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Objective The objective of this review is to discuss the therapeutic use and differential treatment response to Levo-carnitine (l-carnitine) treatment in septic shock, and to demonstrate common lessons learned that are important to the advancement of precision medicine approaches to sepsis. We propose that significant interpatient variability in the metabolic response to l-carnitine and clinical outcomes can be used to elucidate the mechanistic underpinnings that contribute to sepsis heterogeneity. Methods A narrative review was conducted that focused on explaining interpatient variability in l-carnitine treatment response. Relevant biological and patient-level characteristics considered include genetic, metabolic, and morphomic phenotypes; potential drug interactions; and pharmacokinetics (PKs). Main results Despite promising results in a phase I study, a recent phase II clinical trial of l-carnitine treatment in septic shock showed a nonsignificant reduction in mortality. However, l-carnitine treatment induces significant interpatient variability in l-carnitine and acylcarnitine concentrations over time. In particular, administration of l-carnitine induces a broad, dynamic range of serum concentrations and measured peak concentrations are associated with mortality. Applied systems pharmacology may explain variability in drug responsiveness by using patient characteristics to identify pretreatment phenotypes most likely to derive benefit from l-carnitine. Moreover, provocation of sepsis metabolism with l-carnitine offers a unique opportunity to identify metabolic response signatures associated with patient outcomes. These approaches can unmask latent metabolic pathways deranged in the sepsis syndrome and offer insight into the pathophysiology, progression, and heterogeneity of the disease. Conclusions The compiled evidence suggests there are several potential explanations for the variability in carnitine concentrations and clinical response to l-carnitine in septic shock. These serve as important confounders that should be considered in interpretation of l-carnitine clinical studies and broadly holds lessons for future clinical trial design in sepsis. Consideration of these factors is needed if precision medicine in sepsis is to be achieved.

Background High-dose methotrexate (HD-MTX) is used to treat primary central nervous system lymphoma (PCNSL), but potential differences in MTX clearance (CL) due to obesity have not been studied. We characterized the relationship between HD-MTX CL and computed tomography (CT)-generated body composition (morphomic), body size descriptors, and laboratory measurements in a cohort of obese and non-obese patients with PCNSL. Methods Medical records from adult patients with PCNSL treated with HD-MTX over a 10-year period were queried. Individuals with CT data within 30 days of the first cycle of treatment were included. Population pharmacokinetic analysis was performed using a 2-compartment base structural model. We specifically compared body surface area (BSA) to standard body size, morphomic, and renal function estimation methods as covariates of HD-MTX CL. Results The final data set consisted of non-obese (n=45) and obese (n=28) patients with 291 observations (3-7 samples per patient) with a mean (standard deviation) weight of 69.8 (11.6) kg and 104 (14.9) kg, respectively (p=0.0001). Vertebral body height was more informative than BSA of MTX CL. Similarly, a CL model incorporating age, albumin, and serum creatinine was more informative than kidney function equations and body size. The final model of MTX CL was based on age, albumin, serum creatinine, and vertebral body height. Conclusions Common clinical variables coupled with vertebral body height are more predictive of first cycle MTX CL than BSA, alternate body size descriptors, and commonly used kidney function equations.

Objectives To compare daptomycin exposures and predicted safety outcomes with a simulated weight-based and fixed dose in morbidly obese and nonobese subjects. Methods We performed a nonparametric population pharmacokinetic analysis of daptomycin concentration-time data from a prior obese and nonobese kidney function-matched cohort of healthy adult volunteers. Monte Carlo simulations were performed to compare the maximum concentrations (Cmax ), minimum concentrations (Cmin ), and area under the curve (AUC) with the standard daptomycin 6 mg/kg/day dose or a 500-mg daily fixed dose in obese and nonobese subjects. The probability of exceeding a daptomycin Cmin target (24.3 mg/L or higher) associated with creatine phosphokinase (CPK) elevations was computed with the two regimens. Results No significant differences were observed in clearance, volume of distribution at steady state, or terminal half-life between the morbidly obese and nonobese PK models. Daptomycin 6 mg/kg/day resulted in AUC, Cmax , and Cmin values that were ~2-fold higher in morbidly obese subjects relative to nonobese individuals. In contrast, fixed dosing (500 mg/day) resulted in relatively isometric exposures. The fraction of simulated morbidly obese subjects with a Cmin target associated with CPK elevations was 10.8% with 6 mg/kg/day and 2.0% at the 500 mg/day dosage. Conclusions Weight-based maintenance dosing of daptomycin is less likely to yield bioequivalent exposures in morbidly obese subjects and provides credence for the evaluation of fixed maintenance doses across adult body size to improve safety.

As obesity continues to increase in prevalence throughout the world, it becomes important to explore the effects that obesity has on antimicrobial disposition. Physiologic changes in obesity can alter both the volume of distribution and clearance of many commonly used antimicrobials. These changes often present challenges such as estimation of creatinine clearance to predict drug clearance. Although these physiologic changes are increasingly being characterized, few studies assessing alterations in tissue drug distribution and the effects of obesity on antimicrobial pharmacokinetics have been published. The available data are most plentiful for antibiotics that historically have included clinical therapeutic drug monitoring. These data suggest that dosing of vancomycin and aminoglycosides be based on total body weight and adjusted body weight, respectively. Obese patients may require larger doses of beta-lactams to achieve similar concentrations as those of patients who are not obese. Fluoroquinolone pharmacokinetics are variably altered by obesity, which prevents a uniform approach. Data on the pharmacokinetics of drugs that have activity against gram-positive organisms-quinupristin-dalfopristin, linezolid, and daptomycin-reveal that they are altered in the presence of obesity, but more data are needed to solidify dosing recommendations. Limited data are available on nonantibacterials. An understanding of the physiologic changes in obesity and the available literature on specific antibiotics is valuable in providing a framework for rational selection of dosages in this increasingly common population of obese patients.

tudy Objective To compare the likelihood of vancomycin target trough concentration attainment based on infectious diagnosis and/or minimum inhibitory concentration for the organism by using a two-sample approach versus the prior institutional standard of a trough-only approach in obese patients receiving vancomycin. Design Preintervention and postintervention study. Setting Community acute care hospital. Patients One hundred fifty hospitalized adults with a body mass index (BMI) of 30 kg/m2 or greater and treated with vancomycin for at least 48 hours between July 2013 and March 2014 were evaluated to compare the frequency of steady-state therapeutic trough concentration attainment between two approaches: a trough-only dosing method (preintervention group [75 patients]) and a dosing strategy measuring two vancomycin serum concentrations during the elimination phase (peak and trough) to calculate pharmacokinetic parameters and individualize the maintenance regimen (postintervention group [75 patients]). Data for the preintervention group were retrospectively retrieved from a 4-month period for patients admitted between July and October 2013, prior to implementation of the two-point vancomycin dosing protocol. Initial vancomycin empiric dose selection for both groups utilized the same population-based pharmacokinetic equations. Measurements and Main Results Median (5th–95th percentile) age, weight, and BMI were 59 (34–80) years, 105 (79.8–164) kg, and 34.5 (30.0–55.1) kg/m2, respectively, for all patients. The percentages of initial therapeutic trough concentrations achieved in the preintervention and postintervention groups were 32.0% and 42.7%, respectively (p=0.117). For patients with a second trough measurement, 31.0% in the preintervention group and 65.2% in the postintervention group were within the therapeutic range (p=0.024). Conclusion Measurement of two serum vancomycin concentrations significantly improves subsequent target trough concentration attainment in the obese population.

Drug samples are often packaged differently from bulk packaging and thus they may contain a disproportionate amount of waste material. Fifteen drug samples were obtained from seven pharmaceutical companies and the packaging materials were weighed after the samples were removed. The waste produced by the samples was determined for a standard amount of drug and compared with the weight of the waste produced when the same quantity of drug was dispensed through a pharmacy. The average weight of the sample package for a standard course of therapy was significantly greater (por =0.05) than that of the pharmacy-dispensed prescription waste weight. The former was 5+/-4.5-fold heavier than the latter. The waste generated by drug samples in the United States was determined to be 5740 metric tons/year.

Study Objectives. To compare the steady-state pharmacokinetics and safety of saquinavir soft-gelatin capsules (SGC) plus low-dose ritonavir administered once/day in antiretroviral-naive adult patients infected with the human immunodeficiency virus type 1 (HIV-1) and to evaluate any sex-related differences. Design. Single-center, open-label, pharmacokinetic study. Setting. University-affiliated outpatient HIV clinic. Patients. Six men and seven women with HIV-1. Intervention. Each patient received saquinavir SGC 1600 mg and ritonavir 100 mg for a 14-day course of therapy. Nine serial blood samples during 24 hours were collected on day 14 of therapy. Measurements and Main Results. Plasma saquinavir and ritonavir concentrations were measured by high-performance liquid chromatography. Standard noncompartmental methods were used to calculate the pharmacokinetic parameters. The unpaired Student t test was used for the statistical comparison of pharmacokinetic parameters between male and female patients. Once-daily saquinavir SGC plus ritonavir was generally well tolerated. Pharmacokinetic data from five men and five women were evaluable. The median saquinavir area under the concentration–time curve from 0–24 hours (AUC0–24) in the female patients (82,300 ng·hr/ml) was significantly (p=0.036) higher than that in the male patients (47,400 ng·hr/ml). This relationship remained significant for weight-adjusted saquinavir AUC0–24 values. Ritonavir's apparent oral clearance in the women was significantly (p=0.023) lower than that in the men. Conclusion. Significantly higher plasma concentrations of saquinavir were achieved in female compared with male HIV-infected patients receiving once-daily saquinavir SGC 1600 mg plus ritonavir 100 mg.