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. Free serum OSM stimulated precursor cell production through sigmoidal relations, with higher maximum suppression (Imax) and OSM concentration for 50% suppression (IC50) for platelets (89.1% [95% confidence interval: 83.4-93.0], 6.03 pg/mL [4.41-8.26]) than RBCs (57.0% [49.7-64.0], 2.93 pg/mL [2.55-3.36]). Reduction in hemoglobin and platelets increased erythro- and thrombopoietin, respectively, prompting reticulocytosis and (partially) alleviating OSM-restricted hematopoiesis. The physiology-based model was substantiated by preclinical data and utilized in exploration of once-weekly or every other week dosing regimens. Predictions revealed an (for the indication) unacceptable occurrence of grade 2 (67% [58-76], 29% [20-38]) and grade 3 (17% [10-25], 3% [0-7]) anemias, with limited thrombocytopenia. Individual extent of RBC precursor modulation was moderately correlated to skin mRNA gene expression changes. The physiological basis and consideration of interplay among hematopoietic variables makes the model generalizable to other drug and nondrug scenarios, with adaptations for patient populations, diseases, and therapeutics that modulate hematopoiesis or exhibit risk of anemia and/or thrombocytopenia.

Abstract Neutrophil granulocytes are key components of the host response against pathogens, and severe neutropenia, with neutrophil counts below 0.5 × 106 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. A mathematical model for the in vitro dynamics of bacteria and the kinetics of neutrophil‐mediated phagocytosis and digestion was developed, which was extended to in vivo studies in immune‐competent and immune‐compromised mice. Neutrophil‐mediated bacterial killing was described by two first‐order processes—phagocytosis and digestion—scaled by neutrophil concentration, where 50% of the maximum was achieved at neutrophil counts of 1.19 × 106 cells/mL (phagocytosis) and 6.55 × 106 cells/mL (digestion). The process efficiencies diminished as the phagocytosed bacteria to total neutrophils ratio increased (with 50% reduction at a ratio of 3.41). Neutrophil in vivo dynamics were captured through the characterization of myelosuppressive drug effects and postinoculation neutrophil influx into lungs and by system differences (27% bacterial growth and 9.3% maximum capacity, compared with in vitro estimates). Predictions showed how the therapeutically induced reduction of neutrophil counts enabled bacterial growth, especially when falling below 0.5 × 106 cells/mL, whereas control individuals could deal with all tested bacterial burdens (up to 109 colony forming units/g lung). The model‐based characterization of neutrophil‐mediated bacterial killing simultaneously predicted data across in vitro and in vivo studies and may be used to inform the capacity of host–response at the individual level.

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. To identify flucloxacillin dosing regimens that result in theoretically therapeutic concentrations, we developed a population pharmacokinetic (PK) model for the porcine data, and combined it with a human flucloxacillin population PK model for simulations.METHODS:A four-compartment model was developed, and various dosing regimens and modes of administration were simulated. Predicted concentrations were compared to %fT>MIC (0.5 mg/L and 2 mg/L).RESULTS:Continuous infusion (CI) resulted in higher %fT>MIC compared to intermittent administration. For intermittent IV dosing (4, 8 and 12g/24h), fT>MIC (0.5 mg/L) was ≥70% in plasma, and ranged between 42-96% in the sampled tissue in a typical individual. By applying CI, 4g/day was sufficient to achieve ≥98% fT>MIC (0.5 mg/L) in all sampled tissues. For MIC 2 mg/L, ≥50% fT>MIC was only achieved in plasma at CI 8 and 12g/24h and IV 3g q6h.CONCLUSIONS:To reach efficacious flucloxacillin bone and tissue concentrations, dose increment or continuous infusion needs to be considered.

Abstract 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. A piperacillin‐tazobactam loading dose (100 mg/kg) was administered followed by continuous infusion (300 mg/kg/day). The unbound fraction of piperacillin was quantified by high‐performance liquid chromatography and PK were described using population PK modeling. PK data was used to update and extend a previous PK model built on data following intermittent administration. Monte Carlo simulations were performed to assess PTA for targets of 100% time above the minimum inhibitory concentration (100% fT > MIC) and 50% fT > 4xMIC. Results We included 68 fever episodes among 38 children with a median (IQR) age of 6.5 years and body weight of 27.4 kg (15.1–54.0). A three‐compartment model adequately described the concentration‐time data. Median (95% confidence interval) estimates for clearance and piperacillin concentration at steady state were 14.2 L/h/70 kg (13.0; 15.3) and 47.6 mg/L (17.2; 129.5), respectively. Body weight or lean body weight was significantly associated with the PK parameters, and body weight was integrated in the final PK model. Based on piperacillin exposure, continuous infusion was the only dosing regimen to achieve optimal PTA for the P. aeruginosa breakpoint (16 mg/L) with the target of 100% fT > MIC, and a daily dose of 300 mg/kg reached optimal PTA. The strict target of 50% fT > 4xMIC (64 mg/L) was not feasibly attained by any dosing regimen at recommended doses. Conclusion Unlike conventional piperacillin intermittent administration and extended infusion regimens, continuous infusion allows the target of 100% fT > MIC to be reached for children with febrile neutropenia.

Physiological response to endotoxin: Linking hemodynamic and respiratory longitudinal changes through modelling

Neutrophils are key components in the host defence against pathogens. Characterization of neutrophilmediated bacterial killing is warranted to inform on host contribution during bacterial infection ...

Objectives: Piperacillin is a beta-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. Methods: A population pharmacokinetic model was developed using NONMEM 7.4.3, to simulate alternative administration modes and dosing regimens. SCT concentrations were obtained using microdialysis. Piperacillin concentrations were compared to the clinical breakpoint minimum inhibitory concentration (MIC) for Pseudomonas aeruginosa (16 mg/l), with evaluation of the following pharmacokinetic/pharmacodynamics targets: 50% fT > 1 x MIC, 100% fT > 1 x MIC, and 100% fT > 4 x MIC. Results: SCT concentrations were generally lower than plasma concentrations. For the target of 50% free time (fT) > 1 x MIC and 100% fT > 1 x MIC, piperacillin 4 g every 8 h resulted in probability of target attainment (PTA) >90% in both plasma and SCT. PTA > 90% for the target of 100% fT > 4 x MIC was only achieved for continuous infusion. Conclusions: Piperacillin 4 g every 8 h is likely to provide sufficient exposure in both plasma and SCT to treat P.aeruginosa infections in critically ill patients on CRRT, given that targets of 50% fT > 1 x MIC or 100% fT > 1 x MIC are adequate. However, if a more aggressive target of 100% fT > 4 x MIC is adopted, continuous infusion is needed. (C) 2020 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.

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 Escherichia coli growth/killing dynamics at various cefuroxime concentrations to endotoxin release in vitro .

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. Incorporation of such biomarker information into PK and PK/PD models may guide the evaluation of individual response to treatment (right antibiotic, more antibiotic, less antibiotic) and when to stop treatment. Furthermore, translation of results from preclinical systems to clinical scenarios may be improved with the incorporation of biomarker information. Potential biomarkers for these purposes are discussed and a few modelling examples are provided.

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 ( n = 196) were assessed in 78 critically ill patients following continuous infusion of piperacillin-tazobactam (ratio 8:1). The initial dose of 8, 12, or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL).

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. Children with cancer receiving empiric piperacillin-tazobactam to treat infections were included. Piperacillin-tazobactam 100 mg/kg was infused over 5 min every 8 hours (IA). An optimized sample schedule provided six blood samples per subject for piperacillin concentration determination. The evaluated targets included: (1) 100% time of free piperacillin concentration above the minimum inhibitory concentration (fT > MIC) and (2) 50% fT > 4x MIC. MIC50 and MIC90 were defined based on an intrainstitutional MIC range. Results A total of 482 piperacillin concentrations were obtained from 43 children (aged 1-18 years) during 89 fever episodes. Standard IA resulted in insufficient target attainment, with significant differences in piperacillin pharmacokinetics for different body weights. Median fT > MIC was 61.2%, 53.5%, and 36.3% for MIC50 (2.0 mg/L), MIC90 (4.0 mg/L), and breakpoint for Pseudomonas aeruginosa (16.0 mg/L), respectively. Correspondingly, the median fT > 4x MIC was 43%, 36.3%, and 20.1%. Simulations showed that only continuous infusion reached a PTA of 95% for MIC = 16.0 mg/L, while extended infusion lasting half of the dosing interval reached a PTA of 95% for MIC <= 8 mg/L. Conclusions Our data revealed insufficient PTA with standard IA of piperacillin-tazobactam in children with cancer and fever. Alternative dosing strategies, preferably continuous infusion, are required to ensure adequate PTA.

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. Data from six studies of porcine endotoxemia in anesthetized piglets (n = 116) were combined and used in the analysis, with purified endotoxin (Escherichia coli O111:B4) being infused intravenously for 1-30 h in rates of 0.063-16.0 μg/kg/h across studies. All data were modelled simultaneously by means of importance sampling in the non-linear mixed effects modelling software NONMEM. The infused endotoxin followed one-compartment disposition and non-linear elimination, and stimulated the production of TNF-α to describe the rapid increase in plasma concentration. Tolerance development, observed as declining TNF-α concentration with continued infusion of endotoxin, was also driven by endotoxin as a concentration-dependent increase in the potency parameter related to TNF-α production (EC50). Production of IL-6 was stimulated by both endotoxin and TNF-α, and four consecutive transit compartments described delayed increase in plasma IL-6. A model which simultaneously account for the time-courses of endotoxin and two immune response markers, the cytokines TNF-α and IL-6, as well as the development of endotoxin tolerance, was successfully established. This model-based approach is unique in its description of the time-courses and their interrelation and may be applied within research on immune response to bacterial endotoxin, or in pre-clinical pharmaceutical research when dealing with study design or translational aspects.

Background The beta-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>1xMIC and 50% fT>4xMIC) and resultant exposure, across body weights. Methods Forty-three children admitted for 89 febrile episodes contributed 482 samples to the pharmacokinetic analysis. The typical doses required for target attainment were compared for various dosing regimens, in particular prolonged infusions, across MICs and body weights. Results A two-compartment model with inter-fever-episode variability in CL, and body weight included through allometry, described the data. A high CL of 15.4L/h (70kg) combined with high glomerular filtration rate (GFR) values indicated rapid elimination and hyperfiltration. The target of 50% fT>4xMIC was achieved for an MIC of 4.0mg/L in a typical patient with extended infusions of 2-3 (q6h) or 3-4 (q8h)h, at or below the standard adult dose (75 and 100mg/kg/dose for q6h and q8h, respectively). Higher doses or continuous infusion were needed to achieve 100% fT>1xMIC due to the rapid piperacillin elimination. Conclusions The licensed dose for children with febrile neutropenia (80mg/kg q6h as a 30min infusion) performs poorly for attainment of fT(>MIC) pharmacokinetic/pharmacodynamic targets. Given the population pharmacokinetic profile, feasible dosing regimens with reasonable exposure are continuous infusion (100% fT>1xMIC) or prolonged infusions (50% fT>4xMIC).

ABSTRACT 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. Piperacillin concentrations were compared to the clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/pharmacodynamic (PD) targets were evaluated: the percentage of the dosing interval that the free drug concentration is maintained above the MIC ( fT MIC ) of 50% and 100%. A two-compartment population PK model described the data well, with clearance being divided into renal and nonrenal components. The renal component was proportional to the estimated creatinine clearance (eCL CR ) and constituted 74% of the total clearance in a typical individual (eCL CR , 83.9 ml/min). Patients with a high eCL CR (>130 ml/min) were at risk of subtherapeutic concentrations for the current regimen, with a 90% probability of target attainment being reached at MICs of 2.0 (50% fT MIC ) and 0.125 mg/liter (100% fT MIC ). Simulations of alternative dosing regimens and modes of administration showed that dose increment and prolonged infusion increased the chance of achieving predefined PK/PD targets. Alternative dosing strategies may therefore be needed to optimize piperacillin exposure in septic patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02569086.)

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. Serial SCT concentrations were determined using microdialysis and compared with plasma concentrations. A population PK model of SCT and plasma data was developed using NONMEM. Time above clinical breakpoint MIC for Pseudomonas aeruginosa (8 mg/liter) was predicted for each patient. The following targets were evaluated: time for which the free (unbound) concentration is maintained above the MIC of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4×MIC. For all dosing regimens simulated in both plasma and SCT, 40% fT>MIC was attained. However, prolonged meropenem infusion would be needed for 100% fT>MIC and 100% fT>4×MIC to be obtained. Meropenem plasma and SCT concentrations were associated with estimated creatinine clearance (eCLCr). Simulations showed that in patients with increased eCLCr, dose increment or continuous infusion may be needed to obtain therapeutic meropenem concentrations. In conclusion, our results show that using traditional targets of 40% fT>MIC for standard meropenem dosing of 1 g intravenously every 8 h is likely to provide sufficient meropenem concentration to treat the problematic pathogen P. aeruginosa for patients receiving ECMO treatment. However, for patients with an increased eCLCr, or if more aggressive targets, like 100% fT>MIC or 100% fT>4×MIC, are adopted, incremental dosing or continuous infusion may be needed.

The aim of this work was to assess the relationship between the absolute lymphocyte count (ALC), and disability (as measured by the Expanded Disability Status Scale [EDSS]) and occurrence of relapses, 2 efficacy endpoints, respectively, in patients with remitting‐relasping multiple sclerosis. Data for ALC, EDSS, and relapse rate were available from 1319 patients receiving placebo and/or cladribine tablets. Pharmacodynamic models were developed to characterize the time course of the endpoints. ALC‐related measures were then evaluated as predictors of the efficacy endpoints. EDSS data were best fitted by a model where the logit‐linear disease progression is affected by the dynamics of ALC change from baseline. Relapse rate data were best described by the Weibull hazard function, and the ALC change from baseline was also found to be a significant predictor of time to relapse. Presented models have shown that once cladribine exposure driven ALC‐derived measures are included in the model, the need for drug effect components is of less importance (EDSS) or disappears (relapse rate). This simplifies the models and theoretically makes them mechanism specific rather than drug specific. Having a reliable mechanism‐specific model would allow leveraging historical data across compounds, to support decision making in drug development and possibly shorten the time to market.

BACKGROUND AND PURPOSEWe aimed to develop a mechanistic mixed-effects pharmacokinetic (PK)-pharmacodynamic (PD) (PKPD) model for recombinant human growth hormone (rhGH) in hypophysectomized rats and to predict the human PKPD relationship.EXPERIMENTAL APPROACHA non-linear mixed-effects model was developed from experimental PKPD studies of rhGH and effects of long-term treatment as measured by insulin-like growth factor 1 (IGF-1) and bodyweight gain in rats. Modelled parameter values were scaled to human values using the allometric approach with fixed exponents for PKs and unscaled for PDs and validated through simulations relative to patient data.KEY RESULTSThe final model described rhGH PK as a two compartmental model with parallel linear and non-linear elimination terms, parallel first-order absorption with a total s.c. bioavailability of 87% in rats. Induction of IGF-1 was described by an indirect response model with stimulation of kin and related to rhGH exposure through an E-max relationship. Increase in bodyweight was directly linked to individual concentrations of IGF-1 by a linear relation. The scaled model provided robust predictions of human systemic PK of rhGH, but exposure following s.c. administration was over predicted. After correction of the human s.c. absorption model, the induction model for IGF-1 well described the human PKPD data.CONCLUSIONSA translational mechanistic PKPD model for rhGH was successfully developed from experimental rat data. The model links a clinically relevant biomarker, IGF-1, to a primary clinical end-point, growth/bodyweight gain. Scaling of the model parameters provided robust predictions of the human PKPD in growth hormone-deficient patients including variability.

Background and purpose: Infection with Gram-negative bacteria and the immune system’s subsequent recognition of the potent membrane-bound activator endotoxin (ETX), can lead to persistent immune activation. The purpose of the current work was to develop a model-based description of the time-course of ETX concentrations and its effect on the release of the pro-inflammatory, cytokines tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6).Methods: Non-linear mixed effects models were developed based on data from experimental studies in a porcine model of sepsis. Intravenous infusions of E. coli ETX were administered to the piglets at different doses and durations of infusion. ETX, TNF-α and IL-6 plasma levels were measured throughout the infusion time.Results: The concentration-time profile of ETX was well described with a one-compartment model with non-linear elimination. Observation of contamination in early ETX measurements was handled by initializing the central compartment to an estimated parameter. The concentration of ETX over time was used as the driver of the inflammatory response. An indirect response model with ETX stimulated production (Emax model), delayed through a transit chain (three compartments) was used to describe the observed cytokine concentration-time profiles. To describe tolerance to ETX exposure, an exponential time-dependent increase was added to the parameter describing the potency of ETX to stimulate cytokine release (EC50).Conclusions: A mathematical model was developed to depict the time-course of ETX in plasma and its induction of the two immune response markers TNF-α and IL-6. This model-based approach is unique in its description of the three time-courses, and may later be expanded to better understand immune cell release in bacterial infections and sepsis-type pathophysiological changes