Precision Daptomycin Dosing: Comparison of 3-, 2-, 1-, and 0-Concentration Sample Strategies.

Background: Daptomycin is a once-daily lipopeptide antibiotic with a narrow therapeutic window. As higher doses (8-12 mg/kg) are increasingly used to treat resistant gram-positive infections, achieving therapeutic exposure while minimizing toxicity has become critical. Understanding daptomycin therapeutic drug monitoring (TDM) and what sampling strategy may be most precise and feasible are key to guiding appropriate dosing.

Quantification of hepatic steatosis on post-contrast computed tomography scans using artificial intelligence tools.

Purpose: Early detection of steatotic liver disease (SLD) is critically important. In clinical practice, hepatic steatosis is frequently diagnosed using computed tomography (CT) performed for unrelated clinical indications. An equation for estimating magnetic resonance proton density fat fraction (MR-PDFF) using liver attenuation on non-contrast CT exists, but no equivalent equation exists for post-contrast CT.

An ingestible device for automated sampling and location tracing in gastrointestinal tract.

Fluids sampled from the gastrointestinal (GI) tract are of interest for evaluating the bioequivalence of oral medications, and more generally for evaluating GI-related diseases, and for profiling the individual gut microbiome. Existing options for capturing multiple fluid samples from specific locations in the GI tract are limited and invasive, particularly for the small intestine. Here, we report the development of an ingestible capsule for the collection of multiple fluid samples along the GI tract; we additionally report the use of data from sensors within the capsule to determine the sampling regions.

Utilizing Opportunistic Computed Tomography Imaging to Refine Lean Body Weight Estimates in Patients with Obesity.

Introduction: While dual-energy X-ray absorptiometry (DEXA) is the gold standard for measuring lean body weight (LBW), computed tomography (CT) provides muscle composition and distribution metrics that can refine LBW for better weight-based dosing. We explored how existing computed tomography (CT) images could be utilized to better estimate LBW.

Methods: Sixty-three adult patients (71.

Evaluation of High-dose Daptomycin in Children With Methicillin-resistant Staphylococcus aureus Bacteremia: A Case Series.

Daptomycin dosing in pediatrics has not been updated since initial approval to align with contemporary adult dosing recommendations. We observed lower than anticipated exposures with median 24-hour area under the curve of 378 mg·h/L [interquartile range (IQR): 368-413] in 4 children despite use of high doses (17-20 mg/kg/d). There is a critical need to reappraise daptomycin dosing in pediatric patients for Staphylococcus aureus bloodstream infections.

Pharmacokinetic Characterization of Iopamidol and Iohexol for Optimizing Measured Glomerular Filtration Rate Assessment in Clinical Practice and Drug Development.

Accurate kidney function assessment supports healthcare and clinical decision-making in practice and drug development. Measured glomerular filtration rate (mGFR) via iohexol clearance is the gold standard, but cost, supply issues, and logistical challenges limit its clinical use. Iopamidol, another iodinated contrast agent widely used in CT imaging, has not been studied in humans for mGFR assessment.

The pharmacokinetics of antibiotics in patients with obesity: a systematic review and consensus guidelines for dose adjustments.

Obesity can cause physiological changes resulting in antibiotic pharmacokinetic alterations and suboptimal drug exposures. This systematic review aimed to summarise the available evidence on this topic and provide guidance for dose adjustment of antibiotics in adult (age ≥18 years) patients with obesity (BMI >30 kg/m). We searched PubMed, Embase, and CENTRAL databases to find relevant studies published between database inception and Dec 30, 2023.

A comparison between radiomic biological age and chronological age in estimating kidney function.

Accurate kidney function estimation hinges on essential markers of age and body size. The relative benefit of both markers has been debated with the emerging biological age and novel body size descriptors. We used radiomic biomarkers of age-related changes in body composition to construct new biological age indices as covariates of kidney function.

Impact of obesity on doxorubicin pharmacokinetics in women with breast cancer.

IntroductionExperts suggest doxorubicin clearance is decreased in women with a body mass index (BMI) of ≥35 kg/m. However, few data support this recommendation.MethodsWomen receiving doxorubicin for breast cancer in three BMI groups were recruited (n = 15).

GLP-1RA-induced delays in gastrointestinal motility: Predicted effects on coadministered drug absorption by PBPK analysis.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are breakthrough medicines for obesity treatment and have rapidly gained widespread clinical application. Although GLP-1RAs are generally not associated with drug-drug interactions (DDIs) via drug metabolism or transporter pathways, their effects on reduced gastrointestinal (GI) motility could influence the pharmacokinetics of coadministered oral medications.

Objectives: This study uses physiologically based pharmacokinetic (PBPK) modeling to evaluate the DDI potential of GLP-1RA-induced GI motility delays.

Quantitation of Plasma Proteins to Predict Taxane-Induced Peripheral Neuropathy.

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).

The Kinetics of Cystatin C and Serum Creatinine in AKI.

Key Points: Modeling shows that serum cystatin C can detect AKI 6–48 hours earlier than serum creatinine, regardless of baseline kidney function. Absolute value diagnostic cutoffs are more effective than percentage-based thresholds for AKI detection across different CKD stages.

Background: AKI is a common condition affecting a significant portion of hospitalized and critically ill patients.

Examining the Impact of Diet-and-Exercise-Induced Weight Loss on Drug Metabolism and Gastric Emptying in Patients with Obesity.

Obesity significantly influences drug pharmacokinetics (PK), which challenges optimal dosing. This study examines the effects of diet-and-exercise-induced weight loss on key drug-metabolizing enzymes and gastric emptying in patients with obesity, who frequently require medications for comorbidities. Participants followed a structured weight management program promoting weight loss over 3-6 months and were not concomitantly on potential CYP inducers or inhibitors.

Radiomic-based biomarkers: Transforming age and body composition metrics into personalized age-informed indices.

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.

High-dose intranasal insulin in an adaptive dose-escalation study in healthy human participants.

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.

An innovative population pharmacokinetic/pharmacodynamic strategy for attaining aggressive joint PK/PD target of continuous infusion ceftazidime/avibactam against KPC- and OXA-48- producing Enterobacterales and preventing resistance development in critically ill patients.

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.

Fixed dose daptomycin: An opportunity for pharmacokinetic/pharmacodynamic optimization in Staphylococcus aureus infections.

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.

Clinical validation of two volumetric absorptive microsampling devices to support home-based therapeutic drug monitoring of immunosuppression.

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.

Population pharmacokinetic/pharmacodynamic target attainment analysis of IV fosfomycin for the treatment of MDR Gram-negative bacterial infections.

Background: IV fosfomycin is used against MDR Gram-negative bacilli (GNB) but has dose-limiting side effects, especially in patients with impaired kidney function.

Objectives: To determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function.

Methods: Adult patients receiving IV fosfomycin for treatment of GNB were eligible.

Revolutionizing Daptomycin Dosing: A Single 7-11-Hour Sample for Pragmatic Application.

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.

Balancing the scales: achieving the optimal beta-lactam to beta-lactamase inhibitor ratio with continuous infusion piperacillin/tazobactam against extended spectrum beta-lactamase producing .

Piperacillin/tazobactam (TZP) is administered intravenously in a fixed ratio (8:1) with the potential for inadequate tazobactam exposure to ensure piperacillin activity against . Adult patients receiving continuous infusion (CI) of TZP and therapeutic drug monitoring (TDM) of both agents were evaluated. Demographic variables and other pertinent laboratory data were collected retrospectively.

Bioanalysis of six antibiotics from volumetric microsamples: a new tool for precision dosing in critically ill children.

Volumetric absorptive microsamples (VAMS) can support pharmacokinetic / pharmacodynamic studies. We present the bioanalytical method development for the simultaneous quantification of ampicillin, cefepime, ceftriaxone, meropenem, piperacillin, tazobactam, and vancomycin from VAMS. Optimal extraction, chromatographic, and mass spectrometry conditions were identified.

Optimizing anidulafungin exposure across a wide adult body size range.

Echinocandins like anidulafungin are first-line therapies for candidemia and invasive candidiasis, but their dosing may be suboptimal in obese patients. Our objective was to quantify anidulafungin exposure in a cohort of adults across a wide body size range to test if body size affects anidulafungin pharmacokinetics (PK). We enrolled 20 adults between the ages of 18 and 80 years, with an equal distribution of patients above and below a body mass index of 30 kg/m.

Kidney function as a key driver of the pharmacokinetic response to high-dose L-carnitine in septic shock.

Study Objective: Levocarnitine (L-carnitine) has shown promise as a metabolic-therapeutic for septic shock, where mortality approaches 40%. However, high-dose (≥ 6 grams) intravenous supplementation results in a broad range of serum concentrations. We sought to describe the population pharmacokinetics (PK) of high-dose L-carnitine, test various estimates of kidney function, and assess the correlation of PK parameters with pre-treatment metabolites in describing drug response for patients with septic shock.