Predicting the Long-Term Effects of Therapeutic Neutralization of Oncostatin M on Human Hematopoiesis.

Therapeutic neutralization of Oncostatin M (OSM) causes mechanism-driven anemia and thrombocytopenia, which narrows the therapeutic window complicating the selection of doses (and dosing intervals) that optimize efficacy and safety. We utilized clinical data from studies of an anti-OSM monoclonal antibody (GSK2330811) in healthy volunteers (n = 49) and systemic sclerosis patients (n = 35), to quantitatively determine the link between OSM and alterations in red blood cell (RBC) and platelet production. Longitudinal changes in hematopoietic variables (including RBCs, reticulocytes, platelets, erythropoietin, and thrombopoietin) were linked in a physiology-based model, to capture the long-term effects and variability of therapeutic OSM neutralization on human hematopoiesis.

Model-based assessment of neutrophil-mediated phagocytosis and digestion of bacteria across in vitro and in vivo studies.

Neutrophil granulocytes are key components of the host response against pathogens, and severe neutropenia, with neutrophil counts below 0.5 × 10 cells/mL, renders patients increasingly vulnerable to infections. Published in vitro (n = 7) and in vivo (n = 5) studies with time-course information on bacterial and neutrophil counts were digitized to characterize the kinetics of neutrophil-mediated bacterial killing and inform on the immune systems' contribution to the clearance of bacterial infections.

Population Pharmacokinetics of Flucloxacillin In Bone and Soft Tissue- Standard Dosing is Not Sufficient to Achieve Therapeutic Concentrations.

Purpose: Flucloxacillin is a β-lactam penicillin commonly used in the treatment of bone and soft tissue infections. In a recent porcine study, we found surprisingly low time for which the free concentration was maintained above the minimal inhibitory concentration (fT>MIC) in bone and soft tissue, following flucloxacillin oral (PO) and intravenous (IV) administration at 1g every 6h (q6h). In addition to plasma, sampling was obtained from subcutaneous tissue, knee joint, cancellous bone and cortical bone, using microdialysis.

Continuous infusion of piperacillin-tazobactam significantly improves target attainment in children with cancer and fever.

Background: Children with febrile neutropenia commonly exhibit alterations of pharmacokinetic (PK) parameters, leading to decreased β-lactam concentrations.

Aims: This study evaluated piperacillin PK and probability of target attainment (PTA) with continuous infusion of piperacillin-tazobactam, in order to optimize the dosing regimen.

Methods: This prospective PK study included children with cancer, aged 1-17 years, who were treated with piperacillin-tazobactam for suspected or verified infection.

Pharmacodynamics of immune response biomarkers of interest for evaluation of treatment effects in bacterial infections.

This mini-review discusses the pharmacodynamics of immune-related biomarkers in the area of bacterial infectious diseases that could be of interest from a pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) perspective in the evaluation of treatment effects. The host response to an infection is often poorly defined both in preclinical assessments and in clinical practice when it comes to characterisation of PK and PK/PD relationships. Through population modelling, the time courses and variability of immune response variables can be quantified.

Population Pharmacokinetics of Piperacillin following Continuous Infusion in Critically Ill Patients and Impact of Renal Function on Target Attainment.

Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for β-lactams. In an observational study, unbound piperacillin concentrations ( = 196) were assessed in 78 critically ill patients following continuous infusion of piperacillin-tazobactam (ratio 8:1).

Extension of Pharmacokinetic/Pharmacodynamic Time-Kill Studies To Include Lipopolysaccharide/Endotoxin Release from Escherichia coli Exposed to Cefuroxime.

The release of inflammatory bacterial products, such as lipopolysaccharide (LPS)/endotoxin, may be increased upon the administration of antibiotics. An improved quantitative understanding of endotoxin release and its relation to antibiotic exposure and bacterial growth/killing may be gained by an integrated analysis of these processes. The aim of this work was to establish a mathematical model that relates growth/killing dynamics at various cefuroxime concentrations to endotoxin release Fifty-two time-kill experiments informed bacterial and endotoxin time courses and included both static (0×, 0.

Population pharmacokinetics of piperacillin in plasma and subcutaneous tissue in patients on continuous renal replacement therapy.

Objectives: Piperacillin is a β-lactam antimicrobial frequently used in critically ill patients with acute kidney injury treated with continuous renal replacement therapy (CRRT). However, data regarding piperacillin tissue concentrations in this patient population are limited. A prospective observational study was conducted of free piperacillin concentrations during a single 8-h dosing interval in plasma (8 samples) and subcutaneous tissue (SCT) (13 samples), in 10 patients treated with CRRT following piperacillin 4 g given every 8 h as intermittent administration over 3 min.

Population pharmacokinetics of piperacillin in febrile children receiving cancer chemotherapy: the impact of body weight and target on an optimal dosing regimen.

Background: The β-lactam antibiotic piperacillin (in combination with tazobactam) is commonly chosen for empirical treatment of suspected bacterial infections. However, pharmacokinetic variability among patient populations and across ages leads to uncertainty when selecting a dosing regimen to achieve an appropriate pharmacodynamic target.

Objectives: To guide dosing by establishing a population pharmacokinetic model for unbound piperacillin in febrile children receiving cancer chemotherapy, and to assess pharmacokinetic/pharmacodynamic target attainment (100% fT > 1×MIC and 50% fT > 4×MIC) and resultant exposure, across body weights.

A non-linear mixed effect model for innate immune response: In vivo kinetics of endotoxin and its induction of the cytokines tumor necrosis factor alpha and interleukin-6.

Endotoxin, a component of the outer membrane of Gram-negative bacteria, has been extensively studied as a stimulator of the innate immune response. However, the temporal aspects and exposure-response relationship of endotoxin and resulting cytokine induction and tolerance development is less well defined. The aim of this work was to establish an in silico model that simultaneously captures and connects the in vivo time-courses of endotoxin, tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and associated tolerance development.

Piperacillin pharmacokinetics and target attainment in children with cancer and fever: Can we optimize our dosing strategy?

Background: Data on piperacillin-tazobactam pharmacokinetics and optimal dosing in children with cancer and fever are limited. Our objective was to investigate piperacillin pharmacokinetics and the probability of target attainment (PTA) with standard intermittent administration (IA), and to simulate PTA in other dosing regimens.

Procedure: This prospective pharmacokinetic study was conducted from April 2016 to January 2018.

Population Pharmacokinetics of Meropenem in Plasma and Subcutis from Patients on Extracorporeal Membrane Oxygenation Treatment.

The objectives of this study were to describe meropenem pharmacokinetics (PK) in plasma and/or subcutaneous adipose tissue (SCT) in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) treatment and to develop a population PK model to simulate alternative dosing regimens and modes of administration. We conducted a prospective observational study. Ten patients on ECMO treatment received meropenem (1 or 2 g) intravenously over 5 min every 8 h.

Population Pharmacokinetics of Piperacillin in Sepsis Patients: Should Alternative Dosing Strategies Be Considered?

Sufficient antibiotic dosing in septic patients is essential for reducing mortality. Piperacillin-tazobactam is often used for empirical treatment, but due to the pharmacokinetic (PK) variability seen in septic patients, optimal dosing may be a challenge. We determined the PK profile for piperacillin given at 4 g every 8 h in 22 septic patients admitted to a medical ward.