Determination of a vancomycin nephrotoxicity threshold and assessment of target attainment in hematology patients.

An area-under-the-curve (AUC24)-based approach is recommended to guide vancomycin therapeutic drug monitoring (TDM), yet trough concentrations are still commonly used despite associated risks. A definitive toxicity target is lacking, which is important for hematology patients who have a higher risk of nephrotoxicity. The aims were to (1) assess the impact of trough-based TDM on acute kidney injury (AKI) incidence, (2) establish a vancomycin nephrotoxicity threshold, and (3) evaluate the proportion of hematology patients achieving vancomycin therapeutic targets. Retrospective data was collected from 100 adult patients with a hematological malignancy or aplastic anemia who received vancomycin between April 2020 and January 2021. AKI occurrence was determined based on serum creatinine concentrations, and individual pharmacokinetic parameters were estimated using a Bayesian approach. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of pharmacokinetic indices to predict AKI occurrence. The proportion of patients who achieved target vancomycin exposure was evaluated based on an AUC24/MIC ≥400 and the determined toxicity threshold. The incidence of AKI was 37%. ROC curve analysis indicated a maximum AUC24 of 644 mg.h/L over the treatment period was an important predictor of AKI. By Day 4 of treatment, 29% of treatment courses had supratherapeutic vancomycin exposure, with only 62% of courses achieving AUC24 targets. The identified toxicity threshold supports an AUC24 target range of 400-650 mg.h/L, assuming an MIC of 1 mg/L, to optimize vancomycin efficacy and minimize toxicity. This study highlights high rates of AKI in this population and emphasizes the importance of transitioning from trough-based TDM to an AUC-based approach to improve clinical outcomes.

Population pharmacokinetics of posaconazole in allogeneic haematopoietic stem cell transplant patients.

BACKGROUND: Invasive fungal disease (IFD) in the early post-allogeneic HSCT (alloHCT) period is associated with increased likelihood of catastrophic outcomes. The utility of oral modified release (MR) posaconazole tablets is limited by reduced drug absorption from gastrointestinal toxicity induced by cytotoxic chemotherapy, necessitating a switch to the IV posaconazole formulation. OBJECTIVES: To describe the population pharmacokinetics of posaconazole for oral MR and IV formulations in alloHCT patients and determine dosing regimens likely to achieve therapeutic exposures. METHODS: We performed a prospective observational pharmacokinetic study in adult patients in the early post-alloHCT period requiring a change in posaconazole formulation (oral to IV). Samples were analysed using a validated LC-MS/MS method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. RESULTS: Twenty patients aged between 21 and 70 years were included in the study. A two-compartment model, incorporating mucositis/diarrhoea to modify the bioavailability for oral administration best described the data. To achieve ≥90% PTA, simulations showed that higher than currently recommended doses of oral MR posaconazole were required for prophylaxis Cmin targets (≥0.5 and ≥0.7 mg/L), while increased doses of both formulations were required for IFD treatment PK/PD targets, with patients experiencing oral mucositis/diarrhoea unlikely to achieve these. CONCLUSIONS: Increased doses of posaconazole should be considered for both prophylaxis and treatment of IFD to increase the proportion of alloHCT patients achieving therapeutic exposures, particularly the oral formulation in patients with mucositis and/or diarrhoea. Posaconazole therapeutic drug monitoring should be considered for all formulations in this setting.

A Personalized Risk Model for Azacitidine Outcome in Myelodysplastic Syndrome and Other Myeloid Neoplasms Identified by Machine Learning Model Utilizing Real-World Data.

Azacitidine is an approved therapy for higher-risk myelodysplastic syndrome (MDS). However, only 30-40% patients respond to azacitidine, and the responses may take up to six cycles to become evident. Delayed responses and the myelosuppressive effects of azacitidine make it challenging to predict which patients will benefit. This is further compounded by a lack of uniform prognostic tools to identify patients at risk of early treatment failure. Hence, we performed a retrospective analysis of 273 consecutive azacytidine-treated patients. The median overall survival was 16.25 months with only 9% alive at 5 years. By using pre-treatment variables incorporated into a random forest machine learning model, we successfully identified those patients unlikely to benefit from azacytidine upfront (7.99 vs. 22.8 months, p < 0.0001). This model also identified those who required significantly more hospitalizations and transfusion support. Notably, it accurately predicted survival outcomes, outperforming the existing prognostic scoring system. By integrating somatic mutations, we further refined the model and identified three distinct risk groups with significant differences in survival (5.6 vs. 10.5 vs. 43.5 months, p < 0.0001). These real-world findings emphasize the urgent need for personalized prediction tools tailored to hypomethylating agents, reducing unnecessary complications and resource utilization in MDS treatment.

Population Pharmacokinetics of Ganciclovir in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Treatment of cytomegalovirus (CMV) infection in allogeneic hematopoietic stem cell transplantation (alloHCT) patients with ganciclovir is complicated by toxicity and resistance. This study aimed to develop an intravenous ganciclovir population pharmacokinetic model for post-alloHCT patients and to determine dosing regimens likely to achieve suggested therapeutic exposure targets. We performed a prospective observational single-center pharmacokinetic study in adult alloHCT patients requiring treatment with intravenous ganciclovir for CMV viremia or disease. Samples were analyzed using a validated ultraperformance liquid chromatography method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R. Twenty patients aged 18 to 69 years were included in the study. A 2-compartment model with linear elimination from the central compartment and between occasion variability best described the data. Incorporating creatinine clearance (CLCR) estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and presence of continuous renal replacement therapy as covariates for ganciclovir clearance improved the model. Compared to current dosing recommendations, simulations demonstrated loading doses were required to achieve a target AUC24 of 80 to 120 mg.h/L on day 1 of induction therapy. Increased individualization of post-loading induction and maintenance doses based on CLCR is required to achieve the suggested exposures for efficacy (AUC24 >80/>40 mg.h/L for induction/maintenance) while remaining below the exposure thresholds for toxicity (AUC24 <120/<60 mg.h/L for induction/maintenance). Intravenous ganciclovir dosing in alloHCT patients can be guided by CLCR estimated by CKD-EPI. Incorporation of loading doses into induction dosing regimens should be considered for timely achievement of currently suggested exposures.

Application of User-Centered Codesign Principles to Address Barriers in Therapeutic Drug Monitoring.

BACKGROUND: Different software applications have been developed to support health care professionals in individualized drug dosing. However, their translation into clinical practice is limited, partly because of poor usability and integration into workflow, which can be attributed to the limited involvement of health care professionals in the development and implementation of drug dosing software. This study applied codesign principles to inform the design of a drug dosing software to address barriers in therapeutic drug monitoring using vancomycin as an example. METHODS: Three workshops (face-to-face and online) were conducted by design researchers with pharmacists and prescribers. User journey storyboards, user personas, and prototyping tools were used to explore existing barriers to practice and opportunities for innovation through drug dosing software design. A prototype of the software interface was developed for further evaluation. RESULTS: Health care professionals (11 hospital pharmacists and 6 prescribers) with ≥2 years of clinical experience were recruited. Confidence and software usability emerged as the main themes. Participants identified a lack of confidence in vancomycin dosing and pharmacokinetic understanding and difficulty in accessing practice guidelines as key barriers that could be addressed through software implementation. Accessibility to information (eg, guidelines and pharmacokinetic resources) and information presentation (eg, graphical) within the dosing software were dependent on the needs and experience of the user. A software prototype with a speedometer-dial visual to convey optimal doses was well received by participants. CONCLUSIONS: The perspectives of health care professionals highlight the need for drug dosing software to be user centered and adaptable to the needs and workflow of end users. Continuous engagement with stakeholders on tool usability, training, and education is needed to promote the implementation in practice.

Optimizing antifungal prophylaxis in allogeneic stem cell transplantation: A cohort study of two different approaches.

BACKGROUND: Limited consensus exists on the optimal use of antifungal agents to prevent invasive fungal infection in the early post allogeneic hematopoietic stem cell transplant (alloHCT) period, particularly when patients cannot tolerate oral medication administration. METHODS: We undertook a retrospective observational cohort study to assess the tolerability, efficacy, and cost of a new antifungal prophylaxis pathway at a major tertiary alloHCT centre. Patients aged ≥16 years who underwent alloHCT between February 2018 and October 2019 (cohort 1) or between April 2020 and November 2021 (cohort 2) were included. In both cohorts, first line prophylactic therapy was oral posaconazole. The second line drugs where oral therapy was unable to be administered were intravenous voriconazole (cohort 1) versus intravenous posaconazole (cohort 2). RESULTS: There were 142 patients enrolled in the study, 71 in each cohort. The proportion of patients remaining on first-line prophylaxis or progressing to second-, third-, and fourth-line options was 22.5%, 39.4%, 29.6%, and 8.5% in cohort 1 and 39.4%, 59.2%, 1.4%, and 0% in cohort 2, respectively. The frequency of neuropsychiatric adverse events was significantly higher in cohort 1 compared to cohort 2 (49.3% vs. 19.8%, p = .0004). Occurrence of proven and probable fungal infections was not significantly different between cohorts. Antifungal drug expenditure was $359 935 (AUD) more in cohort 1 ($830 486 AUD) compared to cohort 2 ($477 149 AUD). CONCLUSION: The antifungal prophylaxis pathway used in cohort 2 resulted in reduced antifungal-associated adverse effects, less patients requiring progression to 3rd and 4th line prophylaxis and reduced antifungal drug costs.

A coupled human-natural system analysis of freshwater security under climate and population change.

Limited water availability, population growth, and climate change have resulted in freshwater crises in many countries. Jordan's situation is emblematic, compounded by conflict-induced population shocks. Integrating knowledge across hydrology, climatology, agriculture, political science, geography, and economics, we present the Jordan Water Model, a nationwide coupled human-natural-engineered systems model that is used to evaluate Jordan's freshwater security under climate and socioeconomic changes. The complex systems model simulates the trajectory of Jordan's water system, representing dynamic interactions between a hierarchy of actors and the natural and engineered water environment. A multiagent modeling approach enables the quantification of impacts at the level of thousands of representative agents across sectors, allowing for the evaluation of both systemwide and distributional outcomes translated into a suite of water-security metrics (vulnerability, equity, shortage duration, and economic well-being). Model results indicate severe, potentially destabilizing, declines in freshwater security. Per capita water availability decreases by approximately 50% by the end of the century. Without intervening measures, >90% of the low-income household population experiences critical insecurity by the end of the century, receiving <40 L per capita per day. Widening disparity in freshwater use, lengthening shortage durations, and declining economic welfare are prevalent across narratives. To gain a foothold on its freshwater future, Jordan must enact a sweeping portfolio of ambitious interventions that include large-scale desalinization and comprehensive water sector reform, with model results revealing exponential improvements in water security through the coordination of supply- and demand-side measures.

A Systematic Review of the Clinical Pharmacokinetics, Pharmacodynamics and Toxicodynamics of Ganciclovir/Valganciclovir in Allogeneic Haematopoietic Stem Cell Transplant Patients.

BACKGROUND: Ganciclovir (GCV) and valganciclovir (VGCV) are the first-line agents used to prevent and treat cytomegalovirus (CMV) infection in allogeneic haematopoietic stem cell transplant (alloHCT) patients. OBJECTIVE: The aim of this work was to describe available data for the clinical pharmacokinetics, pharmacodynamics and toxicodynamics of GCV and VGCV and the potential of a therapeutic drug monitoring strategy to improve outcomes in the alloHCT population. METHODS: We systematically reviewed the pharmacokinetics (dose-exposure), pharmacodynamics (exposure-efficacy) and toxicodynamics (exposure-toxicity) of GCV and VGCV in alloHCT patients with CMV infection. Studies including alloHCT patients treated for CMV infection reporting the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV or VGCV were searched for using the PUBMED and EMBASE databases from 1946 to 2019. Only studies involving participants > 12 years of age and available in the English language were included. RESULTS: A total of 179 patients were included in the 14 studies that met the inclusion criteria, of which 6 examined GCV pharmacokinetics only, while 8 also examined GCV pharmacodynamics and toxicodynamics. Reported pharmacokinetic parameters showed considerable interpatient variability and were different from other populations, such as solid organ transplant and human immunodeficiency virus-infected patients. Only one study found a correlation between neutropenia and elevated peak and trough GCV concentrations, with no other significant pharmacodynamic and toxicodynamic relationships identified. While therapeutic drug monitoring of GCV is performed in some institutions, no association between GCV therapeutic drug monitoring and clinical outcomes was identified. CONCLUSION: Further studies of the pharmacokinetics, pharmacodynamics and toxicodynamics of GCV/VGCV in alloHCT patients are required to identify a more robust therapeutic range and to subsequently quantify the potential value of therapeutic drug monitoring of GCV/VGCV in the alloHCT population.