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.

A Stratified Analysis of Supersaturation and Precipitation Effects Based on the Refined Developability Classification System (rDCS).

Supersaturation and precipitation within the gastrointestinal tract can influence oral absorption of active pharmaceutical ingredients (APIs). Supersaturation of weakly basic APIs upon transfer from the stomach into the small intestine may enhance their absorption, while salt forms of poorly soluble weak acids may generate supersaturated solutions in both stomach and intestine. Likewise, APIs with solubility-limited absorption may be developed as enabling formulations intended to produce supersaturated solutions of the API in the gut. Integrating the supersaturation/precipitation characteristics of the API into the biopharmaceutical risk classification enables comprehensive mapping of potential developability risks and guides formulation selection towards optimizing oral bioavailability (BA). The refined Developability Classification System (rDCS) provides an approach for this purpose. In this work, the rDCS strategy is revisited and a stratified approach integrating the in vitro supersaturation and precipitation behavior of APIs and their formulations is proposed.

Have We Neglected to Study Target-Site Drug Exposure in Children? A Systematic Review of the Literature.

BACKGROUND AND OBJECTIVE: Drug dosing should ideally be based on the drug concentrations at the target site, which, for most drugs, corresponds to the tissue. The exact influence of growth and development on drug tissue distribution is unclear. This systematic review compiles the current knowledge on the tissue distribution of systemically applied drugs in children, with the aim to identify priorities in tissue pharmacokinetic (PK) research in this population. METHODS: A systematic literature search was performed in the MEDLINE and Embase databases. RESULTS: Forty-two relevant articles were identified, of which 71% investigated antibiotics, while drug classes from the other studies were anticancer drugs, antifungals, anthelmintics, sedatives, thyreostatics, immunomodulators, antiarrhythmics, and exon skipping therapy. The majority of studies (83%) applied tissue biopsy as the sampling technique. Tonsil and/or adenoid tissue was most frequently examined (70% of all included patients). The majority of studies had a small sample size (median 9, range 1-93), did not include the youngest age categories (neonates and infants), and were of low reporting quality. Due to the heterogeneous data from different study compounds, dosing schedules, populations, and target tissues, the possibility for comparison of PK data between studies was limited. CONCLUSION: The influence of growth and development on drug tissue distribution continues to be a knowledge gap, due to the paucity of tissue PK data in children, especially in the younger age categories. Future research in this field should be encouraged as techniques to safely investigate drug tissue disposition in children are available.

Understanding the Conditions Under Which Drugs are Transferred from the Stomach Through the Upper Small Intestine After a High-Calorie, High-Fat Meal.

Information on the conditions under which drugs are transferred from the stomach through the upper small intestine after a high-calorie, high-fat meal is very limited. To simulate the drug presence after disintegration and arrival in the antral region, paracetamol solution and Sporanox® amorphous solid dispersion pellets at two dose levels were administered to the antrum of 8 healthy adults 30 min after administration of a high-calorie, high-fat meal on a crossover basis. The overall median buffer capacity of antral contents was estimated to be 18.0 and 24.0 mmol/ml/ΔpH when titrating with NaOH and HCl, respectively. The corresponding values for the contents of upper the small intestine were 14.0 and 16.8 mmol/ml/ΔpH, respectively. The drug transfer process from the antrum through the upper small intestine occurred with apparent first-order kinetics. The best estimate for the antral emptying half-life was 39min and 45min for paracetamol and itraconazole, respectively, the apparent volume of contents of the upper small intestine was more than double compared with previously reported values in the fasted state, the half-life of drug elimination from the upper small intestine was similar to recent estimates for highly permeable drugs in the fasted state, and the apparent volume of antral contents during the first couple of hours post drug administration was 303mL. Information collected in this study could increase the reliability of in silico and/or in vitro modelling approaches applied in clinical drug development.

Microdialysis as a safe and feasible method to study target-site piperacillin-tazobactam disposition in septic piglets and children.

OBJECTIVES: Knowledge on the tissue penetration of piperacillin-tazobactam in children with sepsis is lacking. In this study, the feasibility and performance of microdialysis experiments were explored in septic piglets and children as part of a translational research project. METHODS: Multiple-day microdialysis investigations were performed in muscle tissue of 22 piglets (of which 11 were septic) and 6 children with sepsis. An in vitro experiment preceded the (pre)clinical trials to derive optimal experimental settings and calibration technique. Linear mixed-effects models quantified the impact of sepsis on relative recovery (RR) and intercatheter, interindividual, interoccasion, and residual variability. RESULTS: In vivo microdialysis was well tolerated in piglets and children, with no significant adverse events reported. Using identical experimental settings, lower RR values were recorded in healthy and septic piglets (range: piperacillin, 17.2-29.1% and tazobactam, 23.5-29.1%) compared with the in vitro experiment (piperacillin, 43.3% and tazobactam, 55.3%), and there were unacceptably low values in children with sepsis (<10%). As a result, methodological changes were made in the pediatric trial. Realistic tissue concentration-time curves were derived in piglets and children. In piglets, sepsis reduced the RR. The greatest contributors to RR variability were residual (>40%) and interoccasion (>30%) variability. The internal standard method was the preferred calibration technique in both piglets and children. CONCLUSIONS: Microdialysis is a safe and applicable method for the measurement of tissue drug concentrations in piglets and children. This study demonstrated the impact of experimental settings, sepsis, and target population on individual RR.

Projection of Target Drug Particle Size in Oral Formulations Using the Refined Developability Classification System (rDCS).

Dissolution limitations to oral absorption can occur if the time required for dissolution is longer than the transit time across the small intestine and/or if dissolution is slower than the drug's permeation through the gut wall. These limitations most often occur for poorly soluble drugs. A standard method for overcoming dissolution issues is to reduce the particle size of the (solid) drug. Building on the refined Developability Classification System (rDCS), this work establishes a novel set of equations with which the appropriate degree of particle size reduction needed to mitigate dissolution limitations to absorption can be calculated. According to the type of data available, the appropriate equation(s) for each situation can be applied. Three case examples are used to illustrate implementation of the equations: voriconazole, lemborexant and istradefylline. Although for voriconazole (rDCS Class I) target radius (rtarget) estimates indicate that particle size reduction is unnecessary, for lemborexant (rDCS Class I) a radius of ≤20 µm would be required to improve absorption. For istradefylline (rDCS Class IIb) the rtarget was approximately 12 µm. Results are commensurate with literature information for these three drugs, signaling that the equations are suitable for application to a wide variety of drug substances.

Optimizing the Use of Antibiotic Agents in the Pediatric Intensive Care Unit: A Narrative Review.

Antibiotics are one of the most prescribed drug classes in the pediatric intensive care unit, yet the incidence of inappropriate antibiotic prescribing remains high in critically ill children. Optimizing the use of antibiotics in this population is imperative to guarantee adequate treatment, avoid toxicity and the occurrence of antibiotic resistance, both on a patient level and on a population level. Antibiotic stewardship encompasses all initiatives to promote responsible antibiotic usage and the PICU represents a major target environment for antibiotic stewardship programs. This narrative review provides a summary of the available knowledge on the optimal selection, duration, dosage, and route of administration of antibiotic treatment in critically ill children. Overall, more scientific evidence on how to optimize antibiotic treatment is warranted in this population. We also give our personal expert opinion on research priorities.

Model-based NIR spectroscopy implementation for in-line assay monitoring during a pharmaceutical suspension manufacturing process.

The implementation of Process Analytical Technology (PAT) instruments is generally achieved stochastically. Sub-optimal PAT locations could introduce variation in the measurements which is not related to the analyte of interest. For this reason, rational approaches should be considered to establish an optimal sensor placement where relevant measurements are possible and the impact of disturbances is minimized. The aim of this paper is to demonstrate how mechanistic modelling can support appropriate sensor implementation by means of a case study. A PAT method was developed for a bottle filling process of a pharmaceutical formulation with the goal of increasing the yield of the process by gaining process understanding and redefining the endpoint of the process. To ensure proper measurements, an advanced measuring interfacing was assembled. The design of this device was rationalized with the help of a model-based approach using three-dimensional Computational Fluid Dynamics modeling. This allows to maximize the performance of the PAT method and exploit its full benefits.

Lung surfactants and different contributions to thin film stability.

The surfactant lining the walls of the alveoli in the lungs increases pulmonary compliance and prevents collapse of the lung at the end of expiration. In premature born infants, surfactant deficiency causes problems, and lung surfactant replacements are instilled to facilitate breathing. These pulmonary surfactants, which form complex structured fluid-fluid interfaces, need to spread with great efficiency and once in the alveolus they have to form a thin stable film. In the present work, we investigate the mechanisms affecting the stability of surfactant-laden thin films during spreading, using drainage flows from a hemispherical dome. Three commercial lung surfactant replacements Survanta, Curosurf and Infasurf, along with the phospholipid dipalmitoylphosphatidylcholine (DPPC), are used. The surface of the dome can be covered with human alveolar epithelial cells and experiments are conducted at the physiological temperature. Drainage is slowed down due to the presence of all the different lung surfactant replacements and therefore the thin films show enhanced stability. However, a scaling analysis combined with visualization experiments demonstrates that different mechanisms are involved. For Curosurf and Infasurf, Marangoni stresses are essential to impart stability and interfacial shear rheology does not play a role, in agreement with what is observed for simple surfactants. Survanta, which was historically the first natural surfactant used, is rheologically active. For DPPC the dilatational properties play a role. Understanding these different modes of stabilization for natural surfactants can benefit the design of effective synthetic surfactant replacements for treating infant and adult respiratory disorders.

Interfacial shear rheology of DPPC under physiologically relevant conditions.

Lipids, and phosphatidylcholines in particular, are major components in cell membranes and in human lung surfactant. Their ability to encapsulate or form stable layers suggests a significant role of the interfacial rheological properties. In the present work we focus on the surface rheological properties of dipalmitoylphosphatidylcholine (DPPC). Literature results are confusing and even contradictory; viscosity values have been reported differ by several orders of magnitude. Moreover, even both purely viscous and gel-like behaviours have been described. Assessing the literature critically, a limited experimental window has been explored correctly, which however does not yet include conditions relevant for the physiological state of DPPC in vivo. A complete temperature and surface pressure analysis of the interfacial shear rheology of DPPC is performed, showing that the monolayer behaves as a viscoelastic liquid with a domain structure. At low frequencies and for a thermally structured monolayer, the interaction of the molecules within the domains can be probed. The low frequency limit of the complex viscosity is measured over a wide range of temperatures and surface pressures. The effects of temperature and surface pressure on the low frequency viscosity can be analysed in terms of the effects of free molecular area. However, at higher frequencies or following a preshear at high shear rates, elasticity becomes important; most probably elasticity due to defects at the edge of the domains in the layer is probed. Preshearing refines the structure and induces more defects. As a result, disagreeing interfacial rheology results in various publications might be due to different pre-treatments of the interface. The obtained dataset and scaling laws enable us to describe the surface viscosity, and its dependence under physiological conditions of DPPC. The implications on functioning of lung surfactants and lung surfactant replacements will be discussed.