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Anselm Jorda,1 Sabine Eberl,1 Alina Nussbaumer-Pröll,1 Maysa Sarhan,2 Maria Weber,1 Lara Elisabeth Tegrovsky,1 Markus Wahrmann,2 Valentin al Jalali,1 Felix Bergmann,1,3 Lena Pracher,1 Amelie Leutzendorff,1 Matthias Farlik,4 Bernd Jilma,1 Markus Zeitlinger1 1Medical University of Vienna, Department of Clinical Pharmacology, Vienna, Austria; 2Medical University of Vienna, Department of Internal Medicine III, Division of Nephrology and Dialysis, Vienna, Austria; 3Medical University of Vienna, Department of Plastic, Reconstructive and Aesthetic Surgery, Vienna, Austria; 4Medical University of Vienna, Department of Dermatology, Vienna, AustriaCorrespondence: Markus Zeitlinger, Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, 1090, Austria, Tel +43 1 40400 29810, Email markus.zeitlinger@meduniwien.ac.atIntroduction: Lipopolysaccharide (LPS) stimulation of human whole blood ex vivo has been widely used to investigate human innate immune responses. However, there are uncertainties regarding the reproducibility and reliability of this assay.Methods: In this prospective, single-center study, cytokine responses (interleukin 8, interferon-α, interferon-γ, interleukin 10, interleukin 1-β, interleukin 6, and tumor necrosis factor-α) to ex vivo whole blood LPS stimulation were assessed in 12 healthy volunteers. Cytokine levels were measured at 0, 2, and 4 h using a multiplex immunoassay (Luminex ®). Stimulation was repeated after six weeks. We examined reproducibility across technical and biological replicates at baseline and between repeated experiments after 6 weeks based on the area under the curve (AUC) of the individual cytokines using Pearson’s correlation coefficient and the mean coefficient of variation.Results: The lowest mean coefficients of variation were observed for the technical replicates (5.4 to 9.2%), followed by the biological replicates (8.1 to 24.8%), and the repeated experiments after 6 weeks (17 to 31.2%). Between the baseline and 6-week AUCs, the following Pearson correlation coefficients R were observed: interleukin 10, 0.97; interferon-α, 0.84; interleukin 1-β, 0.83; interleukin 8, 0.79; interleukin 6, 0.73; interferon-γ, 0.73; and tumor necrosis factor-α, 0.63.Discussion: The level of agreement between the baseline and week-6 cytokine response to ex vivo LPS stimulation was high across the seven cytokines analyzed. While interleukin 10 exhibited the lowest level of variability over time, tumor necrosis factor-α showed the highest variability in repeated experiments, which should be considered in the design and interpretation of future studies.Keywords: LPS, lipopolysaccharide, inflammation, endotoxin

Objectives: To investigate ceftolozane/tazobactam pharmacokinetics (PK) in plasma and interstitial space fluid (ISF) of muscle and subcutaneous tissue and establish a population PK model.Methods: Eight healthy volunteers received four IV doses of 1000/500 mg ceftolozane/tazobactam q8h in a prospective, open-labelled PK study. ISF concentration-time profiles were determined via in vivo microdialysis up to 8 h post-dose and efficacy of unbound ceftolozane and tazobactam was estimated using the time above MIC (%ƒT>MIC) and time above threshold concentration (%T>CT), respectively. A population PK model was established by merging derived plasma and soft tissue PK data.Results: Ceftolozane reached %ƒT>MIC values of 100% in plasma, muscle and subcutaneous ISF for Enterobacteriaceae and 87%, 89% and 87%, respectively, for Pseudomonas aeruginosa. Tazobactam %T>CT was 21%, 22% and 21% in plasma, muscle and subcutaneous ISF, respectively. Plasma protein binding was 6.3% for ceftolozane and 8.0% for tazobactam. Multiple-dose ceftolozane AUC0-8 ISF/plasma ratios were 0.92 ± 0.17 in muscle and 0.88 ± 0.18 in subcutis, and tazobactam ratios were 0.89 ± 0.25 in muscle and 0.87 ± 0.21 in subcutis, suggesting substantial soft tissue penetration.Conclusions: Tazobactam %T>CT values were distinctly below proposed target values, indicating that tazobactam might be underdosed in the investigated drug combination. However, ISF/unbound plasma ratios of ceftolozane and tazobactam support their use in soft tissue infections. A plasma and soft tissue PK model adds important information on the PK profile of ceftolozane/tazobactam. Further investigations in patients suffering from wound infections are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Aims: Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile., Methods: A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug-drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80-125%., Results: The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104-120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112-168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported., Conclusion: A PK assessment of clomipramine and yohimbine indicated a clinically significant drug-drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25-<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies., (© 2024 British Pharmacological Society.)

Background: Cefiderocol may potentially be used to treat skin and soft tissue infections (SSTIs). However, the pharmacokinetics of cefiderocol in human soft tissues have not yet been determined. The objective of the present PK study was to investigate whether target-site concentrations of cefiderocol are sufficiently high for the treatment of SSTIs., Methods: In this pharmacokinetic study, a single intravenous dose of 2 g cefiderocol was administered to eight healthy male volunteers. Drug concentrations were determined in plasma, muscle and subcutis over 8 h. Free plasma concentrations were calculated using the plasma protein binding determined with ultrafiltration. Free tissue concentrations were obtained using microdialysis. Penetration ratios were calculated as AUC0-8h&#95;free&#95;tissue/AUC0-8h&#95;free&#95;plasma. A population pharmacokinetic model was developed, and the probability of target attainment (PTA) was determined using Monte Carlo simulations., Results: Cefiderocol showed good tissue penetration, with mean penetration ratios ± standard deviation of 0.99 ± 0.33 and 0.92 ± 0.30 for subcutis and muscle, respectively. Cefiderocol pharmacokinetics in plasma were best described with a two-compartment model, and tissue concentrations were described by scaling the tissue concentrations to concentrations in the peripheral compartment of the plasma model. For a thrice-daily regimen with 2 g doses intravenously infused over 3 h, PTA was ≥90% for MIC values up to 4 mg/L, both based on free plasma and soft tissue pharmacokinetics., Conclusions: This study indicates that a dose of 2 g cefiderocol achieves concentrations in plasma considered sufficient for treating relevant bacterial species. Assuming a comparable PK/PD target for soft tissues, sufficiently high concentrations would also be achieved in soft tissues., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Landiolol, a highly cardioselective agent with a short half-life (2.4-4 min), is commonly used as a perfusor or bolus application to treat tachycardic arrhythmia. Some small studies suggest that prior oral β-blocker use results in a less effective response to intravenous β-blockers. Methods: This study investigated whether prior chronic oral β-blocker (Lβ) or no prior chronic oral β-blocker (L-) intake influences the response to intravenous push-dose Landiolol in intensive care patients with acute tachycardic arrhythmia. Results: The effects in 30 patients (67 [55-72] years) were analyzed, 10 (33.3%) with and 20 (66.7%) without prior oral β-blocker therapy. Arrhythmias were diagnosed as tachycardic atrial fibrillation in 14 patients and regular, non-fluid-dependent, supraventricular tachycardia in 16 cases. Successful heart rate control (Lβ 4 vs. L- 7, p = 1.00) and rhythm control (Lβ 3 vs. L- 6, p = 1.00) did not significantly differ between the two groups. Both groups showed a significant decrease in heart rate when comparing before and after the bolus administration, without significant differences between the two groups (Lβ -26/min vs. L- -33/min, p = 0.528). Oral β-blocker therapy also did not influence the change in mean arterial blood pressure after Landiolol bolus administration (Lβ -5 mmHg vs. L- -4 mmHg, p = 0.761). Conclusions: A prior chronic intake of β-blockers neither affected the effectiveness of push-dose Landiolol in heart rate or rhythm control nor impacted the difference in heart rate or mean arterial blood pressure before and after the Landiolol boli., Competing Interests: Sebastian Schnaubelt has received speaking and advisory fees from AOP Orphan Pharmaceuticals Corp. (Vienna, Austria) in the past. The company was not involved in the planning, methods, results or discussion of the study. The rest of the authors declare no (potential) conflicts of interest.

Background: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited., Materials and Methods: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus., Results: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ± 1.68 mg/L (mean ± SD) and 106 ± 32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ± 0.03, 0.94 ± 0.46 and 27.1 ± 17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ± 32.1, 1.68 ± 0.72, 22.6 ± 11.0 and 650 ± 426 mg·h/L, respectively., Conclusion: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown., Objectives: To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients., Patients and Methods: Five neurocritical care patients received 600 mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe., Results: The median fAUC0-24 was 57.6 (24.9-365) mg·h/L in plasma, 64.1 (43.5-306.1) mg·h/L in CSF, and 27.0 (10.7-217.6) mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain&#95;or&#95;CSF/fAUCplasma) was 0.5 (0.25-0.81) for cerebral ISF and 0.92 (0.79-1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).The median fAUC0-24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5 mg/L, and in cerebral ISF for MICs of ≤0.25 mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5 mg/L, and in plasma and cerebral ISF for MICs of ≤0.25 mg/L., Conclusions: Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: APN01 is a soluble recombinant human angiotensin-converting enzyme 2 (rhACE2), a key player in the renin-aldosterone-angiotensin system (RAAS). In clinical studies, APN01 was administered intravenously only, so far. The aim of this study (ClinicalTrials.gov: NCT05065645) was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of inhaled APN01., Methods: This was a phase I, double-blind, placebo-controlled, dose-escalation study. Inhalation was conducted via a nebuliser over 15 min in three single ascending dose (SAD) cohorts (n=24) and two multiple ascending dose (MAD) cohorts (n=16: every 12 h for 7 days). Doses in the SAD cohort were 1.25, 2.5 and 5 mg·mL -1 ; doses in the MAD cohort were 2.5 and 5 mg·mL -1 . Safety (including adverse events (AEs), laboratory findings and lung function results), PK and PD data were assessed., Results: In the SAD and MAD cohorts, treatment-related AEs were slightly more frequent in the active treatment group than in the placebo group. AEs were mild to moderate, with no dose-limiting toxicities. No clinically relevant changes in lung function and laboratory results were observed. The mean maximum observed plasma concentration ( C max ) values after single and multiple doses of 5 mg·mL -1 APN01 were 1.88 and 6.61 ng·mL -1 , respectively. Among the PD variables, significance was found for ACE2 and angiotensin 1-5., Conclusions: The application of aerosolised APN01 is safe and well tolerated after single and multiple doses. By achieving a high local concentration in the lungs and low systemic bioavailability, inhaled rhACE2 may present a therapeutic option in ACE2-related diseases., Competing Interests: Conflict of interest: This work was supported by Apeiron Biologics and conducted as contract research at the Medical University of Vienna, Department of Pulmology and Department of Clinical Pharmacology. The funder did not have any role in the execution of the study or interpretation of data. The academic authors declare no conflict of interest., (Copyright ©The authors 2024.)

Background: Pathophysiological changes in severely burned patients alter the pharmacokinetics (PK) of anti-infective agents, potentially leading to subtherapeutic concentrations at the target site. Albumin supplementation, to support fluid resuscitation, may affect pharmacokinetic properties by binding drugs. This study aimed to investigate the PK of piperacillin/tazobactam in burn patients admitted to the ICU before and after albumin substitution as total and unbound concentrations in plasma., Patients and Methods: Patients admitted to the ICU and scheduled for 4.5 g piperacillin/tazobactam administration and 200 mL of 20% albumin substitution as part of clinical routine were included. Patients underwent IV microdialysis, and simultaneous arterial plasma sampling, at baseline and multiple timepoints after drug administration. PK analysis of total and unbound drug concentrations under steady-state conditions was performed before and after albumin supplementation., Results: A total of seven patients with second- to third-degree burns involving 20%-60% of the total body surface were enrolled. Mean (SD) AUC0-8 (h·mg/L) of total piperacillin/tazobactam before and after albumin substitution were 402.1 (242)/53.2 (27) and 521.8 (363)/59.7 (32), respectively. Unbound mean AUC0-8 before and after albumin supplementation were 398.9 (204)/54.5 (25) and 456.4 (439)/64.5 (82), respectively., Conclusions: Albumin supplementation had little impact on the PK of piperacillin/tazobactam. After albumin supplementation, there was a numerical increase in mean AUC0-8 of total and unbound piperacillin/tazobactam, whereas similar Cmax values were observed. Future studies may investigate the effect of albumin supplementation on drugs with a higher plasma protein binding., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Study Objective: The impact of biological sex in peripheral regional anaesthesia is largely unknown. We therefore designed a prospective study in volunteers to investigate the impact of biological sex on pharmacodynamic, pharmacokinetic and morphometric characteristics for peripheral nerve blockade., Methods: The initial study plan was powered to include 90 volunteers to find a difference of 35 min in duration of sensory block (primary outcome variable) with 80% power and alpha error at 5%. After discussions in ethical review, a pilot study of 2 x 12 volunteers from each sex were studied. Female and male volunteers received ultrasound guided nerve blockade with 3.0 mL ropivacaine 7.5 mg mL-1. Sensory duration of blockade, as the primary outcome, was evaluated by pinprick testing. Secondary outcomes were sensory onset time of blockade, pharmacokinetic characteristics and the visibility of ulnar nerves using ultrasound. Analyses included Mann-Whitney U-statistics with P<0.05 (two-sided) as significant., Results: After 24 participants, the median (IQR) duration of sensory blockade was 450 (420; 503) min in women and 480 (450; 510) min in men (P = 0.49). Sensory onset time of blockade, and ultrasound visibility of nerves were also similar between the study groups. The total drug exposure across time (AUC0-infinity) was significantly higher in women (P = 0.017). After a the planned power re-analysis after these 24 study paticipants, which suggested that > 400 subjects would be required with 80% power and alpha error of 5% to find significance for the primary outcome parameter for marginal differences, we terminated the study at this point., Conclusions: We did not detect significant differences between female and male study participants in terms of pharmacodynamic and morphometric characteristics after ultrasound guided ulnar nerve blocks. Women did show significantly greater pharmacokinetic ropivacaine exposures. The results of this study indicate that peripheral regional block pharmacodynamic characteristics are independent of the biological sex, whereas pharmacokinetic parameters are sex-dependent., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Zadrazil et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Peritonitis is a serious complication in patients undergoing automated peritoneal dialysis (APD) that increases morbidity and frequently disqualifies patients from the peritoneal dialysis programme. Ceftazidime/avibactam (CAZ/AVI) is a potential treatment option for APD patients with peritonitis caused by resistant Gram-negative bacteria, but limited data exist on systemic and target-site pharmacokinetics (PK) in patients undergoing APD. This study set out to investigate the PK of CAZ/AVI in plasma and peritoneal dialysate (PDS) of patients undergoing APD., Methods: A prospective, open-label PK study was conducted on eight patients undergoing APD. CAZ/AVI was administered as a single intravenous dose of 2 g/0.5 g over 120 minutes. APD cycles were initiated 15 hours after the study drug administration. Dense PDS and plasma sampling was performed for 24 hours after the start of administration. PK parameters were analysed with population PK modelling. Probability of target attainment (PTA) was simulated for different CAZ/AVI doses., Results: PK profiles of both drugs in plasma and PDS were similar, indicating that the two drugs are well suited for a fixed-dose combination. A two-compartment model best described the PK of both drugs. A single dose of 2 g/0.5 g CAZ/AVI led to concentrations that far exceeded the PK/PD targets of both drugs. In the Monte Carlo simulations, even the lowest dose (750/190 mg CAZ/AVI) achieved a PTA of >90% for MICs up to 8 mg/L (The European Committee on Antimicrobial Susceptibility Testing epidemiological cut-off value for Pseudomonas aeruginosa) in plasma and PDS., Discussion: On the basis of PTA simulations, a dose of 750/190 mg CAZ/AVI would be sufficient to treat plasma and peritoneal fluid infections in patients undergoing APD., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: A population pharmacokinetic model of fosfomycin was developed in healthy volunteers after intravenous administration, and different dosing regimens were evaluated in terms of the probability of target attainment for Escherichia coli using both plasma and urinary pharmacokinetic/pharmacodynamic targets., Methods: Eight healthy men received fosfomycin as both intermittent 8 g q8h and continuous infusion 1 g/h with a loading dose of 8 g in a crossover study design. Dense sampling was conducted during both regimens. Population pharmacokinetic modelling was performed using NONMEM. Monte Carlo simulations were conducted to evaluate the Probability of Target Attainment (PTA) of different dosing regimens using bactericidal (AUC 24h /MIC of 83 and 75%T >MIC ) and bacteriostatic (AUC 24h /MIC of 25) plasma targets and bacteriostatic (AUC 24h /MIC of 3994) urine target., Results: A total of 176 plasma and 86 urine samples were available for PK analysis. A two-compartment model with a urine compartment best described the data. Glomerular filtration rate (GFR) showed a significant correlation with renal clearance and was implemented in the final model. Simulation results show that the dose of 4 g q8h reached 100% of PTA using bactericidal and bacteriostatic targets for MIC up to 16 mg/L., Conclusion: For the clinical breakpoint of 32 mg/L, the standard dosing regimen (4 g q8h) might not be sufficient to reach the bactericidal target. Higher dosing of 8 g q8h as an intermittent infusion or 0.75 g/h as a continuous infusion might be required. Continuous infusion resulted in better attainment of the %T >MIC target than intermittent infusion., (© 2023. The Author(s).)

The present study was carried out to investigate whether PET imaging can be used as a potential substitute for immunohistochemical analysis of tumor samples in prostate cancer (PC) patients. Correlation between imaging signals of 2 PET tracers and the corresponding target structures was assessed. The first tracer was [ 68 Ga]Ga-PSMA (prostate-specific membrane antigen)-HBED-CC ( N , N '-bis [2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine- N , N '-diacetic acid) [ 68 Ga]Ga-PSMA HBED-CC ([ 68 Ga]PSMA), which is already implemented in clinical routines. The second tracer was 16β-[ 18 F]fluoro-5α-dihydrotestosterone (16β-[ 18 F]FDHT), which binds to the androgen receptor (AR). The AR is particularly interesting in PC, because AR expression status and its shift during therapy might directly influence patient care. Methods: This prospective, explorative clinical study included 10 newly diagnosed PC patients. Each patient underwent [ 68 Ga]PSMA PET/MRI and [ 18 F]FDHT PET/MRI scans before prostatectomy. Cancer SUVs were determined and related to background SUVs. After prostatectomy, tumor tissue was sampled, and AR and prostate-specific membrane antigen (PSMA) expression was determined. AR and PSMA expression was evaluated quantitatively with the open-source bioimage analysis software QuPath and with a 4-tier rating system. Correlation between imaging signals and marker expression was statistically assessed. Results: For [ 18 F]FDHT, the SUV max /SUV background ratio showed a significant, strong correlation ( r = 0.72; P = 0.019) with the AR optical density of the correlating tissue sample. The correlation between PSMA optical density and the [ 68 Ga]PSMA SUV max /SUV background ratio was not significant ( P = 0.061), yet a positive correlation trend could be observed ( r = 0.61). SUV max /SUV background ratios were higher for [ 68 Ga]PSMA (mean ± SD, 34.9 ± 24.8) than for [ 18 F]FDHT (4.8 ± 1.2). In line with these findings, the tumor detection rates were 90% for the [ 68 Ga]PSMA PET scan but only 40% for the [ 18 F]FDHT PET scan. The 4-tier rating of PSMA staining intensity yielded very homogeneous results, with values of 3+ for most subjects (90%). AR staining was rated as 1+ in 2 patients (20%), 2+ in 4 patients (40%), and 3+ in 4 patients (40%). Conclusion: [ 18 F]FDHT PET may be useful for monitoring AR expression and alterations in AR expression during treatment of PC patients. This approach may facilitate early detection of treatment resistance and allows for adaptation of therapy to prevent cancer progression. [ 18 F]FDHT PET is inferior to [ 68 Ga]PSMA PET for primary PC diagnosis, but the correlation between [ 68 Ga]PSMA SUVs and PSMA expression is weaker than that between [ 18 F]FDHT and the AR., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: High protein binding (PB) of antibiotics has an impact on their antimicrobial activity. It has been questioned whether in vitro PB determination can capture the dynamic and concentration-dependent PB of highly bound antibiotics., Objectives: This clinical study compared in vitro ultrafiltration (UF) and in vivo IV microdialysis (MD) methods to determine ceftriaxone PB., Methods: Six healthy male volunteers received a single IV 2 g dose of ceftriaxone. Unbound ceftriaxone plasma concentrations were measured with MD and venous plasma sampling with subsequent UF. Pharmacokinetic parameters were determined using non-compartmental pharmacokinetic analysis. Non-linear mixed-effects modelling was used to quantify the PB. The PTA was estimated., Results: The Cmax of ceftriaxone total plasma concentration (297.42 ± 21.0 mg/L) was approximately 5.5-fold higher than for free concentrations obtained with UF (52.83 ± 5.07 mg/L), and only 3.5-fold higher than for free concentrations obtained with MD (81.37 ± 26.93 mg/L). Non-linear, saturable PB binding was confirmed for both UF and MD. Significantly different dissociation constants (Kd) for the albumin/ceftriaxone complex were quantified: in UF it was 23.7 mg/L (95% CI 21.3-26.2) versus 15.9 mg/L (95% CI 13.6-18.6) in MD. Moreover, the estimated number of binding sites (95% CI) per albumin molecule was 0.916 (0.86-0.97) in UF versus 0.548 in MD (0.51-0.59). The PTA obtained with MD was at most 27% higher than with UF., Conclusions: In vitro UF versus in vivo intravasal MD revealed significantly different PB, especially during the distribution phase. The method of PB determination could have an impact on the breakpoint determination and dose optimisation of antibiotics., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The highly β1-selective beta-blocker Landiolol is known to facilitate efficient and safe rate control in non-compensatory tachycardia or dysrhythmia when administered continuously. However, efficacy and safety data of the also-available bolus formulation in critically ill patients are scarce., Methods: We conducted a retrospective cross-sectional study on a real-life cohort of critical care patients, who had been treated with push-dose Landiolol due to sudden-onset non-compensatory supraventricular tachycardia. Continuous hemodynamic data had been acquired via invasive blood pressure monitoring., Results: Thirty patients and 49 bolus applications were analyzed. Successful heart rate control was accomplished in 20 (41%) cases, rhythm control was achieved in 13 (27%) episodes, and 16 (33%) applications showed no effect. Overall, the heart rate was significantly lower (145 (130-150) vs. 105 (100-125) bpm, p < 0.001) in a 90 min post-application observational period in all subgroups. The median changes in blood pressure after the bolus application did not reach clinical significance. Compared with the ventilation settings before the bolus application, the respiratory settings including the required FiO 2 after the bolus application did not differ significantly. No serious adverse events were seen., Conclusions: Push-dose Landiolol was safe and effective in critically ill ICU patients. No clinically relevant impact on blood pressure was noted.

The effects of the human endotoxin challenge on tissue pharmacokinetics are unknown. In the present study, we aimed to assess the effect of the endotoxin challenge on interstitial fluid pharmacokinetics of tedizolid in healthy volunteers using intramuscular microdialysis. Eight healthy male subjects were treated with 200 mg of tedizolid phosphate for 6 days. On Day 6, an intravenous bolus of lipopolysaccharide (LPS) (2 ng/kg body weight) was administered. LPS infusion did not affect plasma pharmacokinetics of tedizolid. In contrast, following LPS infusion, median muscle tissue fAUC (0.83 [0.75-1.15] vs. 1.14 [1.11-1.43] mg × h/L, P = .0078) and muscle tissue fC max (0.15 [0.14-0.19] vs. 0.19 [0.18-0.24] mg/L, P = .0078) were significantly increased by 38% and 24%, respectively. The human endotoxin challenge was associated with increased tissue concentrations of tedizolid, without affecting its plasma concentration-time profile. The human endotoxin challenge combined with microdialysis may be used to investigate the influence of systemic inflammation on tissue pharmacokinetics., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background and Objective: Exhaustive pharmacokinetic (PK) studies in paediatric patients are unavailable for most antibiotics and feasibility of PK studies is limited by challenges, such as low blood volume and venipuncture-related pain. Microdialysis (MD) represents a promising method to overcome these obstacles. The aim of this proof-of-concept study was to develop and validate modified MD catheters that can be used to obtain concentration-time profiles of antibiotics in paediatric patients., Methods: Following extensive in vitro MD experiments, a prospective open-labelled study in ten healthy adult volunteers (HVs) was conducted. Subjects received a single intravenous dose of 1000 mg vancomycin, then plasma and intravascular microdialysate were sampled over 24 h. In vivo MD probe calibration was conducted using the retrodialysis technique. Plasma protein binding was measured using ultrafiltration. Confirmation of the measurements was performed using a Bland-Altman plot, relevant PK parameters were calculated, and a pharmacometric model was established., Results: No safety issues were encountered. The concentration-time curves of microdialysate and plasma measurements showed good alignment. The Bland-Altman plot yielded a mean bias of 0.19 mg/L and 95% limits of agreement of - 9.34 to 9.71 mg/L. A two-compartment model best described plasma PK, model-based estimates for recovery of the MD probes being in high agreement with the observed values. Quantified estimates of fraction unbound were comparable between plasma and microdialysate (p = 0.56)., Conclusions: An innovative MD catheter that can be inserted into small intravenous lines was successfully developed and applied in HV. This proof-of-concept study is encouraging and opens the way to further experiments leading towards future use of MD in paediatric patients., (© 2022. The Author(s).)

Objectives: The efficacy and quality of generic antibacterial drug formulations are often questioned by both healthcare specialists and patients. Therefore, the present study investigated the interchangeability of generic drugs with their originators by comparing bioequivalence parameters and stability data of generic cefepime, linezolid and piperacillin/tazobactam with their respective originator drugs., Methods: In this open-label, randomized, crossover bioequivalence study, three groups of 12 healthy volunteers each received a single intravenous infusion of either 2 g of cefepime or 4.5 g of piperacillin/tazobactam and two generic formulations, or 600 mg of linezolid and one generic formulation. Plasma sampling was performed, with a 5 day washout period between study days. Stability was tested by storing reconstituted generic and originator products according to their own storage specifications and those of the comparator products. All concentrations were measured by LC-MS., Results: Similar ratios of generic/originator (90% CI) Cmax were observed for Cefepime-MIP/Maxipime [93.7 (88.4-99.4)], Cefepime Sandoz/Maxipime [95.9 (89.1-103.2)], Linezolid Kabi/Zyvoxid [104.5 (91.1-119.9)], Piperacillin Kabi/Tazobac [95.9 (90.4-101.7)], Piperacillin Aurobindo/Tazobac [99.7 (84.9-104.7)], Tazobactam Kabi/Tazobac [93.4 (87.4-99.8)] and Tazobactam Aurobindo/Tazobac [97.4 (89.7-105.8)]. Accordingly, similar ratios of AUC0-t were observed for Cefepime-MIP/Maxipime [91.1 (87.6-94.8)], Cefepime Sandoz/Maxipime [97.9 (92.5-103.5)], Linezolid Kabi/Zyvoxid [99.7 (93.3-106.6)], Piperacillin Kabi/Tazobac [92.2 (88.3-96.3)], Piperacillin Aurobindo/Tazobac [99.9 (97.0-102.8)], Tazobactam Kabi/Tazobac [91.4 (86.4-96.7)] and Tazobactam Aurobindo/Tazobac [98.8 (94.3-103.6)]. Stable and similar concentrations were measured for all contiguous substances, regardless of storage conditions., Conclusions: Compared with their respective originator drugs, generic cefepime, linezolid and piperacillin/tazobactam met the predetermined bioequivalence criteria. All formulations were stable under the storage conditions of their respective comparators., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Although temozolomide is widely used in the treatment of childhood central nervous system (CNS) tumors, information on its pharmacokinetic profile in the brain or cerebrospinal fluid (CSF) is sparse. This study aimed at investigating whether measurable and clinically relevant concentrations of temozolomide are reached and maintained in CSF for continuous oral administration in pediatric patients. A population pharmacokinetic model was developed to quantify CSF penetration of temozolomide., Methods: Eleven pediatric CNS tumor patients (aged 4-14 years) treated with oral temozolomide using a metronomic schedule (24-77 mg/m 2 /day) were included. Temozolomide concentrations in 28 plasma samples and 64 CSF samples were analyzed by high-performance liquid chromatography. Population pharmacokinetic modeling and simulations were performed using non-linear mixed effects modeling (NONMEM 7.4.2)., Results: Median temozolomide concentrations in plasma and CSF were 0.96 (range 0.24-5.99) µg/ml and 0.37 (0.06-1.76) µg/ml, respectively. A two-compartment model (central/plasma [1], CSF [2]) with first-order absorption, first-order elimination, and a transit compartment between CSF and plasma adequately described the data. Population mean estimates for clearance (CL) and the volume of distribution in the central compartment (V c ) were 3.29 L/h (95% confidence interval (CI) 2.58-3.95) and 10.5 L (8.17-14.32), respectively. Based on simulations, we found a median area under the concentration vs. time curve ratio (AUC CSF / AUC plasma ratio) of 37%., Conclusion: Metronomic oral temozolomide penetrates into the CSF in pediatric patients, with even higher concentration levels compared to adults., (© 2022. The Author(s).)

Background: Preclinical data suggested anti-inflammatory properties of tedizolid., Objectives: To investigate the influence of tedizolid on the cytokine response to the human endotoxin challenge and the effect of endotoxaemia on the pharmacokinetics and protein binding of tedizolid., Methods: In this cross-over trial, 14 male healthy volunteers underwent two treatment periods: (A) 200 mg of tedizolid phosphate once daily for 6 days (3 days orally and 3 days intravenously), followed by an intravenous bolus of 2 ng/kg body weight of LPS on the last treatment day; and (B) intravenous bolus of LPS (2 ng/kg body weight) without concomitant tedizolid treatment. Participants underwent first period A or B, separated by at least 6 weeks. Plasma was sampled to assess cytokines and the pharmacokinetics of tedizolid., Results: Following the endotoxin challenge, the peak plasma concentration (median [IQR]; 280 [155-502] versus 287 [132-541]  pg/mL; P = 0.875) and AUC0-24 (979 [676-1319] versus 1000 [647-1632]  pg·h/mL; P = 0.638) of interleukin-6 remained unchanged with and without concomitant tedizolid treatment. The peak concentration and AUC0-24 of TNF-α remained also unchanged with and without tedizolid (47 [31-61] versus 54 [27-69]  pg/mL; P = 0.73 and 197 [163-268] versus 234 [146-280]  pg·h/mL; P = 0.875, respectively). The total maximum concentration (mean ± SD; 2.94 ± 0.69 versus 2.96 ± 0.62 mg/L), total AUC0-24 (22.3 ± 3.8 versus 21.1 ± 3.6 mg·h/L) and protein binding (21.4% ± 1.7% versus 21.6% ± 1.9%) of tedizolid were similar with and without the endotoxin challenge., Conclusions: Tedizolid did not attenuate the LPS-induced cytokine response in healthy volunteers. Furthermore, endotoxaemia did not influence the plasma pharmacokinetics of tedizolid., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Inadequate antibiotic exposure in cerebral infections might have detrimental effects on clinical outcome. Commonly, antibiotic concentrations within the CSF were used to estimate cerebral target levels. However, the actual pharmacological active unbound drug concentration beyond the blood-brain barrier is unknown., Objectives: To compare meropenem concentrations in blood, CSF and cerebral microdialysate of neurointensive care patients., Patients and Methods: In 12 patients suffering subarachnoid haemorrhage, 2000 mg of meropenem was administered every 8 h due to an extracerebral infection. Meropenem concentrations were determined in blood, CSF and cerebral microdialysate at steady state (n = 11) and following single-dose administration (n = 5)., Results: At steady state, the free AUC0-8 was 233.2 ± 42.7 mg·h/L in plasma, 7.8 ± 1.9 mg·h/L in CSF and 26.6 ± 14.0 mg·h/L in brain tissue. The brain tissue penetration ratio (AUCbrain/AUCplasma) was 0.11 ± 0.06, which was more than 3 times higher than in CSF (0.03 ± 0.01), resulting in an AUCCSF/AUCbrain ratio of 0.41 ± 0.16 at steady state. After single-dose administration similar proportions were achieved (AUCbrain/AUCplasma = 0.09 ± 0.08; AUCCSF/AUCplasma = 0.02 ± 0.00). Brain tissue concentrations correlated well with CSF concentrations (R = 0.74, P < 0.001), but only moderately with plasma concentrations (R = 0.51, P < 0.001). Bactericidal thresholds were achieved in both plasma and brain tissue for MIC values ≤16 mg/L. In CSF, bactericidal effects were only reached for MIC values ≤1 mg/L., Conclusions: Meropenem achieves sufficient bactericidal concentrations for the most common bacterial strains of cerebral infections in both plasma and brain tissue, even in non-inflamed brain tissue. CSF concentrations would highly underestimate the target site activity of meropenem beyond the blood-brain barrier., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Ablative fractional laser treatment facilitates epidermal drug delivery, which might be an interesting option to increase the topical efficacy of biological drugs in a variety of dermatological diseases. This work aims at investigating safety and tolerability of this new treatment approach in patients with plaque-type psoriasis. Eight patients with plaque-type psoriasis were enrolled in this study. All patients received (i) ablative fractional laser microporation (AFL) of a psoriatic lesion with an Er:YAG laser + etanercept (ETA; Enbrel® solution for injection) (AFL-ETA), (ii) ETA alone on another lesion, and, if feasible, (iii) AFL alone on an additional lesion. Overall, all treatment arms showed a favorable safety profile. AFL-ETA improved the lesion-specific TPSS score by 1.75 vs. baseline, whereas ETA or AFL alone showed a TPSS score improvement of 0.75 points, a difference that was not statistically significant and might be attributable to differences in baseline scores. Topical administration of ETA to psoriatic plaques via AFL-generated micropores was generally well-tolerated. No special precautions seem necessary in future studies. Clinical benefit will need assessment in sufficiently powered follow-up studies., Competing Interests: VL is employed by Takeda, CB is consultant to Takeda. WB and RB are founders of Pantec Biosolutions AG and MBo serves as an advisor for Pantec Biosolutions AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bauer, Lackner, Matzneller, Al Jalali, Pajenda, Ling, Böhler, Braun, Braun, Boesch, Brunner and Zeitlinger.)

Objectives: The efficacy of an anti-infective drug is influenced by its protein binding (PB), since only the free fraction is active. We hypothesized that PB may vary in vitro and in vivo, and used clindamycin, a drug with high and concentration-dependent PB to investigate this hypothesis., Methods: Six healthy volunteers received a single intravenous infusion of clindamycin 900 mg. Antibiotic plasma concentrations were obtained by blood sampling and unbound drug concentrations were determined by means of in vivo intravascular microdialysis (MD) or in vitro ultrafiltration (UF) for up to 8 h post dosing. Clindamycin was assayed in plasma and MD fluid using a validated HPLC-UV (ultraviolet) method. Non-linear mixed effects modelling in NONMEM® was used to quantify the PB in vivo and in vitro., Results: C max was 14.95, 3.39 and 2.32 mg/L and AUC0-8h was 41.78, 5.80 and 6.14 mg·h/L for plasma, ultrafiltrate and microdialysate, respectively. Calculated ratio of AUCunbound/AUCtotal showed values of 13.9%±1.8% and 14.7%±3.1% for UF and microdialysate, respectively. Modelling confirmed non-linear, saturable PB for clindamycin with slightly different median (95% CI) dissociation constants (Kd) for the alpha-1 acid glycoprotein (AAG)-clindamycin complex of 1.16 mg/L (0.91-1.37) in vitro versus 0.85 mg/L (0.58-1.01) in vivo. Moreover, the estimated number of binding sites per AAG molecule was 2.07 (1.79-2.25) in vitro versus 1.66 in vivo (1.41-1.79)., Conclusions: Concentration-dependent PB was observed for both investigated methods with slightly lower levels of unbound drug fractions in vitro as compared with in vivo., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Continuous infusion (CON) of fosfomycin has been proposed as potentially advantageous in certain clinical scenarios. However, no clinical data on the pharmacokinetics (PK) of fosfomycin after CON are available to date. This study aimed to investigate the PK of fosfomycin after CON and compare it with intermittent infusion (INT) of fosfomycin. A randomized two-way crossover study including 8 healthy male volunteers was performed. Each subject received fosfomycin as INT of 8 g over 30 min every 8 h and, separated by a washout period, as CON of 1 g/h preceded by a loading dose of 8 g over 30 min. PK sampling was performed for 18 and 24 h in the CON and INT groups, respectively. Fosfomycin was generally well tolerated. However, 2 out of 8 subjects (25%) developed thrombophlebitis at the infusion site following CON, which was prevented in the following subjects with a simultaneous coinfusion of Ringer's lactate. The steady-state maximum concentration of drug in serum ( C max ) and area under the concentration-time curve from 0 to 24 h at steady state (AUC SS,0-24 ) of fosfomycin after INT were 551.5 ± 67.8 mg/liter and 3,678.5 ± 601.9 h · mg/liter, respectively. CON led to an average steady-state concentration of 183.8 ± 35.9 mg/liter, resulting in a calculated AUC SS,0-24 of 4,411.2 ± 862.4 h · mg/liter, which was 1.2-fold higher than that with INT. CON resulted in a 100% T >MIC (time during which the drug concentration exceeds the MIC) for MICs of ≤128 mg/liter, whereas the % T >MIC for INT was only 44% for an MIC of 128 mg/liter. CON of fosfomycin led to improved PK and PK/pharmacodynamic (PD) determinants in plasma of healthy volunteers. The clinical relevance of these findings remains to be investigated in patients., (Copyright © 2020 American Society for Microbiology.)

About one-sixth of the world's population is affected by a neglected tropical disease as defined by the World Health Organization and Center for Disease Control. Parasitic diseases comprise most of the neglected tropical disease list and they are causing enormous amounts of disability, morbidity, mortality, and healthcare costs worldwide. The burden of disease of the top five parasitic diseases has been estimated to amount to a total 23 million disability-adjusted life-years. Despite the massive health and economic impact, most drugs currently used for the treatment of parasitic diseases have been developed decades ago and insufficient novel drugs are being developed. The current review provides a compilation of the systemic and target-site pharmacokinetics of established antiparasitic drugs. Knowledge of the pharmacokinetic profile of drugs allows for the examination and possibly optimization of existing dosing schemes. Many symptoms of parasitic diseases are caused by parasites residing in different host tissues. Penetration of the antiparasitic drug into these tissues, the target site of infection, is a prerequisite for a successful treatment of the disease. Therefore, for the examination and improvement of established dosing regimens, not only the plasma but also the tissue pharmacokinetics of the drug have to be considered. For the current paper, almost 7000 scientific articles were identified and screened from which 429 were reviewed in detail and 100 were included in this paper. Systemic pharmacokinetics are available for most antiparasitic drugs but in many cases, not for all the relevant patient populations and only for single- or multiple-dose administration. Systemic pharmacokinetic data in patients with organ impairment and target-site pharmacokinetic data for relevant tissues and body fluids are mostly lacking. To improve the treatment of patients with parasitic diseases, research in these areas is urgently needed.

Purpose: Fungal central nervous system (CNS) infections show a high mortality rate and only a few antifungal agents are available to treat these infections. We hypothesize that the different biochemical properties of human cerebrospinal fluid (CSF) compared to the standard growth medium lead to the altered activity of antifungal agents in CSF. We investigated the in vitro activity of two of these agents, i.e., amphotericin B (AmB) and voriconazole (VOR), against three different fungi in CSF in comparison to sabouraud-dextrose broth (SDB)., Methods: CSF samples from patients who did not receive any antibiotics were collected. Time-kill curves were performed in CSF and SDB using static antibiotic concentrations of AmB and VOR against ATCC strains of Candida albicans, Candida krusei, and Cryptococcus neoformans., Results: In our experiments, both AmB and VOR showed superior activity in SDB compared to CSF. Nevertheless, AmB achieved fungicidal activity in CSF after 24 h against all test strains. Voriconazole only achieved fungistatic activity against C. albicans and C. neoformans in CSF., Conclusions: In summary, our data demonstrate that growth of fungal pathogens but even more importantly activity of antifungal agents against Candida and Cryptococcus species can differ significantly in CSF compared to the standard growth medium. Both findings should be taken into consideration when applying PK/PD simulations to fungal infections of the CNS.

Telavancin was discovered by modifying the chemical structure of vancomycin and belongs to the group of lipoglycopeptides. It employs its antimicrobial potential through two distinct mechanisms of action: inhibition of bacterial cell wall synthesis and induction of bacterial membrane depolarization and permeabilization. In this article we review the clinically relevant pharmacokinetic and pharmacodynamic data of telavancin. For comparison, the pharmacokinetic and pharmacodynamic data of the other glycopeptides are presented. Although, in contrast to the newer lipoglycopeptides, telavancin demonstrates a relatively short half-life and rapid total clearance, its apparent volume of distribution (V d ) is almost identical to that of dalbavancin. The accumulation of telavancin after repeated dosing is only marginal, whereas the pharmacokinetic values of the other glycopeptides show much greater differences after administration of multiple doses. Despite its high plasma-protein binding of 90% and relatively low V d of approximately 11 L, telavancin shows near complete equilibration of the free fraction in plasma with soft tissue. The ratio of the area under the plasma concentration-time curve from time zero to 24 h (AUC 24 ) of unbound plasma concentrations to the minimal inhibitory concentration (MIC) required to inhibit growth of 90% of organisms (MIC 90 ) of Staphylococcus aureus and S. epidermidis of telavancin are sufficiently high to achieve pharmacokinetic/pharmacodynamic targets indicative for optimal bacterial killing. Considering both the AUC 24 /MIC ratios of telavancin and the near complete equilibration of the free fraction in plasma with soft tissue, telavancin is an appropriate antimicrobial agent to treat soft tissue infections caused by Gram-positive pathogens. Although the penetration of telavancin into epithelial lining fluid (ELF) requires further investigations, the AUC 24 /MIC ratio for S. aureus indicates that bactericidal activity in the ELF could be expected.