Publications by authors named "Markus Zeitlinger"

187 Publications

Diclofenac in vitro microdialysis study comparing different experimental setups to improve quantitative recovery.

Basic Clin Pharmacol Toxicol 2022 Jan 19. Epub 2022 Jan 19.

Department of Clinical Pharmacology, Medical University of Vienna, Austria.

Several studies investigated diclofenac tissue concentrations using microdialysis (MD). However, thorough evaluations of the optimal MD setup for diclofenac are unavailable. Thus, this in vitro MD study aimed to compare different setups to improve quantitative recovery of diclofenac. In forward and reverse in vitro MD experiments with diclofenac at two concentrations (1ng/mL and 100ng/mL), the perfusion solutions physiological saline 0.9% (PS) and human albumin 1% (HSA) were compared using tissue probes (10-mm membrane) and customized intravenous (iv) probes (30-mm membrane). Using PS, the mean relative recovery of diclofenac at 1 ng/ml was 1.6±0.04% and 3.12±0.00% with the tissue probe and the iv probe, respectively. The respective mean relative recovery for diclofenac at 100ng/mL was 0.02±0.01% and 0.21±0.11%. Using HSA, the mean relative recovery was 314±25% (tissue probe) and 1064±97% (iv probe) for diclofenac at 1 ng/ml and 444±91% and 1415±217% for diclofenac at 100ng/ml. In reverse dialysis using PS, the mean relative loss of diclofenac was 99.2±0.5% (tissue probe) and 95.8±1.7% (iv probe). Using HSA, the mean relative loss was -4.4±7.2% and 0.2±7.5%, respectively. PS and HSA were not suitable perfusion solutions for quantification of absolute diclofenac concentrations. Despite methodological challenges, HSA may be used for comparative experiments or bioequivalence studies.
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http://dx.doi.org/10.1111/bcpt.13709DOI Listing
January 2022

Additional heterologous versus homologous booster vaccination in immunosuppressed patients without SARS-CoV-2 antibody seroconversion after primary mRNA vaccination: a randomised controlled trial.

Ann Rheum Dis 2022 Jan 13. Epub 2022 Jan 13.

Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

Objectives: SARS-CoV-2-induced COVID-19 has led to exponentially rising mortality, particularly in immunosuppressed patients, who inadequately respond to conventional COVID-19 vaccination.

Methods: In this blinded randomised clinical trial, we compare the efficacy and safety of an additional booster vaccination with a vector versus mRNA vaccine in non-seroconverted patients. We assigned 60 patients under rituximab treatment, who did not seroconvert after their primary mRNA vaccination with either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), to receive a third dose, either using the same mRNA or the vector vaccine ChAdOx1 nCoV-19 (Oxford-AstraZeneca). Patients were stratified according to the presence of peripheral B cells. The primary efficacy endpoint was the difference in the SARS-CoV-2 antibody seroconversion rate between vector (heterologous) and mRNA (homologous) vaccinated patients by week 4. Key secondary endpoints included the overall seroconversion and cellular immune response; safety was assessed at week 1 and week 4.

Results: Seroconversion rates at week 4 were comparable between vector (6/27 patients, 22%) and mRNA (9/28, 32%) vaccines (p=0.6). Overall, 27% of patients seroconverted; specific T cell responses were observed in 20/20 (100%) vector versus 13/16 (81%) mRNA vaccinated patients. Newly induced humoral and/or cellular responses occurred in 9/11 (82%) patients. 3/37 (8%) of patients without and 12/18 (67%) of the patients with detectable peripheral B cells seroconverted. No serious adverse events, related to immunisation, were observed.

Conclusions: This enhanced humoral and/or cellular immune response supports an additional booster vaccination in non-seroconverted patients irrespective of a heterologous or homologous vaccination regimen.
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http://dx.doi.org/10.1136/annrheumdis-2021-221558DOI Listing
January 2022

A versatile high-performance LC-MS/MS assay for the quantification of voriconazole and its N-oxide metabolite in small sample volumes of multiple human matrices for biomedical applications.

J Pharm Biomed Anal 2021 Dec 24;210:114551. Epub 2021 Dec 24.

Department of Clinical Pharmacy & Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstraße 31, 12169 Berlin, Germany. Electronic address:

Voriconazole (VRC) pharmacokinetics, in particular its complex metabolism, is still not fully understood which challenges its optimal therapeutic use. To increase knowledge on the pharmacokinetics of this antifungal drug, it is essential to broaden the perspective and expand in vitro and clinical in vivo investigations in particular to aspects such as unbound plasma, target-site and metabolite concentrations. Innovative sampling approaches such as microdialysis, a minimally-invasive technique for the analysis of compound concentrations in target-site human tissue fluids, are associated with bioanalytical challenges, i.e. small sample volumes and low concentrations. Thus, a bioanalytical LC-MS/MS assay for the simultaneous quantification of VRC and its main N-oxide (NO) metabolite in human plasma, ultrafiltrate and microdialysate was developed and validated according to the European Medicines Agency guideline. Quantification was rapid, simple and feasible for clinically relevant concentrations from 5 to 5000 ng/mL in plasma and ultrafiltrate as well as from 4 to 4000 ng/mL in microdialysate. Due to the high sensitivity of the assay, only 20 µL of plasma or ultrafiltrate and 5 µL of microdialysate were required. For VRC and NO in all matrices, between-run accuracy was high with a maximum mean deviation of 7.0% from the nominal value and between-run precision was demonstrated by ≤ 11.8% coefficient of variation. Both compounds proved stable under various conditions. The assay suitability was demonstrated by the application to a clinical study quantifying simultaneously VRC and NO concentrations in plasma, ultrafiltrate and microdialysate. Additionally, the assay was successfully adapted for pharmacokinetic analyses in human tissue-derived in vitro experiments. Overall, by reducing the required sample volume, the bioanalytical method allows for an increased number of plasma samples in vulnerable populations, e.g. infants, and enables the generation of concentration-time profiles with a higher temporal resolution in microdialysis studies. Consequently, the developed assay is apt to elucidate the complex pharmacokinetics of VRC in clinical settings as prerequisite for therapy optimisation.
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http://dx.doi.org/10.1016/j.jpba.2021.114551DOI Listing
December 2021

Microdosing as a Potential Tool to Enhance Clinical Development of Novel Antibiotics: A Tissue and Plasma PK Feasibility Study with Ciprofloxacin.

Clin Pharmacokinet 2022 Jan 7. Epub 2022 Jan 7.

Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Background And Objective: In microdose studies, drug pharmacokinetics is measured in humans after administration of subtherapeutic doses. While previous microdose studies focused primarily on plasma pharmacokinetics, we set out to evaluate the feasibility of microdosing for a pharmacokinetic assessment in subcutaneous tissue and epithelial lining fluid.

Methods: Healthy subjects received a single intravenous bolus injection of a microdose of [C]ciprofloxacin (1.1 µg, 7 kBq) with (cohort A, n = 9) or without (cohort B, n = 9) a prior intravenous infusion of a therapeutic dose of unlabeled ciprofloxacin (400 mg). Microdialysis and bronchoalveolar lavage were applied for determination of subcutaneous and intrapulmonary drug concentrations. Microdose [C]ciprofloxacin was quantified by accelerator mass spectrometry and therapeutic-dose ciprofloxacin by liquid chromatography-tandem mass spectrometry.

Results: The pharmacokinetics of therapeutic-dose ciprofloxacin (cohort A) in plasma, subcutaneous tissue, and epithelial lining fluid was in accordance with previous data. In plasma and subcutaneous tissue, the dose-adjusted area under the concentration-time curve of microdose ciprofloxacin was similar in cohorts A and B and within an 0.8-fold to 1.1-fold range of the area under the concentration-time curve of therapeutic-dose ciprofloxacin. Penetration of microdose ciprofloxacin into subcutaneous tissue was similar in cohorts A and B and comparable to that of therapeutic-dose ciprofloxacin with subcutaneous tissue-to-plasma area under the concentration-time curve ratios of 0.44, 0.44, and 0.38, respectively. Penetration of microdose ciprofloxacin into epithelial lining fluid was highly variable and failed to predict the epithelial lining fluid penetration of therapeutic-dose ciprofloxacin.

Conclusions: Our study confirms the feasibility of microdosing for pharmacokinetic measurements in plasma and subcutaneous tissue. Microdosing combined with microdialysis is a potentially useful tool in clinical antimicrobial drug development, but its applicability for the assessment of pulmonary pharmacokinetics with bronchoalveolar lavage requires further studies.

Clinical Trial Registration: ClinicalTrials.gov NCT03177720 (registered 6 June, 2017).
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http://dx.doi.org/10.1007/s40262-021-01091-1DOI Listing
January 2022

Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time-Kill Approaches.

Antibiotics (Basel) 2021 Dec 4;10(12). Epub 2021 Dec 4.

Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from a target site perspective. The most common approach involves calculating the probability of attaining animal-derived PK/PD index targets, which link PK parameters to antimicrobial susceptibility measures. This approach is time efficient but ignores some aspects of the shape of the PK profile and inter-species differences in drug clearance and distribution, and provides no information on the PD time-course. Time-kill curves, in contrast, depict bacterial response over time. In vitro dynamic time-kill setups allow for the evaluation of bacterial response to clinical PK profiles, but are not representative of the infection site environment. The translational value of in vivo time-kill experiments, conversely, is limited from a PK perspective. Computational PK/PD models, especially when developed using both in vitro and in vivo data and coupled to target site PK models, can bridge translational gaps in both PK and PD. Ultimately, clinical PK and experimental and computational tools should be combined to tailor antibiotic treatment strategies to the site of infection.
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http://dx.doi.org/10.3390/antibiotics10121485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8698708PMC
December 2021

All-cause mortality rates in adults with carbapenem-resistant Gram-negative bacterial infections: a comprehensive review of pathogen-focused, prospective, randomized, interventional clinical studies.

Expert Rev Anti Infect Ther 2022 Jan 12:1-13. Epub 2022 Jan 12.

Infectious Disease Drug Development Consulting, LLC, Easton, CT, USA.

Introduction: Pathogen-focused, randomized, controlled trials (PF-RCT) are important in the fight against carbapenem-resistant (CR) Gram-negative infections. Some recently approved antibiotics and older generic antibiotics with activity against CR Gram-negative bacteria were investigated in PF-RCTs in a variety of infections.

Areas Covered: We searched Pubmed, Cochrane database and international clinical trial databases for PF-RCTs for the period between 2005 and 2020 and compared the study designs, patient populations, infection types, pathogens, and Day-28 all-cause mortality (ACM).

Expert Opinion: PF-RCTs are particularly challenging to quantitatively assess and compare due to the heterogeneity in infection types, pathogens, CR mechanism, inclusion/exclusion criteria, and endpoints. Data interpretation is further complicated by lack of formal statistical analysis plans and/or non-inferiority design, and limited power across most PF-RCTs. The studies with new antibiotics (i.e. plazomicin, meropenem/vaborbactam, cefiderocol) ranked lower regarding feasibility, with relatively small sample sizes (analyzed: 37-118) versus the comparative effectiveness studies of older generic drugs (analyzed: 94-406). ACM ranged between 11.8% and 40% for CR Enterobacterales, 17.7% and 57.4% for CR spp., and 20.0% and 30.8% for CR . The information gathered must be considered carefully alongside the study limitations and caution should be exercised when making direct comparisons across trials.PLAIN LANGUAGE SUMMARYNew antibiotics to treat multidrug-resistant Gram-negative bacterial infections are needed because antimicrobial resistance has become a global threat. In recent years, several pathogen-focused, randomized, controlled clinical trials were conducted to test new antibiotics or combinations of older generic antibiotics in the fight against resistant bacteria. However, these trials were exceptionally challenging and most of them enrolled relatively few patients. These studies were highly heterogeneous in terms of species, antibiotics, infection site, mechanism of resistance, endpoints and patient factors. In these trials, all-cause mortality at Day 28 or Day 30 were numerically lower with the new antibiotics in infections caused by carbapenem-resistant (CR) Enterobacterales. However, in the trials which investigated CR spp. infections, there was no reduction in all-cause mortality at Day 28 or Day 30 with combinations of older generic antibiotics compared with colistin monotherapy. Limited information was available for CR . More pathogen-focused, randomized, controlled clinical trials with more feasible design and higher patient numbers are needed to demonstrate clinical benefit in drug-resistant infections.
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http://dx.doi.org/10.1080/14787210.2022.2020099DOI Listing
January 2022

Comparative Plasma and Interstitial Tissue Fluid Pharmacokinetics of Meropenem Demonstrate the Need for Increasing Dose and Infusion Duration in Obese and Non-obese Patients.

Clin Pharmacokinet 2021 Dec 11. Epub 2021 Dec 11.

Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany.

Background And Objectives: A quantitative evaluation of the PK of meropenem, a broad-spectrum β-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of obese patients is lacking as of date. The objective of this study was the characterisation of meropenem population pharmacokinetics in plasma and ISF in obese and non-obese patients for identification of adequate dosing regimens via Monte-Carlo simulations.

Methods: We obtained plasma and microdialysate concentrations after administration of meropenem 1000 mg to 15 obese and 15 non-obese surgery patients from a prospective clinical trial. After characterizing plasma- and microdialysis-derived ISF pharmacokinetics via population pharmacokinetic analysis, we simulated thrice-daily (TID) meropenem short-term (0.5 h), prolonged (3.0 h), and continuous infusions. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) analysis based on time unbound concentrations exceeded minimum inhibitory concentrations (MIC) on treatment day 1 (%fT) and the sum of PTA weighted by relative frequency of MIC values for infections by pathogens commonly treated with meropenem. To avoid interstitial tissue fluid concentrations below MIC for the entire dosing interval during continuous infusions, a more conservative PK/PD index was selected (%fT).

Results: Adjusted body weight (ABW) and calculated creatinine clearance (CLCR) of all patients (body mass index [BMI] = 20.5-81.5 kg/m) explained a considerable proportion of the between-patient pharmacokinetic variability (15.1-31.0% relative reduction). The ISF:plasma ratio of %fT  was relatively similar for MIC ≤ 2 mg/L but decreased for MIC = 8 mg/L over ABW = 60-120 kg (0.50-0.20). Steady-state concentrations were 2.68 times (95% confidence interval [CI] = 2.11-3.37) higher in plasma than in ISF, supporting PK/PD targets related to four times the MIC during continuous infusions to avoid suspected ISF concentrations constantly below the MIC. A 3000 mg/24 h continuous infusion was sufficient at MIC = 2 mg/L for patients with CLCR ≤ 100 mL/min and ABW < 90 kg, whereas 2000 mg TID prolonged infusions were adequate for those with CLCR ≤ 100 mL/min and ABW > 90 kg. For MIC = 2 mg/L and %fT = 95, PTA was adequate in patients over the entire investigated range of body mass and renal function using a 6000 mg continuous infusion. A prolonged infusion of meropenem 2000 mg TID was sufficient for MIC ≤ 8 mg/L and all investigated ABW and CLCR when employing the PK/PD target %fT  = 40. Short-term infusions of 1000 mg TID were sufficient for CLCR ≤ 130 mL/min and distributions of MIC values for Escherichia coli, Citrobacter freundii, and Klebsiella pneumoniae but not for Pseudomonas aeruginosa.

Conclusions: This analysis indicated a need for higher doses (≥ 2000 mg) and prolonged infusions (≥ 3 h) for obese and non-obese patients at MIC ≥ 2 mg/L. Higher PTA was achieved with prolonged infusions in obese patients and with continuous infusions in non-obese patients.

Trial Registration: EudraCT: 2012-004383-22.
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http://dx.doi.org/10.1007/s40262-021-01070-6DOI Listing
December 2021

Anticoagulant Treatment Regimens in Patients with Covid-19: A Meta-Analysis.

Clin Pharmacol Ther 2021 Dec 4. Epub 2021 Dec 4.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state. It has been hypothesized that higher-dose anticoagulation, including therapeutic-dose and intermediate-dose anticoagulation, is superior to prophylactic-dose anticoagulation in the treatment of COVID-19. This meta-analysis evaluated the efficacy and safety of higher-dose anticoagulation compared with prophylactic-dose anticoagulation in patients with COVID-19. Ten randomized controlled open-label trials with a total of 5,753 patients were included. The risk of death and net adverse clinical events (including death, thromboembolic events, and major bleeding) were similar between higher-dose and prophylactic-dose anticoagulation (risk ratio (RR) 0.96, 95% CI, 0.79-1.16, P = 0.66 and RR 0.87, 95% CI, 0.73-1.03, P = 0.11, respectively). Higher-dose anticoagulation, compared with prophylactic-dose anticoagulation, decreased the risk of thromboembolic events (RR 0.63, 95% CI, 0.47-0.84, P = 0.002) but increased the risk of major bleeding (RR 1.76, 95% CI, 1.19-2.62, P = 0.005). The risk of death showed no statistically significant difference between higher-dose anticoagulation and prophylactic-dose anticoagulation in noncritically ill patients (RR 0.87, 95% CI, 0.50-1.52, P = 0.62) and in critically ill patients with COVID-19 (RR 1.04, 95% CI, 0.93-1.17, P = 0.5). The risk of death was similar between therapeutic-dose vs. prophylactic-dose anticoagulation (RR 0.92, 95% CI 0.69-1.21, P = 0.54) and between intermediate-dose vs. prophylactic-dose anticoagulation (RR 1.01, 95% CI 0.63-1.61, P = 0.98). In patients with markedly increased d-dimer levels, higher-dose anticoagulation was also not associated with a decreased risk of death as compared with prophylactic-dose anticoagulation (RR 0.86, 95% CI, 0.64-1.16, P = 0.34). Without any clear evidence of survival benefit, these findings do not support the routine use of therapeutic-dose or intermediate-dose anticoagulation in critically or noncritically ill patients with COVID-19.
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http://dx.doi.org/10.1002/cpt.2504DOI Listing
December 2021

Comparison of non-invasive Staphylococcus aureus sampling methods on lesional skin in patients with atopic dermatitis.

Eur J Clin Microbiol Infect Dis 2022 Feb 4;41(2):245-252. Epub 2021 Nov 4.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

There is evidence that Staphylococcus aureus colonisation is linked to severity of atopic dermatitis. As no gold standard for S. aureus sampling on atopic dermatitis skin lesions exists, this study compared three commonly used methods. In addition, effectiveness of standard skin disinfection to remove S. aureus colonisation from these inflamed skin lesions was investigated. In 30 atopic dermatitis patients, three different S. aureus sampling methods, i.e. detergent scrubbing, moist swabbing and tape stripping, were performed on naïve and disinfected skin lesions. Two different S. aureus selective media, mannitol salt agar and chromID agar, were used for bacterial growing. Quantifying the S. aureus load varied significantly between the different sampling methods on naïve skin lesions ranging from mean 51 to 1.5 × 10 CFU/cm (p < 0.001). The qualitative detection on naïve skin was highest with the two detergent-based techniques (86% each), while for tape stripping, this value was 67% (all on chromID agar). In comparison, mannitol salt agar was less sensitive (p < 0.001). The disinfection of the skin lesions led to a significant reduction of the S. aureus load (p < 0.05) but no complete eradication in the case of previously positive swab. The obtained data highlight the importance of the selected sampling method and consecutive S. aureus selection agar plates to implement further clinical studies for the effectiveness of topical anti-staphylococcal antibiotics. Other disinfection regimes should be considered in atopic dermatitis patients when complete de-colonisation of certain skin areas is required, e.g. for surgical procedures.
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http://dx.doi.org/10.1007/s10096-021-04365-5DOI Listing
February 2022

Precision Reimbursement for Precision Medicine: Using Real-World Evidence to Evolve From Trial-and-Project to Track-and-Pay to Learn-and-Predict.

Clin Pharmacol Ther 2022 Jan 17;111(1):52-62. Epub 2021 Nov 17.

Massachusetts Institute of Technology Center for Biomedical Innovation, Cambridge, Massachusetts, USA.

Basic scientists and drug developers are accelerating innovations toward the goal of precision medicine. Regulators create pathways for timely patient access to precision medicines, including individualized therapies. Healthcare payors acknowledge the need for change but downstream innovation for coverage and reimbursement is only haltingly occurring. Performance uncertainty, high price-tags, payment timing, and actuarial risk issues associated with precision medicines present novel financial challenges for payors. With traditional drug reimbursement frameworks, payment is based on an assumed randomized controlled trial (RCT) projection of real-world effectiveness, a "trial-and-project" strategy; the clinical benefit realized for patients is not usually ascertained ex post by collection of real-world data (RWD). To mitigate financial risks resulting from clinical performance uncertainty, manufacturers and payors devised "track-and-pay" frameworks (i.e., the tracking of a pre-agreed treatment outcome which is linked to financial consequences). Whereas some track-and-pay arrangements have been successful, inherent weaknesses include the potential for misalignment of incentives, the risk of channeling of patients, and a failure to use the RWD generated to enable continuous learning about treatments. "Precision reimbursement" (PR) intends to overcome inherent weaknesses of simple track-and-pay schemes. In combining the collection of RWD with advanced analytics (e.g., artificial intelligence and machine learning) to generate actionable real-world evidence, with prospective alignment of incentives across all stakeholders (including providers and patients), and with pre-agreed use and dissemination of information generated, PR becomes a "learn-and-predict" model of payment for performance. We here describe in detail the concept of PR and lay out the next steps to make it a reality.
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http://dx.doi.org/10.1002/cpt.2471DOI Listing
January 2022

Similar Piperacillin/Tazobactam Target Attainment in Obese versus Nonobese Patients despite Differences in Interstitial Tissue Fluid Pharmacokinetics.

Pharmaceutics 2021 Aug 31;13(9). Epub 2021 Aug 31.

Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 12169 Berlin, Germany.

Precision dosing of piperacillin/tazobactam in obese patients is compromised by sparse information on target-site exposure. We aimed to evaluate the appropriateness of current and alternative piperacillin/tazobactam dosages in obese and nonobese patients. Based on a prospective, controlled clinical trial in 30 surgery patients (15 obese/15 nonobese; 0.5-h infusion of 4 g/0.5 g piperacillin/tazobactam), piperacillin pharmacokinetics were characterized in plasma and at target-site (interstitial fluid of subcutaneous adipose tissue) via population analysis. Thereafter, multiple 3-4-times daily piperacillin/tazobactam short-term/prolonged (recommended by EUCAST) and continuous infusions were evaluated by simulation. Adequacy of therapy was assessed by probability of pharmacokinetic/pharmacodynamic target-attainment (PTA ≥ 90%) based on time unbound piperacillin concentrations exceed the minimum inhibitory concentration (MIC) during 24 h (%T). Lower piperacillin target-site maximum concentrations in obese versus nonobese patients were explained by the impact of lean (approximately two thirds) and fat body mass (approximately one third) on volume of distribution. Simulated steady-state concentrations were 1.43-times, 95%CI = (1.27; 1.61), higher in plasma versus target-site, supporting targets of %T instead of %T during continuous infusion to avoid target-site concentrations constantly below MIC. In all obesity and renally impairment/hyperfiltration stages, at MIC = 16 mg/L, adequate PTA required prolonged (thrice-daily 4 g/0.5 g over 3.0 h at %T = 50) or continuous infusions (24 g/3 g over 24 h following loading dose at %T = 98) of piperacillin/tazobactam.
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http://dx.doi.org/10.3390/pharmaceutics13091380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464843PMC
August 2021

Meropenem concentrations in brain tissue of neurointensive care patients exceed CSF levels.

J Antimicrob Chemother 2021 10;76(11):2914-2922

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

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.
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http://dx.doi.org/10.1093/jac/dkab286DOI Listing
October 2021

Quantitative analysis of human brain microdialysate for target site pharmacokinetics of major anesthetics ketamine, midazolam and propofol.

J Pharm Biomed Anal 2021 Oct 29;205:114289. Epub 2021 Jul 29.

Department of Neurosurgery, Medical University Vienna, Vienna, Austria. Electronic address:

Brain microdialysis samples of intensive care patients treated with the essential anesthetics ketamine, midazolam and propofol were investigated. Importantly, despite decades of clinical use, comprehensive human cerebral pharmacokinetic data of these drugs is still missing. To encounter this apparent lack of knowledge, we combined cerebral microdialysis with leading-edge analytical instrumentation to monitor the neurochemistry of living human patients. For the quantitative analysis, high performing analytical approaches were developed that can handle minute sample volumes and possible ultralow target analyte levels. The developed methods provided detection limits below 100 ng L for all target analytes and high precision (below 4% RSD intraday). Methods were linear between LODs and 100 μg L for ketamine, 75 μg L for midazolam and 10 μg L for propofol respectively, with coefficients of determination R≥ 0.999. Further, being aware of the error-prone and demanding translation of microdialysis levels to interstitial concentrations, in vitro approaches for recovery testing of microdialysis probes as well as internal normalization approaches were conducted. Thus, we herein report the first cerebral pharmacokinetic data of ketamine, midazolam and propofol determined in microdialysis samples of 15 neurointensive care patients. We could prove blood-brain barrier penetration of all of the investigated anesthetics and could correlate applied dosages and actual brain exposition of ketamine. However, we emphasize the need of an expanded prospective study including individual microdialysis recovery testing as well as matched serum and/or cerebrospinal fluid collection for a more comprehensive cerebral pharmacokinetic understanding.
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http://dx.doi.org/10.1016/j.jpba.2021.114289DOI Listing
October 2021

Phase I Study to Assess Safety of Laser-Assisted Topical Administration of an Anti-TNF Biologic in Patients With Chronic Plaque-Type Psoriasis.

Front Med (Lausanne) 2021 16;8:712511. Epub 2021 Jul 16.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

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 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.
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http://dx.doi.org/10.3389/fmed.2021.712511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322842PMC
July 2021

Microdialysis sampling to monitor target-site vancomycin concentrations in septic infants: a feasible way to close the knowledge gap.

Int J Antimicrob Agents 2021 Oct 18;58(4):106405. Epub 2021 Jul 18.

Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.

This work is dedicated to the memory of Hartmut Derendorf (1953-2020), a pioneer of modern pharmacokinetics and valued mentor of this project.

Objectives: Septic infants/neonates need effective antibiotic exposure, but dosing recommendations are challenging as the pharmacokinetics in this age are highly variable. For vancomycin, which is used as a standard treatment, comprehensive pharmacokinetic knowledge especially at the infection site is lacking. Hence, an exploratory clinical study was conducted to assess the feasibility and safety of microdialysis sampling for vancomycin monitoring at the target site.

Methods: Nine infants/neonates with therapeutic indications for vancomycin treatment were administered 15 mg/kg as 1-hour infusions every 8-24 hours. Microdialysis catheters were implanted in the subcutaneous interstitial space fluid of the lateral thigh. Samples were collected every 30 minutes over 24 hours, followed by retrodialysis for catheter calibration. Prior in vitro investigations have evaluated impact factors on relative recovery and retrodialysis.

Results: In vitro investigations showed the applicability of microdialysis for vancomycin monitoring. Microdialysis sampling was well tolerated in all infants/neonates (23-255 days) without major bleeding or other adverse events. Pharmacokinetic profiles were obtained and showed plausible vancomycin concentration-time courses.

Conclusions: Microdialysis as a minimally invasive technique for continuous longer-term sampling is feasible and safe in infants/neonates. Interstitial space fluid profiles were plausible and showed substantial interpatient variation. Hence, a larger microdialysis trial is warranted to further characterise the pharmacokinetics and variability of vancomycin at the target site and ultimately improve vancomycin dosing in these vulnerable patients.
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http://dx.doi.org/10.1016/j.ijantimicag.2021.106405DOI Listing
October 2021

Microdialysis as a potential tool for comparative assessment of tissue pharmacokinetics of two different patches containing lidocaine: A crossover pilot study.

Int J Clin Pharmacol Ther 2021 Sep;59(9):603-609

Objective: Lidocaine 5% patches are approved for the treatment of post-herpetic neuralgia in adults. Little information is available on the penetration of lidocaine into skin and skin-related soft tissue, which are thought to be closer to the site where lidocaine exerts its pharmacological action on neuronal structures. This pilot study investigated subcutaneous and systemic pharmacokinetics of lidocaine during topical application of two different lidocaine 5% patches.

Materials And Methods: This randomized two-way, two-period crossover study assessed lidocaine concentrations in subcutaneous tissue (by microdialysis) and plasma of n = 5 healthy subjects during 12-hour-long applications of a recently developed lidocaine 5% patch (Laboratorios Gebro Pharma, SA, Barcelona, Spain) and a marketed reference patch (Versatis 5% lidocaine patch, Grünenthal, Brunn am Gebirge, Austria), respectively.

Results: Lidocaine was detectable in subcutaneous tissue within 60 minutes from start of patch application, and in plasma only after a marked delay. The test formulation led to increased exposure to lidocaine in both subcutaneous tissue and plasma.

Conclusion: This study has underscored the potential of microdialysis to comparatively assess the pharmacokinetics of two different drug formulations and encourages its further use in this area.
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http://dx.doi.org/10.5414/CP203922DOI Listing
September 2021

ABCB1 and ABCG2 Together Limit the Distribution of ABCB1/ABCG2 Substrates to the Human Retina and the Single Nucleotide Polymorphism Q141K (c.421C> A) May Lead to Increased Drug Exposure.

Front Pharmacol 2021 16;12:698966. Epub 2021 Jun 16.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, VIE, Austria.

The widely expressed and poly-specific ABC transporters breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) are co-localized at the blood-brain barrier (BBB) and have shown to limit the brain distribution of several clinically used ABCB1/ABCG2 substrate drugs. It is currently not known to which extent these transporters, which are also expressed at the blood-retinal barrier (BRB), may limit drug distribution to the human eye and whether the reduced-function single-nucleotide polymorphism (SNP) Q141K (c.421C > A) has an impact on retinal drug distribution. Ten healthy male volunteers (five subjects with the c.421CC and c.421CA genotype, respectively) underwent two consecutive positron emission tomography (PET) scans after intravenous injection of the model ABCB1/ABCG2 substrate [C]tariquidar. The second PET scan was performed with concurrent intravenous infusion of unlabelled tariquidar to inhibit ABCB1 in order to specifically reveal ABCG2 function.In response to ABCB1 inhibition with unlabelled tariquidar, c.421C > A genotype carriers showed significant increases (as compared to the baseline scan) in retinal radiotracer influx (+62 ± 57%, = 0.043) and volume of distribution (+86 ± 131%, = 0.043), but no significant changes were observed in subjects with the c.421C > C genotype. Our results provide the first evidence that ABCB1 and ABCG2 may together limit the distribution of systemically administered ABCB1/ABCG2 substrate drugs to the human retina. Functional redundancy between ABCB1 and ABCG2 appears to be compromised in carriers of the c.421C > A SNP who may therefore be more susceptible to transporter-mediated drug-drug interactions at the BRB than non-carriers.
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http://dx.doi.org/10.3389/fphar.2021.698966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242189PMC
June 2021

Improved immunogenicity against SARS-CoV-2 in a solid-organ transplant recipient by switching vaccines.

Clin Microbiol Infect 2021 10 27;27(10):1529-1530. Epub 2021 Jun 27.

Department of Clinical Pharmacology, Medical University of Vienna, Austria. Electronic address:

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http://dx.doi.org/10.1016/j.cmi.2021.06.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236129PMC
October 2021

EACPT Virtual Meeting 2021.

Eur J Clin Pharmacol 2021 06;77(Suppl 1):1-42

Heart and Vascular Institute, Pennsylvania State University, Milton S. Hershey Medical Center, Hershey, PA, USA.

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http://dx.doi.org/10.1007/s00228-021-03164-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233188PMC
June 2021

Bio-Distribution and Pharmacokinetics of Topically Administered γ-Cyclodextrin Based Eye Drops in Rabbits.

Pharmaceuticals (Basel) 2021 May 18;14(5). Epub 2021 May 18.

Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

The purpose of this study was to evaluate the ocular pharmacokinetics, bio-distribution and local tolerability of γ-cyclodextrin (γCD) based irbesartan 1.5% eye drops and candesartan 0.15% eye drops after single and multiple topical administration in rabbit eyes. In this randomized, controlled study, a total number of 59 New Zealand White albino rabbits were consecutively assigned to two study groups. Group 1 ( = 31) received irbesartan 1.5% and group 2 ( = 28) candesartan 0.15% eye drops. In both groups, single dose and multiple administration pharmacokinetic studies were performed. Rabbits were euthanized at five predefined time points after single-dose administration, whereas multiple-dose animals were dosed for 5 days twice-daily and then euthanized 1 h after the last dose administration. Drug concentration was measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the retinal tissue, vitreous humor, aqueous humor, corneal tissue and in venous blood samples. Pharmacokinetic parameters including maximal drug concentration (C), time of maximal drug concentration (T), half-life and AUC were calculated. To assess local tolerability, six additional rabbits received 1.5% irbesartan eye drops twice daily in one eye for 28 days. Tolerability was assessed using a modified Draize test and corneal sensibility by Cochet Bonnet esthesiometry. Both γCD based eye drops were rapidly absorbed and distributed in the anterior and posterior ocular tissues. Within 0.5 h after single administration, the C of irbesartan and candesartan in retinal tissue was 251 ± 142 ng/g and 63 ± 39 ng/g, respectively. In the vitreous humor, a C of 14 ± 16 ng/g for irbesartan was reached 0.5 h after instillation while C was below 2 ng/g for candesartan. For multiple dosing, the observed C in retinal tissue was 338 ± 124 ng/g for irbesartan and 36 ± 10 ng/g for candesartan, whereas mean vitreous humor concentrations were 13 ± 5 ng/g and <2 ng/g, respectively. The highest plasma concentrations of both irbesartan (C 5.64 ± 4.08 ng/mL) and candesartan (C 4.32 ± 1.04 ng/mL) were reached 0.5 h (T) after single administration. Local tolerability was favorable with no remarkable differences between the treated and the control eyes. These results indicate that irbesartan and candesartan in γCD based nanoparticle eye drops can be delivered to the retinal tissue of the rabbit's eye in pharmacologically relevant concentrations. Moreover, safety and tolerability profiles appear to be favorable in the rabbit animal model.
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http://dx.doi.org/10.3390/ph14050480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158513PMC
May 2021

Inhaled budesonide for early treatment of COVID-19.

Lancet Respir Med 2021 07 12;9(7):e59. Epub 2021 May 12.

Department of Internal Medicine II, Division of Pulmonology, Medical University of Vienna, 1090 Vienna, Austria.

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http://dx.doi.org/10.1016/S2213-2600(21)00215-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115942PMC
July 2021

Protein binding of clindamycin in vivo by means of intravascular microdialysis in healthy volunteers.

J Antimicrob Chemother 2021 07;76(8):2106-2113

Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

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.
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http://dx.doi.org/10.1093/jac/dkab140DOI Listing
July 2021

A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9.

Eur J Clin Pharmacol 2021 Oct 10;77(10):1473-1484. Epub 2021 May 10.

AFFiRiS AG, Karl Farkas Gasse 22, 1030, Vienna, Austria.

Purpose: AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations.

Methods: This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks.

Results: The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%.

Conclusions: Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development.

Trial Registration: EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.
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http://dx.doi.org/10.1007/s00228-021-03149-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440313PMC
October 2021

Perioperative administration of cefazolin and metronidazole in obese and non-obese patients: a pharmacokinetic study in plasma and interstitial fluid.

J Antimicrob Chemother 2021 07;76(8):2114-2120

Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig, Leipzig, Germany.

Objectives: To assess plasma and tissue pharmacokinetics of cefazolin and metronidazole in obese patients undergoing bariatric surgery and non-obese patients undergoing intra-abdominal surgery.

Patients And Methods: Fifteen obese and 15 non-obese patients received an IV short infusion of 2 g cefazolin and 0.5 g metronidazole for perioperative prophylaxis. Plasma and microdialysate from subcutaneous tissue were sampled until 8 h after dosing. Drug concentrations were determined by HPLC-UV. Pharmacokinetic parameters were calculated non-compartmentally.

Results: In obese patients (BMI 39.5-69.3 kg/m2) compared with non-obese patients (BMI 18.7-29.8 kg/m2), mean Cmax of total cefazolin in plasma was lower (115 versus 174 mg/L) and Vss was higher (19.4 versus 14.2 L). The mean differences in t½ (2.7 versus 2.4 h), CL (5.14 versus 4.63 L/h) and AUC∞ (402 versus 450 mg·h/L) were not significant. The influence of obesity on the pharmacokinetics of metronidazole was similar (Cmax 8.99 versus 14.7 mg/L, Vss 73.9 versus 51.8 L, t½ 11.9 versus 9.1 h, CL 4.62 versus 4.13 L/h, AUC∞ 116 versus 127 mg·h/L). Regarding interstitial fluid (ISF), mean concentrations of cefazolin remained >4 mg/L until 6 h in both groups, and those of metronidazole up to 8 h in the non-obese group. In obese patients, the mean ISF concentrations of metronidazole were between 3 and 3.5 mg/L throughout the measuring interval.

Conclusions: During the time of surgery, cefazolin concentrations in plasma and ISF of subcutaneous tissue were lower in obese patients, but not clinically relevant. Regarding metronidazole, the respective differences were higher, and may influence dosing of metronidazole for perioperative prophylaxis in obese patients.
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http://dx.doi.org/10.1093/jac/dkab143DOI Listing
July 2021

Pharmacological and clinical profile of cefiderocol, a siderophore cephalosporin against gram-negative pathogens.

Expert Rev Clin Pharmacol 2021 Jul 26;14(7):777-791. Epub 2021 Apr 26.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

: Increasing resistance of gram-negative bacteria poses a serious threat to global health. Thus, efficacious and safe antibiotics against resistant pathogens are urgently needed. Cefiderocol, a siderophore cephalosporin, addresses this unmet need.: For this article, we screened all preclinical and clinical studies on cefiderocol published by January 2021 on PubMed. Also, regulatory documents, recent conference contributions, and selected data of antibiotic competitors are reviewed. We provide a comprehensive overview of the mode of action, and activity, pharmacokinetics/pharmacodynamics, and human pharmacokinetics. Last, we discuss the efficacy and safety data from the pivotal trials.: Cefiderocol was potent against virtually all gram-negative pathogens and resistance was rare. The target site pharmacokinetics (i.e. urinary and lung penetration) have been well described in humans and important PK/PD targets were reached. In the clinical trials, cefiderocol was non-inferior to carbapenems in the treatment of complicated urinary tract infections and nosocomial pneumonia. Against carbapenem-resistant gram-negative pathogens, cefiderocol was similar to the best available therapy, which was mainly based on the backbone agent colistin. Overall, a substantial body of evidence supports the clinical use of cefiderocol in patients with gram-negative infections and limited treatment options.
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http://dx.doi.org/10.1080/17512433.2021.1917375DOI Listing
July 2021

Which Analysis Approach Is Adequate to Leverage Clinical Microdialysis Data? A Quantitative Comparison to Investigate Exposure and Reponse Exemplified by Levofloxacin.

Pharm Res 2021 Mar 15;38(3):381-395. Epub 2021 Mar 15.

Institute of Pharmacy, Department of Clinical Pharmacy and Biochemistry, Freie Universitaet Berlin, Berlin, Germany.

Purpose: Systematic comparison of analysis methods of clinical microdialysis data for impact on target-site drug exposure and response.

Methods: 39 individuals received a 500 mg levofloxacin short-term infusion followed by 24-h dense sampling in plasma and microdialysate collection in interstitial space fluid (ISF). ISF concentrations were leveraged using non-compartmental (NCA) and compartmental analysis (CA) via (ii) relative recovery correction at midpoint of the collection interval (midpoint-NCA, midpoint-CA) and (ii) dialysate-based integrals of time (integral-CA). Exposure and adequacy of community-acquired pneumonia (CAP) therapy via pharmacokinetic/pharmacodynamic target-attainment (PTA) analysis were compared between approaches.

Results: Individual AUC estimates strongly varied for midpoint-NCA and midpoint-CA (≥52.3%CV) versus integral-CA (≤32.9%CV) owing to separation of variability in PK parameters (midpoint-CA = 46.5%-143%CV, integral-CA = 26.4%-72.6%CV) from recovery-related variability only in integral-CA (41.0%-50.3%CV). This also led to increased variability of AUC for midpoint-CA (56.0%CV) versus midpoint-NCA and integral-CA (≤33.0%CV), and inaccuracy of predictive model performance of midpoint-CA in plasma (visual predictive check). PTA analysis translated into 33% of evaluated patient cases being at risk of incorrectly rejecting recommended dosing regimens at CAP-related epidemiological cut-off values.

Conclusions: Integral-CA proved most appropriate to characterise clinical pharmacokinetics- and microdialysis-related variability. Employing this knowledge will improve the understanding of drug target-site PK for therapeutic decision-making.
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http://dx.doi.org/10.1007/s11095-021-02994-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994214PMC
March 2021

Detrimental effects of intrahospital transport on cerebral metabolism in patients suffering severe aneurysmal subarachnoid hemorrhage.

J Neurosurg 2021 Mar 12:1-8. Epub 2021 Mar 12.

8Department of Neurosurgery, Johannes Kepler University, Linz, Austria.

Objective: Intrahospital transport for CT scans is routinely performed for neurosurgical patients. Particularly in the sedated and mechanically ventilated patient, intracranial hypertension and blood pressure fluctuations that might impair cerebral perfusion are frequently observed during these interventions. This study quantifies the impact of intrahospital patient transport on multimodality monitoring measurements, with a particular focus on cerebral metabolism.

Methods: Forty intrahospital transports in 20 consecutive patients suffering severe aneurysmal subarachnoid hemorrhage (SAH) under continuous intracranial pressure (ICP), brain tissue oxygen tension (pbtO2), and cerebral microdialysis monitoring were prospectively included. Changes in multimodality neuromonitoring data during intrahospital transport to the CT scanner and the subsequent 10 hours were evaluated using linear mixed models. Furthermore, the impact of risk factors at transportation, such as cerebral vasospasm, cerebral hypoxia (pbtO2 < 15 mm Hg), metabolic crisis (lactate-pyruvate ratio [LPR] > 40), and transport duration on cerebral metabolism, was analyzed.

Results: During the transport, the mean ICP significantly increased from 7.1 ± 3.9 mm Hg to 13.5 ± 6.0 mm Hg (p < 0.001). The ICP exceeded 20 mm Hg in 92.5% of patients; pbtO2 showed a parallel rise from 23.1 ± 13.3 mm Hg to 28.5 ± 23.6 mm Hg (p = 0.02) due to an increase in the fraction of inspired oxygen during the transport. Both ICP and pbtO2 returned to baseline values thereafter. Cerebral glycerol significantly increased from 71.0 ± 54.9 µmol/L to 75.3 ± 56.0 µmol/L during the transport (p = 0.01) and remained elevated for the following 9 hours. In contrast, cerebral pyruvate and lactate levels were stable during the transport but showed a significant secondary increase 1-8 hours and 2-9 hours, respectively, thereafter (p < 0.05). However, the LPR remained stable over the entire observation period. Patients with extended transport duration (more than 25 minutes) were found to have significantly higher levels of cerebral pyruvate and lactate as well as lower glutamate concentrations in the posttransport period.

Conclusions: Intrahospital transport and horizontal positioning during CT scans induce immediate intracranial hypertension and an increase in cerebral glycerol, suggesting neuronal injury. Afterward, sustained impairment of neuronal metabolism for several hours could be observed, which might increase the risk of secondary ischemic events. Therefore, intrahospital transport for neuroradiological imaging should be strongly reconsidered and only indicated if the expected benefit of imaging results outweighs the risks of transportation.
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http://dx.doi.org/10.3171/2020.8.JNS202280DOI Listing
March 2021

Human Biodistribution and Radiation Dosimetry of the P-Glycoprotein Radiotracer [C]Metoclopramide.

Mol Imaging Biol 2021 04 22;23(2):180-185. Epub 2021 Jan 22.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

Purpose: To assess in healthy volunteers the whole-body distribution and dosimetry of [C]metoclopramide, a new positron emission tomography (PET) tracer to measure P-glycoprotein activity at the blood-brain barrier.

Procedures: Ten healthy volunteers (five women, five men) were intravenously injected with 387 ± 49 MBq of [C]metoclopramide after low dose CT scans and were then imaged by whole-body PET scans from head to upper thigh over approximately 70 min. Ten source organs (brain, thyroid gland, right lung, myocardium, liver, gall bladder, left kidney, red bone marrow, muscle and the contents of the urinary bladder) were manually delineated on whole-body images. Absorbed doses were calculated with QDOSE (ABX-CRO) using the integrated IDAC-Dose 2.1 module.

Results: The majority of the administered dose of [C]metoclopramide was taken up into the liver followed by urinary excretion and, to a smaller extent, biliary excretion of radioactivity. The mean effective dose of [C]metoclopramide was 1.69 ± 0.26 μSv/MBq for female subjects and 1.55 ± 0.07 μSv/MBq for male subjects. The two organs receiving the highest radiation doses were the urinary bladder (10.81 ± 0.23 μGy/MBq and 8.78 ± 0.89 μGy/MBq) and the liver (6.80 ± 0.78 μGy/MBq and 4.91 ± 0.74 μGy/MBq) for female and male subjects, respectively.

Conclusions: [C]Metoclopramide showed predominantly renal excretion, and is safe and well tolerated in healthy adults. The effective dose of [C]metoclopramide was comparable to other C-labeled PET tracers.
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http://dx.doi.org/10.1007/s11307-021-01582-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910245PMC
April 2021
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