Vancomycin clearance in obese adults is not predictive of clearance in obese adolescents

Contradictory pharmacokinetic (PK) results have been observed between obese adults and obese adolescents, with absolute clearance (CL) reported to be either unaltered, lower, or higher in obese adolescents compared to obese adults. This study investigates the PK of vancomycin in adolescents and adults who are overweight or obese. Data from 125 overweight and obese adolescents (aged 10-18 years, weight 28.3-188 kg) and 81 overweight and obese adults (aged 29-88 years, weight 66.7-143 kg) were analysed using population PK modelling. In addition to age, sex, renal function estimates, and regular weight descriptors, we evaluated standard weight (WTstandard, defined as weight for length, age, and sex in adolescents and weight for length in adults) and excess weight (WTexcess, defined as total body weight (TBW) minus WTstandard) as covariates in order to distinguish between weight resulting from length versus weight resulting from obesity. Analyzing adolescents and adults together, vancomycin CL was found to increase with TBW and decrease with increasing age (p standard in adolescents and adults, albeit with different functions, with adolescents having a higher CL per WTstandard than adults. Moreover, in this separate model, adolescent males had 21% higher CL than adolescent females of the same WTstandard, while in adults, CL decreased with increasing age (p Pharmacolog

Systems pharmacology of hepatic metabolism in zebrafish larvae

Interspecies translation of pharmacological processes needs to improve to reduce attrition in drug development. Systems pharmacology integrates systems biology and pharmacometrics to characterise and quantify system-specific behaviour upon exposure to drugs in different species. The zebrafish is a suitable vertebrate model organism for systems pharmacology, combining high-throughput potential with high genetic homology to higher vertebrates. Zebrafish larvae have been increasingly used for drug screens, but the influence of internal drug and metabolite exposure is hardly studied. Quantifying this internal exposure is essential for establishing both exposure-response and dose-exposure relationships, needed for translation. The zebrafish may also serve as a suitable model species for translational studies on the occurrence of hepatotoxicity and the influence of hepatic dysfunction on drug metabolism. Pharmacolog

One Dimensional Oxygen Ordering in YBa2Cu3O(7-delta)

A model consisting of oxygen-occupied and -vacant chains is considered, with repulsive first and second nearest-neighbor interactions V1 and V2, respectively. The statistical mechanics and the diffraction spectrum of the model is solved exactly and analytically with the only assumption V1 >> V2. At temperatures T ~ V1 only a broad maximum at (1/2,0,0) is present, while for ABS(delta - 1/2) > 1/14 at low enough T, the peak splits into two. The simple expression for the diffraction intensity obtained for T << V1 represents in a more compact form previous results of Khachaturyan and Morris[1],extends them to all delta and T/V2 and leads to a good agreement with experiment. [1] A.G.Khachaturyan and J.W.Morris, Jr., Phys.Rev.Lett. 64,76(1990)Comment: 13 pages,Revtex,3 figures available upon request but can be plotted using simple analytical functions,CNEA-CAB 92/04

Towards personalized treatment of pain using a quantitative systems pharmacology approach

Pain is a complex biopsychosocial phenomenon of which the intensity, location and duration depends on various underlying components. Treatment of pain is associated with considerable inter-individual variability, and as such, requires a personalized approach. However, a priori prediction of optimal analgesic treatment for individual patients is still challenging. Another challenge is the assessment and treatment of pain in patients unable to self-report pain. In this mini-review, we first provide a brief overview of the various components underlying pain, and their associated biomarkers. These include clinical, psychosocial, neurophysiological, and biochemical components. We then discuss the use of empirical and mechanism-based pharmacokinetic-pharmacodynamic modelling to support personalized treatment of pain. Finally, we propose how these concepts can be extended to a quantitative systems pharmacology (QSP) approach that integrates the components of clinical pain and treatment response. This integrative approach can support predictions of optimal pharmacotherapy of pain, compared with approaches that focus on single components of pain. Moreover, combination of QSP modelling with state-of-the-art metabolomics approaches may offer unique possibilities to identify novel pain biomarkers. Such biomarkers could support both the personalized treatment of pain and translational drug development of novel analgesic agents. In conclusion, a QSP approach will likely improve our ability to predict pain and treatment response, paving the way for personalized treatment of pain

Beyond the randomized clinical trial: innovative data science to close the pediatric evidence gap

Despite the application of advanced statistical and pharmacometric approaches to pediatric trial data, a large pediatric evidence gap still remains. Here, we discuss how to collect more data from children by using real-world data from electronic health records, mobile applications, wearables, and social media. The large datasets collected with these approaches enable, and may demand, the use of artificial intelligence and machine learning to allow the data to be analyzed for decision-making. Applications of this approach are presented, which include the prediction of future clinical complications, medical image analysis, identification of new pediatric endpoints and biomarkers, the prediction of treatment non-responders and the prediction of placebo-responders for trial enrichment. Finally, we discuss how to bring machine learning from science to pediatric clinical practice. We conclude that advantage should be taken of the current opportunities offered by innovations in data science and machine learning to close the pediatric evidence gap.Pharmacolog

Disorder-Driven Pretransitional Tweed in Martensitic Transformations

Defying the conventional wisdom regarding first--order transitions, {\it solid--solid displacive transformations} are often accompanied by pronounced pretransitional phenomena. Generally, these phenomena are indicative of some mesoscopic lattice deformation that ``anticipates'' the upcoming phase transition. Among these precursive effects is the observation of the so-called ``tweed'' pattern in transmission electron microscopy in a wide variety of materials. We have investigated the tweed deformation in a two dimensional model system, and found that it arises because the compositional disorder intrinsic to any alloy conspires with the natural geometric constraints of the lattice to produce a frustrated, glassy phase. The predicted phase diagram and glassy behavior have been verified by numerical simulations, and diffraction patterns of simulated systems are found to compare well with experimental data. Analytically comparing to alternative models of strain-disorder coupling, we show that the present model best accounts for experimental observations.Comment: 43 pages in TeX, plus figures. Most figures supplied separately in uuencoded format. Three other figures available via anonymous ftp

Impact of post-hatching maturation on the pharmacokinetics of paracetamol in zebrafish larvae

Zebrafish larvae are increasingly used in pharmacological and toxicological studies, but it is often overlooked that internal exposure to exogenous compounds, rather than the incubation medium concentration, is driving observed effects. Moreover, as the zebrafish larva is a developing organism, continuous physiological changes impact pharmacokinetic or toxicokinetic processes like the absorption and elimination of exogenous compounds, influencing the interpretation of observations and conclusions drawn from experiments at different larval ages. Here, using paracetamol as paradigm compound, mathematical modelling is used to quantify absorption and elimination rates from internal exposure over time profiles after waterborne treatment, as well as changes in these parameters in post-hatching larvae of 3, 4, and 5 days post fertilisation (dpf). An increase of 106% in absorption rate was observed between 3 and 4 dpf, but no further increase at 5 dpf, and an increase of 17.5% in elimination rate for each dpf. Paracetamol clearance, determined from elimination rate constants and reported total larval volumes of 253, 263, and 300 nL at 3, 4, and 5 dpf respectively, correlates best with higher vertebrates at 5 dpf. This suggests that when studying direct effects of exogenous compounds, experiments with zebrafish larvae are best performed at 5 dpf.PharmacologyAnalytical BioScience

Modelling inflammatory biomarker dynamics in a human lipopolysaccharide (LPS) challenge study using delay differential equations

Clinical studies in healthy volunteers challenged with lipopolysaccharide (LPS), a constituent of the cell wall of Gram-negative bacteria, represent a key model to characterize the Toll-like receptor 4 (TLR4)-mediated inflammatory response. Here, we developed a mathematical modelling framework to quantitatively characterize the dynamics and inter-individual variability of multiple inflammatory biomarkers in healthy volunteer LPS challenge studies. Data from previously reported LPS challenge studies were used, which included individual-level time-course data for tumour necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), interleukin 8 (IL-8) and C-reactive protein (CRP). A one-compartment model with first-order elimination was used to capture the LPS kinetics. The relationships between LPS and inflammatory markers was characterized using indirect response (IDR) models. Delay differential equations were applied to quantify the delays in biomarker response profiles. For LPS kinetics, our estimates of clearance and volume of distribution were 35.7 L h(-1) and 6.35 L, respectively. Our model adequately captured the dynamics of multiple inflammatory biomarkers. The time delay for the secretion of TNF-alpha, IL-6 and IL-8 were estimated to be 0.924, 1.46 and 1.48 h, respectively. A second IDR model was used to describe the induced changes of CRP in relation to IL-6, with a delayed time of 4.2 h. The quantitative models developed in this study can be used to inform design of clinical LPS challenge studies and may help to translate preclinical LPS challenge studies to humans.Pharmacolog

Mechanistic and quantitative understanding of pharmacokinetics in zebrafish larvae through nanoscale blood sampling and metabolite modelling of paracetamol

Zebrafish larvae are increasingly used for pharmacological research, but internal drug exposure is often not measured. Understanding pharmacokinetics is necessary for reliable translation of pharmacological results to higher vertebrates, including humans. Quantification of drug clearance and distribution requires measurements of blood concentrations. Additionally, measuring drug metabolites is of importance to understand clearance in this model organism mechanistically. We therefore mechanistically study and quantify pharmacokinetics in zebrafish larvae, and compare this to higher vertebrates, using paracetamol (acetaminophen) as paradigm compound. A method was developed to sample blood from zebrafish larvae at five days post fertilization. Blood concentrations of paracetamol and its major metabolites, paracetamol-glucuronide and paracetamol-sulphate, were measured. Blood concentration data were combined with measured amounts in larval homogenates and excreted amounts and simultaneously analysed through non-linear mixed effects modelling, quantifying absolute clearance and distribution volume. Blood sampling from zebrafish larvae was most successful from the posterior cardinal vein with median volume (interquartile range) of 1.12 (0.676-1.66) nL per blood sample. Samples were pooled (n=15-35) to reach measurable levels. Paracetamol blood concentrations at steady state were only 10% of the external paracetamol concentration. Paracetamol-sulphate was the major metabolite and its formation was quantified using a time-dependent metabolic formation rate. Absolute clearance and distribution volume correlated well to reported values in higher vertebrates, including humans. Based on blood concentrations and advanced data analysis, the mechanistic and quantitative understanding of paracetamol pharmacokinetics in zebrafish larvae has been established. This will improve the translational value of this vertebrate model organism in drug discovery and development.Analytical BioSciencesPharmacolog

Quantifying the pharmacodynamics of morphine in the treatment of postoperative pain in preverbal children

While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration-effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT-Behavior (COMFORT-B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up-titration). In responders to morphine up-titration, the COMFORT-B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT-B score is expected. In general, lower baseline COMFORT-B scores (2.1 points on average) in younger children (postnatal age 10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.Pharmacolog