Dosing Strategies Research Articles

Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships

This work aimed to characterize the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) to identify venetoclax doses to be administered to pediatric patients in the phase 3 study. Data from 121 patients across three phase 1 studies enrolling pediatric patients with R/R malignancies were utilized to develop a population pharmacokinetic model to describe venetoclax pharmacokinetics in pediatric patients. Individual patient average venetoclax plasma concentration up to the event of interest, derived based on the population pharmacokinetics analysis, was used to evaluate the exposure-response relationships to efficacy (complete response) and safety (neutropenia and thrombocytopenia) endpoints for patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine (n = 36). The population pharmacokinetic model was then used to simulate exposures in pediatric age- and weight-based subgroups to identify the venetoclax doses for pediatric patients. The pharmacokinetic data were adequately described by the two-compartment population pharmacokinetic model with first-order absorption and elimination. The model accounted for cytochrome P450 3A developmental changes using a maturation function and incorporated allometric scaling to account for growth and body size effect. Weight was identified as a statistically significant covariate on clearance and volume of distribution and retained in the final model. Population pharmacokinetic estimates were comparable to previously reported estimates in adults. Exposure-response analyses suggested that the clinical efficacy of venetoclax in combination with high-dose cytarabine (HDAC) is maximized at 600 mg adult-equivalent, and higher doses are unlikely to enhance clinical efficacy. Venetoclax 600 mg adult-equivalent was selected for further development in combination with HDAC. Additionally, venetoclax 400 mg adult-equivalent was selected for bridging/maintenance therapy in combination with azacitidine. Flat exposure-response relationships were observed with Grade ≥3 neutropenia and thrombocytopenia. Doses were selected based on weight (allometric scaling) for children aged ≥2 years old and based on weight and CYP3A ontogeny for children aged <2 years. The selected age- and weight-based dosing scheme of venetoclax is projected to achieve venetoclax exposures in pediatric subgroups comparable to those observed in adults receiving venetoclax 400 mg or 600 mg. This work characterized the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients and guided the selection of pediatric dosing regimens in support of the venetoclax phase 3 trial in pediatric AML (NCT05183035). NCT03236857, NCT03181126, and NCT03194932.

Characterization of Ganciclovir Dosing for the Management of Cytomegalovirus in Solid Organ Transplant Recipients Receiving Sustained Low-Efficiency Dialysis.

The optimal dosing of intravenous ganciclovir in patients receiving sustained low-efficiency dialysis (SLED) remains unclear. The primary objective is to characterize the dosing of ganciclovir for treating and preventing cytomegalovirus (CMV) in Solid Organ Transplant Recipients receiving SLED. The secondary objective is to evaluate the safety and efficacy of the dosing practices described in this study. Retrospective review of electronic medical records from solid organ transplant recipients (SOTRs) admitted to the Medical Surgical Intensive Care Unit at the Toronto General Hospital (TGH) between November 28, 2016, and September 1, 2021, was conducted. Patients concurrently receiving ganciclovir and SLED were included. Among the 27 encounters for CMV prevention, 18 patients underwent 8-hour SLED, 6 underwent 24-hour SLED, and 3 received other SLED durations. Most patients (80%) on 8-hour SLED began ganciclovir at 2.5 mg/kg/d, whereas 80% of those on 24-hour SLED started at 5 mg/kg/d. No breakthrough viremia occurred at 5 mg/kg/d, with 1 instance at 2.5 mg/kg/d. Cytopenia rates were higher at 5 mg/kg/d (33% vs 20%). For treatment (n = 20), 16 patients underwent 8-hour SLED, 2 underwent 24-hour SLED, and 2 underwent 12-hour SLED. Most (75%) on 8-hour SLED started at 2.5 mg/kg/d, whereas all on 24-hour SLED began at 5 mg/kg/d. Viral eradication rates were 75% and 60% at 2.5 and 5 mg/kg/d, respectively, with higher cytopenia rates at 5 mg/kg/d (37.5% vs 0%). Dose adjustments were primarily in response to refractory disease or cytopenia. At our institution, ganciclovir dosing patterns suggest that for patients requiring 8-hour SLED, there is clinician comfort in using 2.5 mg/kg/d for prevention and 5 mg/kg/d for treatment. In 24-hour SLED, 5 mg/kg/d may be considered for prevention. Higher doses may be considered for CMV treatment; however, we found greater variability in the dosing practices for these patients. Further research with larger sample sizes and ganciclovir drug-level assessments is needed to optimize dosing strategies for CMV treatment.

Successful rapid improvement of acute respiratory distress syndrome induced by EGFR-mutated non-small cell lung cancer with almonertinib: a case report

BackgroundAcute respiratory distress syndrome (ARDS) is a life-threatening condition frequently encountered in critically ill patients, including those with advanced non-small cell lung cancer (NSCLC). Almonertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has shown promise as a first-line treatment for NSCLC with classical EGFR mutations. However, its efficacy in NSCLC patients suffering from ARDS has not been well-documented.Case PresentationWe report the case of a 63-year-old Chinese Han female with severe NSCLC complicated by ARDS. Upon hospital admission, the patient exhibited progressive dyspnea and required intubation to maintain oxygenation. Pathological analysis of bronchoalveolar lavage fluid sediment confirmed lung adenocarcinoma, and genetic testing of blood identified an EGFR E19 mutation. The patient was treated with almonertinib, resulting in significant clinical improvement and successful extubation after nine days. Radiographic imaging showed substantial reduction in pulmonary lesions, highlighting the efficacy of almonertinib.ConclusionThis case represents the first documented successful treatment of ARDS induced by EGFR E19 mutated NSCLC using almonertinib. The favorable clinical response observed in this critically ill patient suggests that almonertinib may be a viable therapeutic option for managing severe complications in NSCLC. Further research is necessary to corroborate these findings and optimize dosage and toxicity management strategies for broader clinical application.

Gaucher disease in Brazil: a comprehensive 16year retrospective study on survival, cost, and treatment insights.

Gaucher's disease (GD), a lysosomal storage disorder, poses significant treatment challenges. This 23-year study assesses survival rates and treatment efficacy in Brazilian GD patients, integrating data from a 16-year cohort (2000-2015) and the TABNET/DATASUS medicines distribution data (1999-2022). To investigate the survival of GD patients in Brazil, identifying key risk factors and evaluating the impact of treatments funded by the Brazilian National Health System (SUS). A 16-year retrospective cohort study was conducted using the National Database of SUS. Patients diagnosed with GD and treated with Enzyme Replacement Therapy (ERT) or Substrate Synthesis Inhibition (SSI) from 2000 to 2015 were included. Survival analysis was performed using Kaplan-Meier method and Cox proportional hazards model. The data from TABNET/DATASUS system from 1999 to 2022 was used to assess the trend in drug distribution beyond the main cohort. The study included 1,234 patients. Survival rates at 5 and 10years were 93.2% and 88.5%, respectively, with age and comorbidities like diabetes, cardiovascular diseases, and Parkinson's disease significantly affecting survival. Patients who received doses lower than DDD (n = 880) demonstrated a survival probability of 91.8%. In contrast, those with doses equal to the DDD (n = 15) showed a 100% survival probability, as no events were observed in this group. The greater than DDD group (n = 339) exhibited a survival probability of 81%. A log-rank test indicated a borderline statistical significance (p = 0.058) in the survival distributions among the different DDD adherence, with the lower dose group showing a favorable trend. This study provides insights into the survival rates and associated risk factors for GD patients in Brazil, contributing to the global understanding of GD and its management. While we acknowledge the inherent limitations of relying largely on electronic medical records and categorical codes, our findings underscore the need for early diagnosis, timely initiation of treatment, effective management of comorbidities, and personalized dosing strategies to improve patient outcomes. Future studies should aim to incorporate clinical verification of electronic data to further enhance the reliability and applicability of these findings.

The impact of supplementing vitamin D through different methods on the prognosis of COVID-19 patients: a systematic review and meta-analysis.

To analyze the impact of different methods of Vitamin D administration on the prognosis of COVID-19 patients. A comprehensive literature search was conducted across four databases: PubMed, Embase, Web of Science, and Cochrane, up to January 5, 2024. Eligible studies included randomized controlled trials and cohort studies that compared Vitamin D supplementation with control groups in COVID-19 patients. Outcomes of interest were mortality rate, ICU (Intensive Care Unit) admission rate, length of hospital stay, and endotracheal intubation rate. Subgroup analyses were performed based on the dosing regimen (single-dose vs. continuous-dose), total Vitamin D intake within 14 days (≥100,000 IU vs. <100,000 IU), and baseline serum Vitamin D levels (deficient group: 25OHD < 30 ng/mL vs. non-restricted group). A random-effects model was employed for meta-analysis to account for heterogeneity among studies. A total of 21 studies involving 4,553 participants were included. In terms of mortality, Vitamin D supplementation significantly reduced the mortality rate (RR = 0.72, 95% CI: 0.54-0.94, I 2 = 54%, p = 0.02), with continuous dosing being more effective (RR = 0.53, 95% CI: 0.34-0.83, I 2 = 55%, p = 0.006) compared to single-dose (RR = 0.88, 95% CI: 0.69-1.12, I 2 = 21%, p = 0.3), and lower total doses (<100,000 IU) showing greater benefit (RR = 0.30, 95% CI: 0.21-0.44, I 2 = 0%, p < 0.0001). Mortality was significantly reduced in the Vitamin D-deficient group (25OHD < 30 ng/mL) (RR = 0.73, 95% CI: 0.59-0.89, I 2 = 0%, p = 0.002) but not in the non-restricted group. Regarding ICU admission, supplementation reduced ICU admission rates (RR = 0.58, 95% CI: 0.38-0.88, I 2 = 74%, p = 0.01), with continuous dosing (RR = 0.44, 95% CI: 0.22-0.90, I 2 = 74%, p = 0.02) being more effective than single-dose (RR = 0.79, 95% CI: 0.61-1.03, I 2 = 22%, p = 0.08), and lower doses (<100,000 IU) providing more significant reduction (RR = 0.31, 95% CI: 0.21-0.47, I 2 = 0%, p = 0.001). ICU admission rates were significantly reduced in the Vitamin D-deficient group (RR = 0.63, 95% CI: 0.42-0.93, I 2 = 0%, p = 0.02) but not in the non-restricted group (RR = 0.59, 95% CI: 0.32-1.11, I 2 = 86%, p = 0.1). For length of hospital stay, no significant differences were observed between Vitamin D and control groups (MD = -1, 95% CI: -2.16 to 0.16, p = 0.13), and subgroup analyses by dosing regimen, total dose, and baseline Vitamin D levels also showed no significant differences. Similarly, for endotracheal intubation, there was no significant difference in intubation rates between groups (RR = 0.78, 95% CI: 0.56-1.08, p = 0.13), and subgroup analyses confirmed no significant effect of different dosing strategies or baseline Vitamin D status on intubation rates. Vitamin D supplementation improves clinical outcomes in COVID-19 patients by reducing mortality and ICU admission rates, particularly when administered continuously with a total dose of less than 100,000 IU over 14 days, and among those with baseline Vitamin D deficiency (25OHD < 30 ng/mL). However, there were no significant effects on the length of hospital stay or endotracheal intubation rates, regardless of the dosing regimen or baseline Vitamin D levels. These findings emphasize the importance of considering both the total dose over 14 days and baseline Vitamin D status to optimize therapeutic benefits.

The Effectiveness of Curcumin in Treating Oral Mucositis Related to Radiation and Chemotherapy: A Systematic Review.

Chemotherapy (CT) and radiation therapy (RT), while effective against cancer, often cause severe side effects, such as oral mucositis and other oral diseases. Oral mucositis, characterized by inflammation and ulceration of the oral mucosa, is one of the most painful side effects that can reduce quality of life and limit cancer treatment. Curcumin, a polyphenol from Curcuma longa, has garnered attention for its anti-inflammatory, antioxidant, and anti-carcinogenic properties, which protect the oral mucosa by reducing oxidative stress and modulating inflammation. This study reviews the therapeutic potential of curcumin in preventing and managing oral mucositis caused by CT and RT. Clinical trials show curcumin's effectiveness in reducing the incidence and severity of oral mucositis. Although curcumin supplementation appears to be a promising and cost-effective approach for mitigating oral complications in cancer patients, further clinical trials are needed to confirm its efficacy and optimize dosing strategies.

Therapeutic drug monitoring-guided piperacillin dosing in critically ill patients undergoing continuous renal replacement therapy: a systematic review.

Continuous renal replacement therapy (CRRT) complicates antibiotic dosing in critically ill patients due to altered pharmacokinetics. The optimal dosing of piperacillin remains unclear. Therapeutic drug monitoring (TDM) can personalize piperacillin therapy and improve outcomes. This review investigates the effects of TDM-guided piperacillin dosing on pharmacokinetic target attainment and clinical outcomes in CRRT patients, analyses correlations with clinical outcomes, provides optimal dosing strategies for piperacillin and identifies future research areas. A systematic search of PubMed, Scopus and Web of Science was conducted until December 2023, identifying studies on piperacillin pharmacokinetics and clinical outcomes in adult CRRT patients. Data on study characteristics, piperacillin exposures, TDM use, target attainment rates, mortality and length of stay were extracted. The risk of bias was assessed using the Newcastle-Ottawa Scale. Eleven observational studies were included. High pharmacokinetic variability was evident, with piperacillin target non-attainment in up to 74% of cases without TDM. Two studies with routine TDM showed increased target attainment rates of 80%-100%. Mortality ranged from 17% to 56%, with supratherapeutic concentrations (≥100 mg/L) associated with higher mortality. The impact of optimized piperacillin exposures on outcomes was inconclusive. Most studies demonstrated a low risk of bias. TDM-guided piperacillin dosing in CRRT patients improved target attainment rates (≥80%). Mortality rates ranged from 17% to 56%, with inconsistent correlations between drug exposures and survival. Supratherapeutic concentrations were linked to higher mortality. Standardized TDM protocols are needed. Future research should establish clear exposure-response relationships and the impact of TDM on clinical outcomes.

Therapeutic Efficacy of Extracellular Vesicles Derived from Stem Cell for Alzheimer's Disease: A Meta-Analysis Study.

Alzheimer's disease (AD) poses a significant public health challenge, increasingly affecting patients' finances, mental health, and functional abilities as the global population ages. Stem cell-derived extracellular vesicles (SC-EVs) have emerged as a promising cell-free therapeutic approach for AD, although their precise mechanisms remain unclear. This meta-analysis aims to evaluate the effectiveness of SC-EVs in treating AD. We systematically searched PubMed, EMBASE, and Web of Science databases up to December 31, 2023, identifying studies investigating SC-EVs therapy in AD rodent models. Outcome measures included Morris water maze and Y maze tests, β-amyloid pathology, and inflammatory markers. Statistical analyses utilized Stata 15.1 and R software. This meta-analysis of 16 studies (2017-2023, 314 animals) demonstrates significant efficacy of SC-EVs therapy in AD models. Pooled analyses demonstrated that SC-EVs therapy significantly increased the learning function as measured by Morris water maze tests (MWM) by -1.83 (95% CI = -2.51 to -1.15, p < 0.0001), Y maze test by 1.66 (95% CI = 1.03 to 2.28, p < 0.0001), decreased Aβ plaques in the hippocampal by -2.10 (95% CI = -2.96 to -1.23, p < 0.0001), and proinflammatory cytokines Tumor necrosis factor alpha (TNFα) by -2.61 (95% CI = -4.87 to -0.35, p < 0.05), Interleukin-1 beta (IL-1β) by -2.37 (95% CI = -3.68 to -1.05, p < 0.001). SC-EVs therapy shows promise in enhancing cognitive function and mitigating AD progression in preclinical models. Future research should focus on standardizing methodologies and comparing SC-EVs isolation techniques and dosing strategies to facilitate clinical translation.

Lenacapavir: Playing the Long Game in the New Era of Antiretrovirals.

The mainstay of antiretroviral therapy (ART) has been combination oral therapy. While oral ART is highly effective, nonadherence remains a chief concern. Addressing this concern in recent years is the emergence of long-acting antiretrovirals for the treatment and prevention of HIV-1 infection. The most recently approved long-acting antiretroviral is the first-in-class capsid inhibitor lenacapavir (LEN) for heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. Due to its biannual subcutaneous dosing scheme to inhibit the HIV-1 capsid, LEN exhibits unique pharmacokinetics and reinforces an evolving era of ART. In this review, we evaluate published and accepted research articles, conference proceedings, and clinical trial records to provide a comprehensive overview of LEN for treatment and preliminary data for the prevention of HIV-1 infection. These data include clinical trials outcomes, in vitro and in vivo resistance profiles, and preclinical data supporting downstream indications. We also discuss the unique clinical pharmacology of LEN with the goal of serving as a resource toward subsequent physiologically based, population-based, and other miscellaneous pharmacometric-focused analyses. Given the dynamic nature of the HIV treatment and prevention research fields, we also discuss ongoing studies related to LEN for treatment-naïve adults and for prevention. Lastly, we discuss important pharmacologic gaps in special populations, drug-drug interactions, and at the sites of action germane to HIV treatment and prevention. The information discussed in this review will provide knowledge and understanding of the unique pharmacologic properties of LEN to assist clinicians and researchers as they navigate the dynamic HIV research landscape.

Population pharmacokinetic study in children with vascular anomalies: body weight as a key variable in predicting the initial dose and dosing frequency of sirolimus.

The main challenges faced when using sirolimus in children with vascular anomalies (VAs) still include significant pharmacokinetic (PK) variability, uncertainty in the target concentration range, as well as inconsistencies in initial dosing and dosing frequency. The aim of this study is to establish a new population pharmacokinetic (PPK) model for children with VAs to guide the individualized use of sirolimus. A PPK study was performed using data from children with VAs who received sirolimus between July 2017 and April 2022. A nonlinear mixed-effect modeling with a one-compartment model structure was applied. Monte Carlo simulation was employed to propose specific dosing recommendations to achieve the target trough concentrations (C trough) of 5-15ng/mL. In total, 134 blood concentrations from 49 pediatric patients were used to characterize the sirolimus pharmacokinetics. Covariate analysis identified body weight (BW) as a significant factor affecting clearance (CL) in the final PPK model. The typical clearance rate and distribution volume, standardized to a BW of 16kg, were 4.06L/h (4% relative standard error, RSE) and 155L (26% RSE), respectively. Optimal dosing regimens were simulated for different BWs. For a twice-daily regimen, the recommended doses were 0.05, 0.06, 0.07, and 0.08mg/kg/day for BW of <10, 10-20, 20-40, and ≥40kg, respectively; for a once-daily regimen, the recommended doses were 0.06, 0.07, 0.08, and 0.09mg/kg/day for BW of <10, 10-30, 30-50, and ≥50kg, respectively. Notably, sirolimus C trough could be maintained between 5-15ng/mL across various dosing frequencies based on the recommended dosing regimen. We established a PPK model of sirolimus for children with VAs and proposed an initial dosing strategy. Integrating initial dose and medication frequency recommendations into sirolimus' guidelines will broaden its clinical options and simplify the clinical management for childhood VAs.

Siamese based few-shot learning lightweight transformer model for coagulant and disinfectant dosage simultaneous regulation

Deep learning (DL) has emerged as a transformative and promising approach to address inefficient resource management due to imprecise chemical dosing in conventional manual-dependent drinking water treatment. However, the scarcity of high-quality data and limited computing resources of embedded devices hinder the development and deployment of state-of-the-art (SOTA) DL models. Herein, a novel lightweight Transformer (LighT) model integrated with the Siamese structure was proposed for simultaneous regulation of coagulant dosage (FeCl3 and PAC) and disinfectant dosage (NaClO) and compared with other attention-based DL models. The results demonstrate that LighT showed robust few-shot learning effectiveness and outperformed other models in multi-output prediction (R2 values of 0.99 and RMSE of 0.20 mg/L, 0.16 mg/L and 0.45 mg/L, respectively). The LighT model also exhibited enhanced cost-effectiveness with a 79.74 % compression in model parameters and a 36.14 % decrease in inference time. The LighT-based chemical dosage prediction program was sustained for one month of operation, which can save chemical dosage by 15.81 % while maintaining satisfactory product water quality, indicating the potential of LighT for economizing chemical dosing strategy in drinking water treatment.

Handling delayed or missed direct oral anticoagulant doses: model-informed individual remedial dosing

AbstractNonadherence to direct oral anticoagulant (DOAC) pharmacotherapy may increase the risk of thromboembolism or bleeding, and delayed or missed doses are the most common types of nonadherence. Current recommendations from regulatory agencies or guidelines regarding this issue lack evidence and fail to consider individual differences. This study aimed to develop individual remedial dosing strategies when the dose was delayed or missed for DOACs, including rivaroxaban, apixaban, edoxaban, and dabigatran etexilate. Remedial dosing regimens based on population pharmacokinetic (PK)-pharmacodynamic (PD) modeling and simulation strategies were developed to expeditiously restore drug concentration or PD biomarkers within the therapeutic range. Population PK-PD characteristics of DOACs were retrieved from previously published literature. The effects of factors that influence PK and PD parameters were assessed for their impact on remedial dosing regimens. A web-based dashboard was established with R-shiny to recommend remedial dosing regimens based on patient traits, dosing schedules, and delay duration. Addressing delayed or missed doses relies on the delay time and specific DOACs involved. Additionally, age, body weight, renal function, and polypharmacy may marginally affect remedial strategies. The proposed remedial dosing strategies surpass current recommendations, with less deviation time beyond the therapeutic range. The online dashboard offers quick and convenient solutions for addressing missed or delayed DOACs, enabling individualized remedial dosing strategies based on patient characteristics to mitigate the risks of bleeding and thrombosis.

Personalized dosimetry assessment of [177Lu]Lu-PSMA-617 radioligand therapy in the management of metastatic castration-resistant prostate cancer

Introduction Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is revolutionizing the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) patients. This study aimed to establish patient-specific radiation dosimetry for [177Lu]Lu-PSMA-617 RLT in Iranian patients with mCRPC. Method Twelve biopsy-proven prostate cancer patients (aged 68.73 ± 5.26 yr) underwent 6.62 ± 0.36 GBq [177Lu]Lu-PSMA-617 RLT. Post-therapy whole-body planar scans were acquired approximately at 4, 48, and 72 h post-administration, alongside a single SPECT/CT around 48 h using Siemens Symbia T2 to obtain cumulated activity. An imaging protocol and dosimetry approach were designed to balance between time efficacy and accuracy in post-therapeutic dosimetry. Using accurate activity calibration, S-values were calculated by importing SPECT/CT images as the source/geometry into the Geant4 application for the tomographic emission (GATE) Monte Carlo (MC) toolkit. The Medical Internal Radiation Dose (MIRD) scheme was followed for subsequent absorbed dose (AD) calculations in organs at risk (OAR) and tumoral lesions using the dose actor and accumulated activities for precise dose estimations. Results Using the MC approach, the mean ADs to the liver, spleen, right and left kidneys, and tumor lesions were 0.11 ± 0.04 Gy/GBq, 0.08 ± 0.03 Gy/GBq, 0.34 ± 0.09 Gy/GBq, 0.34 ± 0.10 Gy/GBq, and 0.83 ± 0.54 Gy/GBq, respectively. Notably, tumoral lesions demonstrated significantly higher ADs, indicating enhanced uptake of radiopharmaceuticals by malignant cells. Conclusions This study indicates that the ADs of OARs and tumoral lesions from [177Lu]Lu-PSMA-617 RLT in patients with mCRPC are consistent with existing literature. The dosimetry findings suggest that increasing the administered activity of [177Lu]Lu-PSMA-617 RLT is feasible and does not pose a significant risk of adverse effects on OARs, as supported by our data. However, to validate the safety and efficacy of higher doses, further clinical follow-up studies are recommended.

Development and Validation of a High-Performance Liquid Chromatography-Ultraviolet Spectrometry Method for Ampicillin and its Application in Routine Therapeutic Drug Monitoring of Intensive Care Patients.

Ampicillin/sulbactam, a combination of a β-lactam and β-lactamase inhibitor, is widely used in clinical settings. However, therapeutic drug monitoring (TDM) of ampicillin is not commonly performed, particularly in intensive care units (ICUs). The purpose of this study was to develop and validate a rapid and cost-effective high-performance liquid chromatography (HPLC)-ultraviolet spectrometry method to quantify ampicillin in human serum and evaluate its clinical application in ICU patients. Sample cleanup included a protein precipitation protocol, followed by chromatographic separation on a C18 reverse-phase HPLC column within 12.5 minutes using gradient elution of the mobile phase. The assay was validated according to the German Society of Toxicology and Forensic Chemistry criteria. Clinical applications involved the retrospective analysis of TDM data from ICU patients receiving continuous infusion of ampicillin/sulbactam, including the attainment of target ranges and individual predicted and observed pharmacokinetics. The method was robust, with linear relations between the peak area responses and drug concentrations in the range of 2-128 mg/L. The coefficient of variation for precision and the bias for accuracy (both interday and intraday) were less than 10%. Clinical application revealed variable pharmacokinetics of ampicillin in ICU patients (clearance of 0.5-31.2 L/h). TDM-guided dose adjustments achieved good therapeutic drug exposure, with 92.9% of the samples being within the optimal (16-32 mg/L) or quasioptimal (8-48 mg/L) range. This method provides a practical solution for the routine TDM of ampicillin, facilitating individualized dosing strategies to ensure adequate therapeutic drug exposure. Given its simplicity, cost-effectiveness, and clinical relevance, HPLC-ultraviolet spectrometry holds promise for broad implementation in hospital pharmacies and clinical laboratories.

Serum ganciclovir drug exposure in children receiving standard ganciclovir dosing.

Intravenous ganciclovir (GCV) is used for the treatment of cytomegalovirus (CMV) infection in immunocompromised children. Although the therapeutic target for treatment is unclear, studies have shown a serum area under the concentration-time curve (AUC24h) ≥40 mg/L·h correlates with effective CMV prevention. This study aimed to externally validate existing GCV population pharmacokinetic (PopPK) models and develop a model if needed and evaluate the serum AUC24h achieved with standard GCV dosing and propose an optimized dosing strategy for immunocompromised children. Ganciclovir drug monitoring data from two pediatric hospitals were retrospectively collected, and published pediatric PopPK models were externally validated. The population AUC24h with standard GCV dosing (5 mg/kg twice daily) was calculated, and an optimized dosing strategy was determined using Monte Carlo simulations to achieve an AUC24h between 40 and 100 mg/L·h. Overall, 161 samples from 23 children with a median (range) age of 9.0 years (0.4-17.0) and weight of 28.2 kg (5.6-73.3) were analyzed. Transferability of published pediatric PopPK models was limited. Thus, a one-compartment model with first-order absorption and elimination with weight and serum creatinine as covariates was developed. The median (5th-95th percentiles) steady state AUC24h with standard dosing was 38.3 mg/L·h (24.8-329.2) with 13 children having an AUC24h <40 mg/L·h, particularly those aged <4 years (8/13). An optimized simulated GCV dosing regimen, ranging from 2 to 13 mg/kg twice daily for children with normal renal function, achieved 61%-78% probability of target attainment. Standard GCV dosing likely results in inadequate drug exposure in more than half of the children, particularly those aged <4 years. An optimized dosing regimen has been proposed for clinical validation.

A novel strategy for enhancing high solid anaerobic digestion of fecal slag and food waste using percolate recirculation and dosage of nano zero-valent iron

To speed up reaching UN Sustainable Development Goal 6 for safe sanitation by 2030, integrating high-solid anaerobic digestion (HSAD) into decentralized systems could recycle fecal slag (FS) and food waste (FW), aiding a circular economy and toilet revolution. In this study, a percolate recirculation system and conductive material were used to improve mass transfer, stability, and enhance methane production in HSAD of FS and FW. This setup consists of a percolate tank and a digester tank, where nano-zero valent iron (nZVI) was dosed in the percolate tank (PnZVI in P) and the digester tank (PnZVI in D) and compared with a control with no additive (PControl). The highest cumulative methane yield of 519.43 mL/gVS was achieved in PnZVI in D, which was 4.52 and 3.59 times higher than that of PControl (144.59 mL/gVS) and PnZVI in P (114.96 mL/gVS). This finding demonstrates that the dosing strategy of PnZVI in D facilitated effective interaction among organic matter, microbial communities, and nZVI, resulting in organics removal efficiencies of 67.42 % (total solid) and 77.22 % (volatile solid). Moreover, microbial community analysis supported the efficacy of the PnZVI in D strategy, revealing the enrichment of Clostridium sensu stricto 1 (46.91 %), which potentially engaged in interspecies electron transport (Interspecies hydrogen transfer (IHT) and direct interspecies electron transfer (DIET)) with Methanobacterium (81.19 %) and Methanosarcina (17.11 %). These interactions contribute to enhanced methane yield and stability maintenance in the HSAD system with percolate recirculation. The findings of this study demonstrate that the implementation of HSAD of FS and FW, coupled with percolate recirculation and the addition of nZVI, holds promise for enabling sustainable sanitation practices in developing regions. Moreover, this approach not only facilitates resource recovery but also eliminates the requirement for water.

Gene-based drug therapy for children and youth treated with psychoactive medications.

Psychoactive medications are increasingly used to treat children and youth with mental health conditions, but individual variations in response highlight the need for precision medicine. Pharmacogenetic (PGx) testing is a key component of precision medicine. The number of commercial pharmacogenetic testing companies promoting PGx, with the promise of achieving individualized and effective treatment of mental health conditions, has grown exponentially in recent years. Scientific evidence supporting the use of PGx to manage mental health conditions is limited, especially for paediatric populations. This practice point outlines steps guiding the use and interpretation of PGx testing for psychoactive medications in clinical settings, along with key supportive resources. Practice guidelines have been developed for variants in pharmacogenes encoding cytochrome P450 drug-metabolizing enzymes (e.g., CYP2C19, CYP2D6, CYP2C9) as one determinant of drug concentrations in blood, which can support both drug choice and dosing strategy for certain anti-psychotics, anti-depressants, and anti-epileptics. Adverse drug reactions to some anti-epileptic drugs (e.g., carbamazepine and phenytoin) have been associated with certain human leukocyte antigen types and variants in DNA polymerase gamma (POLG; valproic acid). Evidence remains limited for genetic variants of drug target proteins, making it challenging to identify patients with altered treatment responses at a therapeutic blood concentration.

Use of stable isotope labeled (SIL) antibodies in cassette dosing to improve pharmacokinetics screening efficiency of ADCs with novel cytotoxic payloads

Stable isotope labelling by amino acids in cell culture (SILAC) is an established technique used in quantitative mass spectrometry (MS)-based proteomics. SILAC is also used to generate stable isotope labelled (SIL) antibodies for internal standards (IS) used in LC-MS/MS bioassays to improve quantitative robustness. Total antibody (TAb) is measured to evaluate pharmacokinetics (PK) of antibody drug conjugate (ADC) candidates measured by either ligand binding (LBA) or LC-MS/MS. Herein, we describe an application of SILAC, where multiple SIL combinations of an antibody are used for cassette dosing and PK evaluation. Our preclinical studies demonstrate SILAC-labelled ADC therapeutics did not alter antibody PK. Furthermore, with cassette dosing SIL antibodies exhibited comparable exposure to discretely administered unlabelled test articles in rats. In addition, SIL antibodies were conjugated to cytotoxic payloads to create SIL ADCs and cassette dosed in a cynomolgus monkey PK study and SIL ADCs yielded comparable PK results to discrete dosed unlabelled ADCs. In conclusion, SIL antibodies used with a cassette dosing strategy increases PK screening throughput of ADC candidates in preclinical species. Additionally, cassette dosing strategy further facilitates the responsible use of laboratory animals to achieve the three-Rs (Replacement, Reduction, and Refinement).

Real-World Use and Outcomes of Apixaban for Early Post-Surgical Fontan Thromboprophylaxis.

Patients with Fontan physiology are at heightened risk of thrombosis related to passive venous return leading to increased stasis, as well as acquired thrombophilia from congestive hepatopathy. Variability exists for post-Fontan thromboprophylaxis, with no consensus on best practices. Direct oral anticoagulants offer advantages over conventional anticoagulants including fewer drug-drug interactions, no dietary restrictions, and less frequent monitoring. Herein, we report our single center experience utilizing apixaban thromboprophylaxis in children post-Fontan procedure. Single center, retrospective, cohort study evaluating apixaban thromboprophylaxis dosing strategies, efficacy, and safety in children admitted post-Fontan procedure at Boston Children's Hospital. Between September 2019 and December 2023, 62 children, median age 3.2years (2.1-10.5years), weight 13.9kg (9.5-56.3kg) received apixaban at a median of 93days post-Fontan (7-1421days). Over a total of 93days of apixaban exposure, there was 1 treatment-related thrombosis event (0.07 per 1000 person-days on apixaban) and 3 combined treatment-related clinically relevant non-major (CRNM) and major bleeding events (0.22 per 1000 person-days on apixaban). Apixaban for post-Fontan thromboprophylaxis was feasible with low rates of bleeding and thrombosis.

Pharmacokinetics and Pharmacodynamics of Systemic Corticosteroids in Autoimmune and Inflammatory Diseases: A Review of Current Evidence.

Systemic corticosteroids have a long history of use in the treatment of autoimmune and inflammatory diseases. Both efficacy and safety show large interindividual variability (IIV), suggesting that corticosteroids may have the potential for individualised dosing strategies to optimise therapy. This systematic review aims to provide an overview of current evidence on the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of systemic corticosteroids in patients with autoimmune and inflammatory diseases. A systematic literature search was conducted in PubMed and Embase for PK/PD studies of systemic corticosteroids in autoimmune and inflammatory diseases in humans published until December 2023. Studies were scored from 1 to 5 according to criteria for the levels of evidence, as inspired by the Oxford Centre for Evidence-Based Medicine. Twelve studies (1981-2016) were included. The majority of these studies had a small sample size. The corticosteroids involved were prednisone, prednisolone, methylprednisolone and budesonide. Substantial IIV of corticosteroid PK was described in all studies. Evidence for a relationship between the PK of corticosteroids and efficacy was inconclusive and limited. However, there was some evidence for a relationship between the PK of prednisolone and the severity of Cushingoid features. There is insufficient evidence to draw firm conclusions on the potential associations between PK and clinical outcome of systemic corticosteroid treatment in autoimmune and inflammatory diseases. This is remarkable given the many decades that steroid drugs have been used in clinical care. Prospective research is recommended with robust and well-defined cohorts to fully quantify the PK/PD associations of corticosteroids.