, CVs) ranged from 1.70% to 11.2%, and 0.290% to 5.30%, respectively. For unbound flucloxacillin, within-day accuracy ranged from 103% to 106% and between-day accuracy from 102% to 105%. The within- and between-day CVs ranged from 1.92% to 7.11%. Results of the international quality control programme showed that the assay is reliable. CONCLUSIONS: The method provided reliable, precise and accurate measurement of seven commonly prescribed antibiotics, including the unbound concentration of flucloxacillin. This method is now routinely applied in research and clinical practice.

How to Dose Vancomycin in Overweight and Obese Patients with Varying Renal (Dys)function in the Novel Era of AUC 400-600 mg·h/L-Targeted Dosing.

BACKGROUND AND OBJECTIVE: The latest vancomycin guideline recommends area under the curve (AUC)-targeted dosing and monitoring for efficacy and safety. However, guidelines for AUC-targeted starting dosing in patients with obesity and/or renal insufficiency are currently lacking. This study quantifies the pharmacokinetics (PK) of vancomycin in this population and provides AUC-targeted dosing recommendations. METHODS: Vancomycin concentrations (n = 1188) from therapeutic drug monitoring of 210 overweight and obese patients with varying degrees of renal (dys)function from the ward (74.8%) and intensive care unit (ICU, 25.2%) were pooled with published rich concentration-time data (n = 207) from 20 (morbidly) obese subjects undergoing bariatric surgery. A population model was developed using NONMEM 7.4. Stochastic simulations were performed to design dosing guidelines targeting an AUC24 between 400-600 mg·h/L. RESULTS: Vancomycin clearance (CL) was found to increase linearly with total bodyweight and with renal function (CKD-EPI) in a power relation. Additionally, CL proved 15.5% lower in ICU patients. Our model shows that, to reach the target AUC between 400 and 600 mg·h/L in the first 48 h, two loading doses are required for both continuous infusion and intermittent dosing regimens. Maintenance doses were found to require adjustment for total bodyweight, renal function, and ICU admission status. With this guideline, the median AUC24 is well within the target from the start of the treatment onwards. CONCLUSIONS: To achieve safe and effective vancomycin exposure for maintenance doses in overweight and obese patients, renal function, total bodyweight, and ICU admission status should be taken into account. TRIAL REGISTRATION: The AMIGO trial was registered in the Dutch Trial Registry [NTR6058].

Meta-pharmacokinetic analysis of posaconazole following dosing of oral suspension, delayed-release tablet, and intravenous infusion in patients vs. healthy volunteers: Impact of clinical characteristics and race.

OBJECTIVES: To investigate the potential impact of clinical characteristics and the Chinese race on posaconazole pharmacokinetics in patients using an integrated population pharmacokinetic model for posaconazole oral suspension (SUS), delayed-release tablet (DR-tablet), and intravenous (IV) infusion that was developed in healthy volunteers (HV). METHODS: 1046 concentrations from 105 prospectively studied Caucasian patients receiving either of the three posaconazole formulations were pooled with 3898 concentrations from 182 HV. Clinical characteristics were tested for significance. The impact of Chinese race was assessed using 292 opportunistic samples from 80 Chinese patients receiving SUS. RESULTS: Bioavailability of SUS (Fsus) in patients decreased from 38.2% to 24.6% when the dose was increased from 100 mg to 600 mg. Bioavailability of DR-tablet (Ftab) was 59% regardless of dose. Mucositis, diarrhoea, administration through a nasogastric tube, and concomitant use of proton pump inhibitors or metoclopramide reduced Fsus by 61%, 36%, 44%, 48%, and 29%, respectively, putting patients with these characteristics at increased risk of inadequate exposure. Clearance decreased from 7.0 to 5.1 L/h once albumin levels were <30 g/L. Patients showed an 84.4% larger peripheral volume of distribution (Vp) and 67.5% lower intercompartmental clearance (Q) compared with HV. No racial difference could be identified. CONCLUSIONS: Pharmacokinetics of posaconazole in patients differ considerably to those in HV, with altered Fsus that is also impacted by clinical covariates, an Ftab similar to fasted conditions in HV, and altered parameters for clearance, Vp, and Q. There was no evidence to indicate that Chinese patients require a different dose to Caucasian patients.

High Variability in Isavuconazole Unbound Fraction in Clinical Practice: A Call to Reconsider Pharmacokinetic/Pharmacodynamic Targets and Breakpoints.

Isavuconazole exposure-response relationships have been studied with a focus on total rather than unbound exposure, assuming a constant unbound fraction of 1%. We observed a median (range) unbound fraction of 1.59% (0.42-5.30%) in patients. This highly variable protein binding asks for re-evaluation of current pharmacokinetic and pharmacodynamic targets for isavuconazole.

A protocol for an international, multicentre pharmacokinetic study for Screening Antifungal Exposure in Intensive Care Units: The SAFE-ICU study.

Objective: To describe whether contemporary dosing of antifungal drugs achieves therapeutic exposures in critically ill patients that are associated with optimal outcomes. Adequate antifungal therapy is a key determinant of survival of critically ill patients with fungal infections. Critical illness can alter an antifungal agents' pharmacokinetics, increasing the risk of inappropriate antifungal exposure that may lead to treatment failure and/or toxicity. Design setting and participants: This international, multicentre, observational pharmacokinetic study will comprise adult critically ill patients prescribed antifungal agents including fluconazole, voriconazole, posaconazole, isavuconazole, caspofungin, micafungin, anidulafungin, and amphotericin B for the treatment or prophylaxis of invasive fungal disease. A minimum of 12 patients are targeted for enrolment for each antifungal agent, across 12 countries and 30 intensive care units to perform descriptive pharmacokinetics. Pharmacokinetic sampling will occur during two dosing intervals (occasions): firstly, between days 1 and 3, and secondly, between days 4 and 7 of the antifungal course, collecting three samples per occasion. Patients' demographic and clinical data will be collected. Main outcome measures: The primary endpoint of the study is attainment of pharmacokinetic/pharmacodynamic target exposures that are associated with optimal efficacy. Thirty-day mortality will also be measured. Results and conclusions: This study will describe whether contemporary antifungal drug dosing achieves drug exposures associated with optimal outcomes. Data will also be used for the development of antifungal dosing algorithms for critically ill patients. Optimised drug dosing should be considered a priority for improving clinical outcomes for critically ill patients with fungal infections.

Pharmacokinetic investigations of isavuconazole in paediatric cancer patients show reduced exposure of isavuconazole after opening capsules for administration via a nasogastric tube.

OBJECTIVES: To study the isavuconazole pharmacokinetics in a real-life paediatric cohort and confirm whether the isavuconazole exposures are within the adult exposure range. Furthermore, we are the first to describe unbound isavuconazole pharmacokinetics. METHODS: In this prospective, observational study, the isavuconazole dosing regimen was as follows (IV/oral/nasogastric tube): 5.4 mg/kg isavuconazole (maximum 200 mg/dose) three times daily on Days 1 and 2, followed by 5.4 mg/kg isavuconazole (maximum 200 mg/dose) once daily. At least one pharmacokinetic curve was assessed. Non-linear mixed effects modelling was used for analysis. Monte Carlo simulations were performed with the above mentioned maintenance dose for IV administrations and a weight band dosing regimen for oral/nasogastric tube administrations: I) <18 kg (100 mg daily); II) 18-37 kg (150 mg daily); III)>37 kg (200 mg daily). RESULTS: Seventeen paediatric patients with a median age of 9 years (range 1-17) and median weight of 26.0 kg (range 8.4-78.5) were evaluated. A two-compartment model describing linear pharmacokinetics of the unbound concentrations and saturable protein binding fitted the isavuconazole concentrations best. The absolute bioavailability of isavuconazole was 41.0% (95% CI: 32.4%-50.8%). The median (IQR) simulated exposures (AUC0-24h, SS) of the total isavuconazole concentrations after IV and oral/nasogastric tube administration were 87.7 mg·h/L (70.5-105.1) and 50.3 mg·h/L (39.0-62.4), respectively. The unbound isavuconazole fraction (unbound/total) ranged from 0.5% to 2.3%. CONCLUSIONS: This study revealed low bioavailability after nasogastric tube administration with opened capsules. Isavuconazole exposures were in the expected range following IV administration. Total and unbound isavuconazole pharmacokinetics were reported with a 5-fold range in the unbound fraction.

Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies.

BACKGROUND AND OBJECTIVES: Isavuconazole is a broad-spectrum antifungal agent for the management of invasive fungal disease. Optimised drug exposure is critical for patient outcomes, specifically in the critically ill population. Solid information on isavuconazole pharmacokinetics including protein binding in patients in the intensive care unit is scarce. We aimed to describe the total and unbound isavuconazole pharmacokinetics and subsequently propose a dosage optimisation strategy. METHODS: A prospective multi-centre study in adult intensive care unit patients receiving isavuconazole was performed. Blood samples were collected on eight timepoints over one dosing interval between days 3-7 of treatment and optionally on one timepoint after discontinuation. Total and unbound isavuconazole pharmacokinetics were analysed by means of population pharmacokinetic modelling using NONMEM. The final model was used to perform simulations to assess exposure described by the area under the concentration-time curve and propose an adaptive dosing approach. RESULTS: Population pharmacokinetics of total and unbound isavuconazole were best described by an allometrically scaled two-compartment model with a saturable protein-binding model and interindividual variability on clearance and the maximum binding capacity. The median (range) isavuconazole unbound fraction was 1.65% (0.83-3.25%). After standard dosing, only 35.8% of simulated patients reached a total isavuconazole area under the concentration-time curve > 60 mg·h/L at day 14. The proposed adaptive dosing strategy resulted in an increase to 62.3% of patients at adequate steady-state exposure. CONCLUSIONS: In critically ill patients, total isavuconazole exposure is reduced and protein binding is highly variable. We proposed an adaptive dosing approach to enhance early treatment optimisation in this high-risk population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04777058.

Oral antimicrobial agents in patients with short bowel syndrome: worth a try!

BACKGROUND: The use of oral antimicrobial agents in patients with short bowel syndrome (SBS) is challenging due to the changes in gastrointestinal anatomy that may result in diminished absorption and altered drug bioavailability. Prospective studies evaluating bioavailability of antimicrobial agents after oral administration in SBS patients are lacking. OBJECTIVES: To determine the bioavailability of orally administered antimicrobial agents commonly used for treatment in SBS patients to guide clinical decision making when faced with infections. METHODS: We performed an explorative, clinical study investigating the pharmacokinetics (PK) of clindamycin, ciprofloxacin, flucloxacillin and fluconazole in SBS patients with intestinal failure. Participants received a combination of two antimicrobial agents simultaneously. To determine the oral bioavailability, participants received a single oral and IV dose of both agents on two occasions, after which they underwent intensive PK sampling on six predefined time points up to 12 hours after administration. Primary outcome was the oral bioavailability of these antimicrobial agents. Secondary outcomes were intravenous PK characteristics following non-compartmental analysis. RESULTS: Eighteen SBS patients were included: the mean (SD) age was 59 (17) years and 61% of participants were female. The median observed (IQR) bioavailability of ciprofloxacin, clindamycin, flucloxacillin and fluconazole were 36% (24-50), 93% (56-106), 50% (32-76) and 98% (61-107), respectively. CONCLUSION: The bioavailability of selected antimicrobial agents in certain patients with SBS appeared to be better than expected, providing a feasible treatment option. Due to the large observed differences between patients, therapeutic drug monitoring should be part of the treatment to safeguard adequate exposure in all patients. TRIAL REGISTRATION: Registered in the Dutch Trial Register (NL7796) and EudraCT number 2019-002587-28.

An update on drug-drug interactions for care of the acutely ill in the era of COVID-19.

PURPOSE: To provide key pharmacological concepts underlying drug-drug interactions (DDIs), a decision-making framework, and a list of DDIs that should be considered in the context of contemporary acutely ill patients with COVID-19. SUMMARY: DDIs are frequently encountered in the acutely ill. The implications of DDIs include either increased risk of drug toxicity or decreased effectiveness, which may have severe consequences in the acutely ill due to lower physiological and neurocognitive reserves in these patients. In addition, an array of additional therapies and drug classes have been used for COVID-19 that were not typically used in the acute care setting. In this update on DDIs in the acutely ill, we provide key pharmacological concepts underlying DDIs, including a discussion of the gastric environment, the cytochrome P-450 (CYP) isozyme system, transporters, and pharmacodynamics in relation to DDIs. We also provide a decision-making framework that elucidates the identification of DDIs, risk assessment, selection of alternative therapies, and monitoring. Finally, important DDIs pertaining to contemporary acute care clinical practice related to COVID-19 are discussed. CONCLUSION: Interpreting and managing DDIs should follow a pharmacologically based approach and a systematic decision-making process to optimize patient outcomes.

The battle against fungi: lessons in antifungal stewardship from COVID 19 times

The COVID-19 pandemic has highlighted the detrimental effect of secondary pathogens in patients with a primary viral insult. In addition to superinfections with bacterial pathogens, invasive fungal infections were increasingly reported. The diagnosis of pulmonary fungal infections has always been challenging; however, it became even more problematic in the setting of COVID-19, particularly regarding the interpretation of radiological findings and mycology test results in patients with these infections. Moreover, prolonged hospitalization in ICU, coupled with underlying host factors. such as preexisting immunosuppression, use of immunomodulatory agents, and pulmonary compromise, caused additional vulnerability to fungal infections in this patient population. In addition, the heavy workload, redeployment of untrained staff, and inconsistent supply of gloves, gowns, and masks during the COVID-19 outbreak made it harder for healthcare workers to strictly adhere to preventive measures for infection control. Taken together, these factors favored patient-to-patient spread of fungal infections, such as those caused by Candida auris, or environment-to-patient transmission, including nosocomial aspergillosis. As fungal infections were associated with increased morbidity and mortality, empirical treatment was overly used and abused in COVID-19-infected patients, potentially contributing to increased resistance in fungal pathogens. The aim of this paper was to focus on essential elements of antifungal stewardship in COVID-19 for three fungal infections, COVID-19-associated candidemia (CAC), -pulmonary aspergillosis (CAPA), and -mucormycosis (CAM).

Repurposing antifungals: population pharmacokinetics of itraconazole and hydroxy-itraconazole following administration of a nanocrystal formulation.

OBJECTIVES: To describe itraconazole and hydroxy-itraconazole pharmacokinetics following intravenous (IV) administration of a previously developed nanocrystal formulation (NCF) in haematopoietic cell transplant (HCT) recipients for prophylaxis of invasive fungal disease. METHODS: In a prospective Phase II study, 10 HCT recipients received itraconazole NCF administered in 2-hour infusions of 200 mg twice daily for 2 days, followed by 200 mg once daily until Day 14. Full pharmacokinetic curves were obtained on Days 7 and 14. Additional samples were collected pre- and post-infusion until Day 6, pre-infusion on Days 10 and 12, and during washout on Days 16, 17, 18, 19 and 28. Itraconazole and hydroxy-itraconazole pharmacokinetics were analysed by non-linear mixed-effects population pharmacokinetic modelling. RESULTS: Four-hundred and seventy-one itraconazole and 471 paired hydroxy-itraconazole concentrations from 10 patients were included for analysis. Data were best described by a semi-mechanistic model with central and peripheral itraconazole compartments and a hydroxy-itraconazole compartment with dissolution of itraconazole drug particles from nanocrystals and first-order distribution and elimination. The final model included interindividual variability on itraconazole clearance and hydroxy-itraconazole clearance. CONCLUSIONS: This study provides information on the pharmacokinetic properties of the itraconazole NCF useful for development of this formulation. Our results suggest that itraconazole NCF is a suitable formulation and may warrant renewal in the setting of repurposing. Our findings may be useful for the reformulation of other highly lipophilic compounds as well.

An Integrated Population Pharmacokinetic Analysis for Posaconazole Oral Suspension, Delayed-Release Tablet, and Intravenous Infusion in Healthy Volunteers.

BACKGROUND: Posaconazole is widely used for the prophylaxis and treatment of invasive fungal diseases. Because of the limited and variable absorption of the initially available oral suspension, a delayed-release tablet and intravenous formulation were developed. OBJECTIVE: This study aimed to characterize the pharmacokinetics, including the absolute oral bioavailability, of all posaconazole formulations in healthy volunteers. METHODS: Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from eight phase I clinical studies on the three formulations of various single and multiple dosage regimens between 50 and 400 mg. Analysis and simulations were performed using NONMEM 7.5.0. In the covariate analysis, the influence of food (fed vs fasted), nonlinearity, and for the delayed-release tablet, comedication (antacid, ranitidine, esomeprazole, and metoclopramide) were tested. RESULTS: A two-compartment model with respectively, four and eight absorption transit compartments, best described the profiles of the oral suspension and delayed-release tablet. For the suspension, both a food effect and a dose-dependent nonlinear bioavailability were quantified, resulting in lower bioavailability when fasted or at a higher dose. The typical bioavailability of the suspension at 100 mg and 400 mg was derived to be respectively, 17.1% and 10.1% under fasted conditions and 59.1% and 49.2% under fed conditions. The absolute bioavailability of the delayed-release tablet was 58.8% (95% confidence interval 33.2-80.4) under fasted conditions and approached complete absorption under fed conditions for dosages up to 300 mg. Food intake reduced the absorption rate constant of the suspension by 52.2% (confidence interval 45.2-59.2). The impact of comedication on the absorption of the delayed-release tablet was not statistically significant. Model-based simulations indicate that under fed conditions, the licensed dosages of the three formulations yield a steady-state trough concentration ≥ 0.7 mg/L in over 90% of healthy volunteers. About 35% of healthy volunteers who receive the licensed 300-mg delayed-release tablet under fasted conditions do not achieve this target, while for the suspension this percentage varies between 55 and 85%, depending on the dose. CONCLUSIONS: For both oral posaconazole formulations, we quantified bioavailability and absorption rate, including food effects, in healthy volunteers. The pharmacokinetic superiority of the delayed-release tablet was demonstrated under both fed and fasted conditions, compared with the oral suspension. The impact of food on the bioavailability of the delayed-release tablet was larger than anticipated, suggesting that administering the delayed-release tablet with food enhances absorption.

Therapeutic drug monitoring-guided treatment versus standard dosing of voriconazole for invasive aspergillosis in haematological patients: a multicentre, prospective, cluster randomised, crossover clinical trial.

OBJECTIVES: Voriconazole therapeutic drug monitoring (TDM) is recommended based on retrospective data and limited prospective studies. This study aimed to investigate whether TDM-guided voriconazole treatment is superior to standard treatment for invasive aspergillosis. METHODS: A multicentre (n = 10), prospective, cluster randomised, crossover clinical trial was performed in haematological patients aged ≥18 years treated with voriconazole. All patients received standard voriconazole dose at the start of treatment. Blood/serum/plasma was periodically collected after treatment initiation of voriconazole and repeated during treatment in both groups. The TDM group had measured voriconazole concentrations reported back, with dose adjustments made as appropriate, while the non-TDM group had voriconazole concentrations measured only after study completion. The composite primary endpoint included response to treatment and voriconazole treatment discontinuation due to an adverse drug reaction related to voriconazole within 28 days after treatment initiation. RESULTS: In total, 189 patients were enrolled in the study. For the composite primary endpoint, 74 patients were included in the non-TDM group and 68 patients in the TDM group. Here, no significant difference was found between both groups (P = 0.678). However, more trough concentrations were found within the generally accepted range of 1-6 mg/L for the TDM group (74.0%) compared with the non-TDM group (64.0%) (P < 0.001). CONCLUSIONS: In this trial, TDM-guided dosing of voriconazole did not show improved treatment outcome compared with standard dosing. We believe that these findings should open up the discussion for an approach to voriconazole TDM that includes drug exposure, pathogen susceptibility and host defence. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration no. NCT00893555.