Clinical Pharmacokinetics of Amikacin in Pediatric Patients : A Comprehensive Review of Population Pharmacokinetic Analyses

Amikacin plays a key role in the treatment of severe hospital-acquired infections with Gram-negative bacteria. Therapeutic use of amikacin is challenged by high inter-individual variability (IIV) combined with a narrow therapeutic spectrum. Pediatric patients represent a particularly fragile population where adequate dosing is crucial yet challenging to achieve due significant IIV associated with developmental processes and other factors. The current review provides an overview of parametric population pharmacokinetic analyses of amikacin in pediatric patients and associated patient-specific determinants of IIV. We searched PubMed for parametric population pharmacokinetic analyses of amikacin in pediatric patients. Information on patient population, study design, pharmacokinetic model characteristics, and identified patient-specific predictors of IIV was collected. Comparative analyses across studies were conducted to characterize quantitative differences reported for different studies and patient populations. Eight eligible publications were identified, of which six analyses involved neonates up to 3 months of age and two studies investigated older pediatric patients (age 2–17 years). Most commonly included covariates were current body weight for both clearance and volume of distribution, followed by age-related covariates on clearance in neonatal studies (four of six models). Quantitative comparisons of different models reported generally showed similar developmental effects in neonatal populations. The present review provides a comprehensive overview of parametric population pharmacokinetic studies for amikacin. Future studies could address the knowledge gap of patients between 3 months and 2 years of age. Furthermore, systematic studies of additional potential predictors for IIV (e.g., sepsis, inflammatory markers, renal function biomarkers) could be of relevance to address the significant IIV remaining after inclusion of the most commonly identified covariates

Clinical Pharmacokinetics of Amikacin in Pediatric Patients : A Comprehensive Review of Population Pharmacokinetic Analyses

Amikacin plays a key role in the treatment of severe hospital-acquired infections with Gram-negative bacteria. Therapeutic use of amikacin is challenged by high inter-individual variability (IIV) combined with a narrow therapeutic spectrum. Pediatric patients represent a particularly fragile population where adequate dosing is crucial yet challenging to achieve due significant IIV associated with developmental processes and other factors. The current review provides an overview of parametric population pharmacokinetic analyses of amikacin in pediatric patients and associated patient-specific determinants of IIV. We searched PubMed for parametric population pharmacokinetic analyses of amikacin in pediatric patients. Information on patient population, study design, pharmacokinetic model characteristics, and identified patient-specific predictors of IIV was collected. Comparative analyses across studies were conducted to characterize quantitative differences reported for different studies and patient populations. Eight eligible publications were identified, of which six analyses involved neonates up to 3 months of age and two studies investigated older pediatric patients (age 2–17 years). Most commonly included covariates were current body weight for both clearance and volume of distribution, followed by age-related covariates on clearance in neonatal studies (four of six models). Quantitative comparisons of different models reported generally showed similar developmental effects in neonatal populations. The present review provides a comprehensive overview of parametric population pharmacokinetic studies for amikacin. Future studies could address the knowledge gap of patients between 3 months and 2 years of age. Furthermore, systematic studies of additional potential predictors for IIV (e.g., sepsis, inflammatory markers, renal function biomarkers) could be of relevance to address the significant IIV remaining after inclusion of the most commonly identified covariates

Clinical Pharmacokinetics and Pharmacodynamics of Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs) have demonstrated signifcant clinical impact in improving overall survival of several malignancies associated with poor outcomes; however, only 20–40% of patients will show long-lasting survival. Further clarifcation of factors related to treatment response can support improvements in clinical outcome and guide the development of novel immune checkpoint therapies. In this article, we have provided an overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance. In response to the variation in treatment exposure of ICIs and the signifcant healthcare costs associated with these agents, arguments for both dose individualization and generalization are provided. We address important issues related to the efcacy and safety, the pharmacodynamics (PD), of ICIs, including exposure–response relationships related to clinical outcome. The unique PK and PD aspects of ICIs give rise to issues of confounding and suboptimal surrogate endpoints that complicate interpretation of exposure–response analysis. Biomarkers to identify patients benefting from treatment with ICIs have been brought forward. However, validated biomarkers to monitor treatment response are currently lacking

Differential metabolic host response to pathogens associated with community-acquired pneumonia

Background: Metabolic changes induced by the host immune response to pathogens found in patients with community-acquired pneumonia (CAP) may provide insight into its pathogenesis. In this study, we characterized differences in the host metabolic response to common CAP-associated pathogens. Method: Targeted metabolomic profiling was performed on serum samples obtained from hospitalized CAP patients (n = 119) at admission. We quantified 347 unique metabolites across multiple biochemical classes, including amines, acylcarnitines, and signaling lipids. We evaluated if unique associations between metabolite levels and specific CAP-associated pathogens could be identified. Results: Several acylcarnitines were found to be elevated in C. burnetii and herpes simplex virus and lowered in M. pneumoniae as compared to other pathogens. Phenylalanine and kynurenine were found elevated in L. pneumophila as compared to other pathogens. S-methylcysteine was elevated in patients with M. pneumoniae, and these patients also showed lowered cortisol levels in comparison to almost all other pathogens. For the herpes simplex virus, we observed a unique elevation of eicosanoids and several amines. Many lysophosphatidylcholines showed an altered profile in C. burnetii versus S. pneumoniae, L. pneumophila, and respiratory syncytial virus. Finally, phosphatidylcholines were negatively affected by the influenza virus in comparison to S. pneumoniae. Conclusions: In this exploratory analysis, metabolites from different biochemical classes were found to be altered in serum samples from patients with different CAP-associated pathogens, which may be used for hypothesis generation in studies on differences in pathogen host response and pathogenesis of CAP