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PURPOSE: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting toxicity of paclitaxel in patients with cancer. TIPN prediction is challenging although patients with higher systemic paclitaxel exposure have higher TIPN risk. This study aimed to identify protein predictors of TIPN and paclitaxel pharmacokinetics (PK). METHODS: This is a retrospective analysis of a prospective study of females with early-stage breast cancer receiving weekly paclitaxel. TIPN was assessed using the sensory subscale of the European Organisation for Research and Treatment of Cancer QLQ-Chemotherapy-Induced Peripheral Neuropathy (CIPN)20 (CIPN8). A blood sample was collected within 10 minutes before the end of the first paclitaxel infusion to measure plasma proteins using liquid chromatography-mass spectrometry and to estimate maximum systemic paclitaxel concentration (C max). A second sample was collected approximately 24 hours after the first infusion to estimate paclitaxel time above threshold (T c >0.05). Linear mixed-effect and regression models were used to identify proteins predictive of TIPN and paclitaxel PK parameters, respectively, using a Bonferroni-adjusted α =.0006. RESULTS: Data from 36 participants were included in the analysis testing associations of 83 proteins with TIPN or PK. Higher levels of complement C3 were associated with more severe TIPN trajectories (P =.0002). No proteins were associated with either C max or T c >0.05 (all P >.0006). CONCLUSION: Complement C3 concentration at the end of initial paclitaxel infusion may be useful for identifying patients with breast cancer and potentially other tumor types who could benefit from TIPN prevention strategies to improve long-term treatment outcomes. [ABSTRACT FROM AUTHOR]

Chronological age has been the standard for quantifying the aging process. While it is simple to quantify it cannot fully discern the biological variability of aging between individuals. The growing body of interest in this variability of human aging has led to the introduction of new biomarkers to operationalize biological age. The inclusion of body composition may provide additional value to biological aging as a prediction and estimation factor of individual health outcomes. Diagnostic images based on radiomic techniques such as Computed Tomography contain an untapped wealth of patient‐specific data that remain inaccessible to healthcare providers. These images are beneficial for collecting information from body composition that adds precision and granularity when compared to traditional measures. This information can subsequently be aggregated to construct models for changes in the human body associated with aging. In addition, aging leads to a natural decline in the best parameter of drug dosing in older adults, glomerular filtration rate. Since the conventional models of kidney function are correlated with age and body composition, the radiomic biomarkers representing age‐related changes in body composition may also serve as potential new imaging biomarkers of kidney function for personalized dosing. Our review introduces potential radiomic biomarkers as measures of body composition change targeting the aging processes. As a functional example, we have hypothesized an age‐related model of radiomics as a covariate of kidney function to improve personalized dosing. Future research focusing on evaluating this hypothesis in human subject studies is acknowledged. [ABSTRACT FROM AUTHOR]

Objectives Ceftazidime/avibactam is a key antibiotic for carbapenemase-producing Enterobacterales (CPE) Gram-negative infections, but current dosing may be suboptimal to grant activity. This study explores the population pharmacokinetics/pharmacodynamics (PK/PD) of continuous infusion (CI) ceftazidime/avibactam for maximizing treatment efficacy in critically ill patients. Methods A retrospective analysis of adult patients receiving CI ceftazidime/avibactam and therapeutic drug monitoring (TDM) of both compounds was performed. Population PK/PD modelling identified the most accurate method for estimating ceftazidime/avibactam clearance based on kidney function and Monte Carlo simulations investigated the relationship between various CI dosing regimens and aggressive joint PK/PD target attainment of ceftazidime/avibactam. Results The European Kidney Function Consortium (EKFC) equation best described kidney function for ceftazidime/avibactam clearance. The findings challenge the current approach of only reducing the ceftazidime/avibactam dose based on kidney function by identifying dose adjustments in patients with augmented kidney function. Our CI ceftazidime/avibactam dosing strategies, adjusted by TDM, showed promise for achieving optimal aggressive joint PK/PD targets and potentially improving clinical/microbiological outcomes against KPC- and OXA-48-producing Enterobacterales. The risk of neurotoxicity associated with these strategies appears acceptable. Conclusions This study suggests that adjusting ceftazidime/avibactam dosing regimen based solely on eCLcr might be suboptimal for critically ill patients. Higher daily doses delivered by CI and adjusted based on TDM have the potential to improve aggressive joint PK/PD target attainment and potentially clinical/microbiological outcomes. Further investigations are warranted to confirm these findings and establish optimal TDM-guided dosing strategies for ceftazidime/avibactam in clinical practice. [ABSTRACT FROM AUTHOR]

Aims: Dried blood volumetric absorptive microsamples (VAMS) may facilitate home‐based sampling to enhance therapeutic drug monitoring after transplantation. This study aimed to clinically validate a liquid chromatography–tandem mass spectrometry assay using 2 VAMS devices with different sampling locations (Tasso‐M20 for the upper arm and Mitra for the finger). Patient preferences were also evaluated. Methods: Clinical validation was performed for tacrolimus and mycophenolic acid by comparison of paired VAMS and venipuncture samples using Passing–Bablok regression and Bland–Altman analysis. Conversion of mycophenolic acid VAMS to serum concentrations was evaluated using haematocrit‐dependent formulas and fixed correction factors defined a priori. Patients' perspectives, including useability, acceptability and feasibility, were also investigated using established questionnaires. Results: Paired samples (n = 50) were collected from 25 kidney transplant recipients. Differences for tacrolimus whole‐blood concentration were within ±20% for 86 and 88% of samples from the upper arm and fingerstick, respectively. Using correction factors of 1.3 for the upper‐arm and 1.47 for finger‐prick samples, 84 and 76% of the paired samples, respectively, were within ±20% for mycophenolic acid serum concentration. Patient experience surveys demonstrated limited pain and acceptable useability of the upper‐arm device. Conclusions: Tacrolimus and mycophenolic acid can be measured using 2 common VAMS devices with similar analytical performance. Patients are supportive of home‐based monitoring with a preference for the Tasso‐M20 device. [ABSTRACT FROM AUTHOR]

Intranasal insulin is a putative neuroprotective therapy after cardiac arrest, but safety in humans at doses extrapolated from animal models is unknown. This phase I, open‐label adaptive dose‐escalation study explores the maximum tolerated dose of intranasal insulin in healthy human participants. Placebo or insulin at doses from 0 to 1000 units was given to healthy participants intranasally on repeated weekly visits. Serum glucose, insulin, and C‐peptide levels were measured serially at 0, 15, 30, 60, 120, 180, and 240 min after administration. Twenty‐four participants (12 female, median age 53, IQR 35–61) were enrolled. There was minimal change in average serum glucose after administration of intranasal insulin. Average serum insulin increased slightly in a dose‐dependent manner, reaching maximum concentrations at 15 min. C‐peptide decreased over time from administration in all groups. One participant had severe hypoglycemia (24 mg/dL at 45 min) and a different participant had mild hypoglycemia (51 mg/dL at 30 min), both after receiving 600 U intranasal insulin. Hypoglycemic episodes were associated with increases in serum insulin. Both participants continued in the study without hypoglycemia after additional doses. High‐dose intranasal insulin up to 1000 U was generally well tolerated, with minimal measurable systemic absorption and without significant aggregate changes in mean glucose. Idiosyncratic episodic systemic absorption and hypoglycemia require further study and additional caution in potential clinical application. Further study of its target engagement and efficacy as a neuroprotective therapy after cardiac arrest at these doses is warranted. [ABSTRACT FROM AUTHOR]

Precision daptomycin dosing faces clinical implementation barriers despite known exposure-safety concerns with the use of twice the regulatory-approved doses. We propose achieving a single 7–11-hour post-dose plasma target concentration of 30 mg/L to 43 mg/L to be a practical starting point to facilitate precision daptomycin dosing. [ABSTRACT FROM AUTHOR]

Introduction High-grade gliomas (HGGs) are common and aggressive pediatric and adult brain tumors. The median overall survival (OS) of adult patients diagnosed with glioblastoma (GBM), grade IV glioma, is 12.6 [...], Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFR[alpha] alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFR[alpha]-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFR[alpha]-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFR[alpha] alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor-bearing mice (mutant TP53, mutant PDGFR[alpha], H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFR[alpha]-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.

Background: Daptomycin is a high‐use intravenous antimicrobial agent affording the convenience of once‐daily dosing. Prior studies suggest an opportunity to use a more operationally convenient fixed rather than weight‐based dosing but this approach has not been studied prospectively. Methods: This study quantified the probability of toxicity and efficacy end points by prospectively testing a fixed dose regimen of daptomycin (750 mg) in obese and non‐obese adults. At least, three daptomycin concentrations were measured at steady‐state for each patient. A population pharmacokinetic model was constructed to evaluate concentration‐time profiles and investigate covariates of daptomycin clearance. Simulations were performed to evaluate the probability of achieving efficacy (24‐h area under the curve (AUC0‐24) ≥ 666 mg∙h/L) and toxicity (minimum concentration (Cmin) ≥24.3 mg/L) targets for fixed (500–1000 mg) and weight‐based (6–12 mg/kg) daptomycin doses. Results: Thirty‐one patients (16 females, 15 males) with median (interquartile range (IQR)) age of 50 (30, 62) years and weight of 74 (54, 156) kg were included in the final analysis. Fixed dose daptomycin (750 mg) resulted in similar exposure across weights with a median (IQR) AUC0‐24 of 819 (499, 1501) mg∙h/L and 749 (606, 1265) mg∙h/L in patients weighing ≤74 kg and >74 kg, respectively. Overall, male sex and increased kidney function necessitate higher fixed and weight‐based doses to achieve efficacy. Creatine phosphokinase elevation was observed in two patients (6.5%) and predicted to be lower with fixed versus weight‐based regimens. Conclusions: Fixed daptomycin dosing adjusted for sex and kidney function is expected to improve the efficacy‐to‐toxicity ratio, transitions of care, and costs compared to weight‐based doses. However, no empiric dosing approach is predicted to achieve ≥90% efficacy while minimizing the risk of toxicity, so therapeutic drug monitoring should be considered on a patient‐specific basis. [ABSTRACT FROM AUTHOR]

Tacrolimus is widely reported to display diurnal variation in pharmacokinetic parameters with twice‐daily dosing. However, the contribution of chronopharmacokinetics versus food intake is unclear, with even less evidence in the pediatric population. The objectives of this study were to summarize the existing literature by meta‐analysis and evaluate the impact of food composition on 24‐hour pharmacokinetics in pediatric kidney transplant recipients. For the meta‐analysis, 10 studies involving 253 individuals were included. The pooled effect sizes demonstrated significant differences in area under the concentration–time curve from time 0 to 12 hours (standardized mean difference [SMD], 0.27; 95% confidence interval [CI], 0.03‐0.52) and maximum concentration (SMD, 0.75; 95% CI, 0.35‐1.15) between morning and evening dose administration. However, there was significant between‐study heterogeneity that was explained by food exposure. The effect size for minimum concentration was not significantly different overall (SMD, −0.09; 95% CI, −0.27 to 0.09) or across the food exposure subgroups. A 2‐compartment model with a lag time, linear clearance, and first‐order absorption best characterized the tacrolimus pharmacokinetics in pediatric participants. As expected, adding the time of administration and food composition covariates reduced the unexplained within‐subject variability for the first‐order absorption rate constant, but only caloric composition significantly reduced variability for lag time. The available data suggest food intake is the major driver of diurnal variation in tacrolimus exposure, but the associated changes are not reflected by trough concentrations alone. [ABSTRACT FROM AUTHOR]

Introduction: Cefazolin is the leading antibiotic used to prevent surgical site infections worldwide. Consensus guidelines recommend adjustment of the cefazolin dose above and below 120 kg without regard to body composition. Algorithms exist to repurpose radiologic data into body composition (morphomics) and inform dosing decisions in obesity. Objectives: To compare the current standard of body weight to morphomic measurements as covariates of cefazolin pharmacokinetics and aid dose stratification of cefazolin in patients with obesity undergoing colorectal surgery. Methods: This prospective study measured cefazolin plasma, fat, and colon tissue concentrations in colorectal surgery patients in order to develop a morphomics‐informed population pharmacokinetic (PopPK) model to guide dose adjustments. A physiologically‐based pharmacokinetic (PBPK) model was also constructed to inform tissue partitioning in morbidly obese patients (n = 21, body mass index ≥35 kg/m2 with one or more co‐morbid conditions). Results: Morphomics and pharmacokinetic data were available in 58 patients with a median [min, max] weight and age of 95.9 [68.5, 148.8] kg and 55 [25, 79] years, respectively. The plasma‐to‐subcutaneous fat partition coefficient was predicted to be 0.072 and 0.060 by the PopPK and PBPK models, respectively. The estimated creatinine clearance (eCLcr) and body depth at the third lumbar vertebra (body depth_L3) were identified as covariates of cefazolin exposure. The probability of maintaining subcutaneous fat concentrations above 2 μg/mL for 100% of a 4‐h surgical period was below 90% when eCLcr ≥105 mL/min and body depth_L3 ≥ 300 mm and less sensitive to the rate of infusion between 5 and 60 min. Conclusions: Kidney function and morphomics were more informative than body weight as covariates of cefazolin target site exposure. Data from more diverse populations, consensus on target cefazolin exposure, and comparative studies are needed before a change in practice can be implemented. [ABSTRACT FROM AUTHOR]