Penetration of Antibiotics into Subcutaneous and Intramuscular Interstitial Fluid: A Meta-Analysis of Microdialysis Studies in Adults.

BACKGROUND AND OBJECTIVE: The interstitial fluid of tissues is the effect site for antibiotics targeting extracellular pathogens. Microdialysis studies investigating these concentrations in muscle and subcutaneous tissue have reported notable variability in tissue penetration. This study aimed to comprehensively summarise the existing data on interstitial fluid penetration in these tissues and to identify potential factors influencing antibiotic distribution. METHODS: A literature review was conducted, focusing on subcutaneous and intramuscular microdialysis studies of antibiotics in both adult healthy volunteers and patients. Random-effect meta-analyses were used to aggregate effect size estimates of tissue penetration. The primary parameter of interest was the unbound penetration ratio, which represents the ratio of the area under the concentration-time curve in interstitial fluid relative to the area under the concentration-time curve in plasma, using unbound concentrations. RESULTS: In total, 52 reports were incorporated into this analysis. The unbound antibiotic exposure in the interstitial fluid of healthy volunteers was, on average, 22% lower than in plasma. The unbound penetration ratio values were higher after multiple dosing but did not significantly differ between muscle and subcutaneous tissue. Unbound penetration ratio values were lower for acids and bases compared with neutral antibiotics. Neither the molecular weight nor the logP of the antibiotics accounted for the variations in the unbound penetration ratio. Obesity was associated with lower interstitial fluid penetration. Conditions such as sepsis, tissue inflammation and tissue ischaemia were not significantly associated with altered interstitial fluid penetration. CONCLUSIONS: This study highlights the variability and generally lower exposure of unbound antibiotics in the subcutaneous and intramuscular interstitial fluid compared with exposure in plasma. Future research should focus on understanding the therapeutic relevance of these differences and identify key covariates that may influence them.

Comparison of monoclonal antibody disposition predictions using different physiologically based pharmacokinetic modelling platforms.

Physiologically based pharmacokinetic (PBPK) models can be used to leverage physiological and in vitro data to predict monoclonal antibody (mAb) concentrations in serum and tissues. However, it is currently not known how consistent predictions of mAb disposition are across PBPK modelling platforms. In this work PBPK simulations of IgG, adalimumab and infliximab were compared between three platforms (Simcyp, PK-Sim, and GastroPlus). Accuracy of predicted serum and tissue concentrations was assessed using observed data collected from the literature. Physiological and mAb related input parameters were also compared and sensitivity analyses were carried out to evaluate model behavior when input values were altered. Differences in serum kinetics of IgG between platforms were minimal for a dose of 1 mg/kg, but became more noticeable at higher dosages (> 100 mg/kg) and when reference (healthy) physiological input values were altered. Predicted serum concentrations of both adalimumab and infliximab were comparable across platforms, but were noticeably higher than observed values. Tissue concentrations differed remarkably between the platforms, both for total- and interstitial fluid (ISF) concentrations. The accuracy of total tissue concentrations was within a three-fold of observed values for all tissues, except for brain tissue concentrations, which were overpredicted. Predictions of tissue ISF concentrations were less accurate and were best captured by GastroPlus. Overall, these simulations show that the different PBPK platforms generally predict similar mAb serum concentrations, but variable tissue concentrations. Caution is therefore warranted when PBPK models are used to simulate effect site tissue concentrations of mAbs without data to verify the predictions.

Predicting Volume of Distribution in Neonates: Performance of Physiologically Based Pharmacokinetic Modelling.

The volume of distribution at steady state (Vss) in neonates is still often estimated through isometric scaling from adult values, disregarding developmental changes beyond body weight. This study aimed to compare the accuracy of two physiologically based pharmacokinetic (PBPK) Vss prediction methods in neonates (Poulin & Theil with Berezhkovskiy correction (P&T+) and Rodgers & Rowland (R&R)) with isometrical scaling. PBPK models were developed for 24 drugs using in-vitro and in-silico data. Simulations were done in Simcyp (V22) using predefined populations. Clinical data from 86 studies in neonates (including preterms) were used for comparison, and accuracy was assessed using (absolute) average fold errors ((A)AFEs). Isometric scaling resulted in underestimated Vss values in neonates (AFE: 0.61), and both PBPK methods reduced the magnitude of underprediction (AFE: 0.82-0.83). The P&T+ method demonstrated superior overall accuracy compared to isometric scaling (AAFE of 1.68 and 1.77, respectively), while the R&R method exhibited lower overall accuracy (AAFE: 2.03). Drug characteristics (LogP and ionization type) and inclusion of preterm neonates did not significantly impact the magnitude of error associated with isometric scaling or PBPK modeling. These results highlight both the limitations and the applicability of PBPK methods for the prediction of Vss in the absence of clinical data.

High throughput determination of the biofilm prevention concentration for Pseudomonas aeruginosa biofilms using a synthetic cystic fibrosis sputum medium.

The presence of Pseudomonas aeruginosa biofilms in cystic fibrosis (CF) patients suffering from chronic lung infections contributes to the failure of antimicrobial therapy. Conventionally, the minimal inhibitory concentration (MIC) is determined to assess the antimicrobial susceptibility of a pathogen, however this parameter fails to predict success in treating biofilm-associated infections. In the present study we developed a high throughput method to determine the antimicrobial concentration required to prevent P. aeruginosa biofilm formation, using a synthetic cystic fibrosis sputum medium (SCFM2). Biofilms were grown in SCFM2 for 24 h in the presence of antibiotics (tobramycin, ciprofloxacin or colistin), whereafter biofilms were disrupted and a resazurin staining was used to quantify the number of surviving metabolically active cells. In parallel, the content of all wells was plated to determine the number of colony forming units (CFU). Biofilm preventing concentrations (BPCs) were compared to MICs and minimal bactericidal concentrations (MBCs) determined according to EUCAST guidelines. Correlations between the resazurin-derived fluorescence and CFU counts were assessed with Kendall's Tau Rank tests. A significant correlation between fluorescence and CFU counts was observed for 9 out of 10 strains investigated, suggesting the fluorometric assay is a reliable alternative to plating for most P. aeruginosa isolates to determine biofilm susceptibility in relevant conditions. For all isolates a clear difference between MICs and BPCs of all three antibiotics was observed, with the BPCs being consistently higher than the MICs. Additionally, the extent of this difference appeared to be antibiotic-dependent. Our findings suggest that this high throughput assay could be a valuable addition to evaluate the antimicrobial susceptibility in P. aeruginosa biofilms in the context of CF.

Predictive Performance of Physiologically Based Pharmacokinetic Modelling of Beta-Lactam Antibiotic Concentrations in Adipose, Bone, and Muscle Tissues.

Physiologically based pharmacokinetic (PBPK) models consist of compartments representing different tissues. As most models are only verified based on plasma concentrations, it is unclear how reliable associated tissue profiles are. This study aimed to assess the accuracy of PBPK-predicted beta-lactam antibiotic concentrations in different tissues and assess the impact of using effect site concentrations for evaluation of target attainment. Adipose, bone, and muscle concentrations of five beta-lactams (piperacillin, cefazolin, cefuroxime, ceftazidime, and meropenem) in healthy adults were collected from literature and compared with PBPK predictions. Model performance was evaluated with average fold errors (AFEs) and absolute AFEs (AAFEs) between predicted and observed concentrations. In total, 26 studies were included, 14 of which reported total tissue concentrations and 12 unbound interstitial fluid (uISF) concentrations. Concurrent plasma concentrations, used as baseline verification of the models, were fairly accurate (AFE: 1.14, AAFE: 1.50). Predicted total tissue concentrations were less accurate (AFE: 0.68, AAFE: 1.89). A slight trend for underprediction was observed but none of the studies had AFE or AAFE values outside threefold. Similarly, predictions of microdialysis-derived uISF concentrations were less accurate than plasma concentration predictions (AFE: 1.52, AAFE: 2.32). uISF concentrations tended to be overpredicted and two studies had AFEs and AAFEs outside threefold. Pharmacodynamic simulations in our case showed only a limited impact of using uISF concentrations instead of unbound plasma concentrations on target attainment rates. The results of this study illustrate the limitations of current PBPK models to predict tissue concentrations and the associated need for more accurate models. SIGNIFICANCE STATEMENT: Clinical inaccessibility of local effect site concentrations precipitates a need for predictive methods for the estimation of tissue concentrations. This is the first study in which the accuracy of PBPK-predicted tissue concentrations of beta-lactam antibiotics in humans were assessed. Predicted tissue concentrations were found to be less accurate than concurrent predicted plasma concentrations. When using PBPK models to predict tissue concentrations, this potential relative loss of accuracy should be acknowledged when clinical tissue concentrations are unavailable to verify predictions.

Altered intravenous drug disposition in people living with cystic fibrosis: A meta-analysis integrating top-down and bottom-up data.

Cystic fibrosis (CF) has been linked to altered drug disposition in various studies. However, the magnitude of these changes, influencing factors, and underlying mechanisms remain a matter of debate. The primary aim of this work was therefore to quantify changes in drug disposition (top-down) and the pathophysiological parameters known to affect pharmacokinetics (PKs; bottom-up). This was done through meta-analyses and meta-regressions in addition to theoretical PK simulations. Volumes of distribution and clearances were found to be elevated in people living with CF. These increases were larger in studies which included patients with pulmonary exacerbations. Differences in clearance were smaller in more recent studies and when results were normalized to body surface area or lean body mass instead of body weight. For the physiological parameters investigated, measured glomerular filtration rate and serum cytokine concentrations were found to be elevated in people living with CF, whereas serum albumin and creatinine levels were decreased. Possible pathophysiological mechanisms for these alterations relate to renal hyperfiltration, increases in free fraction, and inflammation. No differences were detected for cardiac output, body fat, fat free mass, hematocrit, creatinine clearance, and the activity of drug metabolizing enzymes. These findings imply that, in general, lower total plasma concentrations of drugs can be expected in people living with CF, especially when pulmonary exacerbations are present. Given the potential effect of CF on plasma protein binding and the variability in outcome observed between studies, the clinical relevance of adapting existing dosage regimens should be evaluated on a case-by-case basis.

Pharmacokinetics in Patients with Cystic Fibrosis: A Systematic Review of Data Published Between 1999 and 2019.

BACKGROUND: Cystic fibrosis is a lethal inherited disease that affects multiple organs. To provide optimal pharmacological treatment of comorbidities associated with cystic fibrosis, relevant alterations in pharmacokinetics must be known. OBJECTIVE: The objective of this study was to compare the pharmacokinetics of drugs between patients with cystic fibrosis and controls, based on clinical study reports published from 1999 to 2019. METHODS: Clinical studies were considered if patients with cystic fibrosis and patients without cystic fibrosis/healthy volunteers were included, a drug was administered orally/intravenously and pharmacokinetic parameters were compared. RESULTS: In total, 32 clinical studies were included. Twenty-one studies reported absorption parameters. For multiple drugs, speed and/or extent of oral absorption were lower in cystic fibrosis. This phenomenon is possibly related to pathophysiological changes in the gastrointestinal tract associated with cystic fibrosis. However, a large proportion of drugs had comparable absorption kinetics. Twenty-one studies discussed volume of distribution, which was comparable between groups for most drugs. Initial differences became smaller when scaled to body composition. For some highly protein-bound drugs, inflammation-related changes in plasma proteins helped explain residual variability between cystic fibrosis and controls. Twenty-four studies elaborated on clearance, whereby higher clearances were observed in cystic fibrosis. In contrast with previously published reviews, no evidence was found for increased activities of drug-metabolising enzymes nor for up-regulation of active transport processes involved in drug disposition. In most cases, scaling clearance parameters to body composition and/or incorporating differences in plasma protein concentration accounted for these larger clearances. IMPLICATIONS: There is no evidence that genetic defects causing cystic fibrosis directly lead to altered pharmacokinetics. However, co-morbidities can have a potential impact on drug absorption and disposition. Because of gastrointestinal complications, it is not advisable to extrapolate drug absorption parameters from healthy volunteers to patients with cystic fibrosis. Differences observed in the volume of distribution and clearance in patients with cystic fibrosis can potentially be explained by correcting for lean body mass.