Frazee, Erin N.

AbstractHigh‐dose methotrexate (HDMTX) pharmacokinetics (PKs), including the best estimated glomerular filtration rate (eGFR) equation that reflects methotrexate (MTX) clearance, requires investigation. This prospective, observational, single‐center study evaluated adult patients with lymphoma treated with HDMTX. Samples were collected at predefined time points up to 96 h postinfusion. MTX and 7‐hydroxy‐MTX PKs were estimated by standard noncompartmental analysis. Linear regression determined which serum creatinine‐ or cystatin C‐based eGFR equation best predicted MTX clearance. The 80 included patients had a median (interquartile range [IQR]) age of 68.6 years (IQR 59.2–75.6), 54 (67.5%) were men, and 74 (92.5%) were White. The median (IQR) dose of MTX was 7.6 (IQR 4.8–11.3) grams. Median clearance was similar across three dosing levels at 4.5–5.6 L/h and was consistent with linear PKs. Liver function, weight, age, sex, concomitant chemotherapy, and number of previous MTX doses did not impact clearance. MTX area under the curve (AUC) values varied over a fourfold range and appeared to increase in proportion to the dose. The eGFRcys (ml/min) equation most closely correlated with MTX clearance in both the entire cohort and after excluding outlier MTX clearance values (r = 0.31 and 0.51, respectively). HDMTX as a 4‐h infusion displays high interpatient pharmacokinetic variability. Population PK modeling to optimize MTX AUC attainment requires further evaluation. The cystatin C‐based eGFR equation most closely estimated MTX clearance and should be investigated for dosing and monitoring in adults requiring MTX as part of lymphoma management.

OBJECTIVES: Beta-lactam antibiotics exhibit high interindividual variability in drug concentrations in patients with critical illness which led to an interest in the use of therapeutic drug monitoring to improve effectiveness and safety. To implement therapeutic drug monitoring, it is necessary to define the beta-lactam therapeutic range—in essence, what drug concentration would prompt a clinician to make dose adjustments up or down. This objective of this narrative review was to summarize evidence for the “floor” (for effectiveness) and “ceiling” (for toxicity) for the beta-lactam therapeutic range to be used with individualized therapeutic drug monitoring. DATA SOURCES: Research articles were sourced from PubMed using search term combinations of “pharmacokinetics,” “pharmacodynamics,” “toxicity,” “neurotoxicity,” “therapeutic drug monitoring,” “beta-lactam,” “cefepime,” “meropenem,” “piperacillin/tazobactam,” “ICU,” and “critical illness.” STUDY SELECTION: Articles were selected if they included preclinical, translational, or clinical data on pharmacokinetic and pharmacodynamic thresholds for effectiveness and safety for beta-lactams in critical illness. DATA SYNTHESIS: Experimental data indicate a beta-lactam concentration above the minimum inhibitory concentration of the organism for greater than or equal to 40–60% of the dosing interval is needed, but clinical data indicate that higher concentrations may be preferrable. In the first 48 hours of critical illness, a free beta-lactam concentration at or above the susceptibility breakpoint of the most likely pathogen for 100% of the dosing interval would be reasonable (typically based on Pseudomonas aeruginosa). After 48 hours, the lowest acceptable concentration could be tailored to 1–2× the observed minimum inhibitory concentration of the organism for 100% of the dosing interval (often a more susceptible organism). Neurotoxicity is the primary dose-dependent adverse effect of beta-lactams, but the evidence remains insufficient to link a specific drug concentration to greater risk. CONCLUSIONS: As studies advance the understanding of beta-lactam exposure and response in critically ill patients, it is essential to clearly define the acceptable therapeutic range to guide regimen selection and adjustment.

Background: Goals of managing patients with acute kidney injury (AKI) are mitigating disease progression and ensuring safety while providing supportive care because no effective treatment exists. One strategy recommended in guidelines to meet these goals is optimizing medication management. Unfortunately, guideline implementation appears to be lacking as observed by the frequent occurrence of medication errors and adverse drug events. Objective: To address this performance gap in the care of hospitalized patients receiving nephrotoxins and renally eliminated drugs, we sought to provide a potential intervention based on theory-informed behavior change. Methods: Formative research with a qualitative analysis identifying what needs to change in patient care was completed by obtaining clinician opinion and expert opinion and reviewing the published literature. Frontline providers, including 8 physicians, 4 pharmacists, and a multiprofessional group of authors, provided insight into possible barriers to appropriate prescribing. Capability, Opportunity, Motivation and Behavior model and Theoretical Domain Framework were applied to characterize behavior change interventions and inform a potential implementation intervention for changing inappropriate prescribing behaviors. Results: Lack of knowledge about appropriate drug management in patients at risk for adverse outcomes was provided as a major barrier. Other reported barriers included a lack of: (1) tools to assist with drug management, (2) motivation to make changes, (3) routinization, and (4) an accountable clinician. Conclusions and Relevance: Assigning a designated clinician to execute a stepwise, routine care process following the checklist provided is a recommended intervention to overcome barriers. The intended impact is behavior change that reduces inappropriate prescribing.

Abstract Background The class of antibiotics known as β-lactams are a commonly used due to their effectiveness and safety. Therapeutic drug monitoring has been proposed but requires an accurate assay along with well-characterized preanalytic stability, as β-lactams are known to be relatively unstable. Methods A high-throughput LC-MS/MS assay validation and stability study was performed for cefepime, meropenem, and piperacillin and tazobactam in serum. Patient samples, standards, and QCs were crashed with acetonitrile containing internal standard. Following centrifugation, an aliquot of the supernatant was diluted with clinical laboratory reagent water and analyzed by LC-MS/MS. Results The assay showed linearity between 0.5 and 60 µg/mL for each analyte. The intra- and interassay reproducibility at 3 different concentrations (approximately 2, 25, and 40 µg/mL) was <5% for each analyte. Accuracy studies for each analyte were compared using linear regression and demonstrated: slope = 1.0 ± 0.1; r2 ≥ 0.980; and y intercept 95% CI that included zero. Minimal ion suppression or enhancement was observed, and no significant carryover was observed up to 500 µg/mL of each analyte. Stability studies demonstrated significant loss in serum for each analyte at ambient and refrigerated temperatures (2–8 °C) and at −20 °C over days or weeks. In contrast, when stored at −80 °C, no significant loss was observed. Conclusions The LC-MS/MS assay showed acceptable performance characteristics for quantitation of β-lactams. With well-characterized stability, this assay can be used with residual specimens for pharmacokinetic modeling, which may lead to individualized dosing and improved patient care.