Impact Of Interindividual Variability Research Articles

Oral Fosfomycin Efficacy with Variable Urinary Exposures following Single and Multiple Doses against Enterobacterales: the Importance of Heteroresistance for Growth Outcome.

Oral fosfomycin trometamol is licensed as a single oral dose for the treatment of uncomplicated urinary tract infections, with activity against multidrug-resistant uropathogens. The impact of interindividual variability in urinary concentrations on antimicrobial efficacy, and any benefit of giving multiple doses, is uncertain. We therefore performed pharmacodynamic profiling of oral fosfomycin, using a dynamic bladder infection in vitro model, to assess high and low urinary exposures following a single oral dose and three repeat doses given every 72 h, 48 h, and 24 h against 16 clinical isolates with various MICs of fosfomycin (8 Escherichia coli, 4 Enterobacter cloacae, and 4 Klebsiella pneumoniae isolates). Baseline fosfomycin high-level-resistant (HLR) subpopulations were detected prior to drug exposure in half of the isolates (2 E. coli, 2 E. cloacae, and 4 K. pneumoniae isolates; proportion, 1 × 10-5 to 5 × 10-4% of the total population). Fosfomycin exposures were accurately reproduced compared to mathematical modeling (linear regression slope, 1.1; R2, 0.99), with a bias of 3.8% ± 5.7%. All 5/5 isolates with MICs of ≤1 μg/ml had no HLR and were killed, whereas 8/11 isolates with higher MICs regrew regardless of exposure to high or low urinary concentrations. A disk diffusion zone of <24 mm was a better predictor for baseline HLR and regrowth. Administering 3 doses with average exposures provided very limited additional kill. These results suggest that baseline heteroresistance is important for treatment response, while increased drug exposure and administering multiple doses may not be better than standard single-dose fosfomycin therapy.

Exploring drug solubility in fasted human intestinal fluid aspirates: Impact of inter-individual variability, sampling site and dilution

One of the main factors defining intestinal drug absorption is the solubility of the compound in the gastrointestinal environment. This study reports the solubility of a series of 27 commonly used acidic, neutral and basic drugs in human intestinal fluid samples collected from the duodenum or jejunum of healthy volunteers under fasted state conditions. The interindividual variability as well as the impact of factors such as pH, sampling site and bile salts on the solubility in human intestinal fluids was investigated. The solubility measurements were evaluated using a statistical experimental design. Variability in solubility across volunteers and sampling sites was highly compound-specific and appeared to be substantial for weak acids and bases and for lipophilic drugs. Both pH of the samples and the abundance of amphiphilic components were responsible for the variability observed in the solubility values obtained. The results confirm strong interindividual differences in intraluminal solubility, especially for compounds with high lipophilicity and/or compounds with a pKa value within the physiological pH range. It is important to recognize this variability in intestinal drug solubility as it may considerably influence the therapeutic outcome among patients.

A Bayesian hierarchical method to account for random effects in cytogenetic dosimetry based on calibration curves

The dicentric chromosome assay (DCA) is one of the most sensitive and reliable methods of inferring doses of radiation exposure in patients. In DCA, one calibration curve is prepared in advance by in vitro irradiation to blood samples from one or sometimes multiple healthy donors in considering possible inter-individual variability. Although the standard method has been demonstrated to be quite accurate for actual dose estimates, it cannot account for random effects, which come from such as the blood donor used to prepare the calibration curve, the radiation-exposed patient, and the examiners. To date, it is unknown how these random effects impact on the standard method of dose estimation. We propose a novel Bayesian hierarchical method that incorporates random effects into the dose estimation. To demonstrate dose estimation by the proposed method and to assess the impact of inter-individual variability in samples from multiple donors on the estimation, peripheral blood samples from 13 occupationally non-exposed, non-smoking, healthy individuals were collected and irradiated with gamma rays. The results clearly showed significant inter-individual variability and the standard method using a sample from a single donor gave anti-conservative confidence interval of the irradiated dose. In contrast, the Bayesian credible interval for irradiated dose calculated by the proposed method using samples from multiple donors properly covered the actual doses. Although the classical confidence interval of calibration curve with accounting inter-individual variability in samples from multiple donors was roughly coincident with the Bayesian credible interval, the proposed method has better reasoning and potential for extensions.

A reappraisal of the vital effect in cultured benthic foraminifer &amp;lt;I&amp;gt;Bulimina marginata&amp;lt;/I&amp;gt; on Mg/Ca values: assessing temperature uncertainty relationships

Abstract. The reconstruction of past temperatures is often achieved through measuring the Mg/Ca value of foraminiferal test carbonate. The diversity in foraminiferal Mg/Ca–temperature calibrations suggests that there is also a biological control on this proxy. This study presents a new Mg/Ca–temperature calibration for the benthic foraminifer Bulimina marginata, based on cultures under a range of temperatures (4–14 °C). Measured Mg/Ca values for B. marginata correlate with temperature (Mg/Ca = (1.10 ± 0.10) e(0.045±0.009)T, R2 = 0.28 p &lt; 0.01). The inter-individual variability is, however, also significant (standard deviation is 10–35% of the average). Before applying this or any calibration, the effect of the inter-individual variability on the accuracy of the Mg/Ca–temperature calibration has to be evaluated. The inter-individual variability is quantified and split into three components, namely (1) an analytical error, (2) an environmental effect and (3) a vital effect. The effect of inter-individual variability on the accuracy of Mg/Ca–temperature calibrations depends on the sensitivity of the calibration used and the number of individuals measured (temperature uncertainty = (0.33 · N−0.50)/sensitivity). The less sensitive a calibration, the greater is the impact of inter-individual variability, which can partly be circumvented by measuring more individuals. This study shows the link between inter-individual variability and sensitivity and quantifies their influence on the accuracy of Mg/Ca–temperature calibrations. Differences in the sensitivity of the Mg/Ca–temperature calibration of foraminifera may depend on the environmental conditions in which foraminifera live and their concurring ecological strategies.

Prediction of in vivo drug clearance from in vitro data. I: Impact of inter-individual variability

The Simcyp® Population-Based ADME Simulator was used to predict median drug clearances and their associated variance from in vitro data. Fifteen drugs satisfied the entry criteria for the study and the relevant information (in vitro metabolism data and in vivo human clearance values) were collated from the literature. Predicted values of median clearances fell within 2-fold of observed values for 73% of the drugs (oral route) and 78% of the drugs (intravenous route) when microsomal binding was disregarded, and for 93% (oral) and 100% (intravenous) when it was considered. Irrespective of whether microsomal binding was considered, the predicted fold variability fell within 2-fold of the observed variability for 80% (oral) and 67% (intravenous) of the drugs.

Insulin-like growth factor physiology and cancer risk

In the past few years, both laboratory investigations and population studies have provided strong circumstantial evidence that insulin-like growth factor (IGF) physiology influences cancer risk. In contrast to the influence of germ line mutations that are rare but are associated with very high risks, the impact of inter-individual variability in IGF physiology on risk appears to be modest but to effect a relatively high percentage of the population. Although this field of investigation is young, attention is already being given to the possibility that it may be relevant to clinical assessment of risk and/or to the identification of novel prevention strategies and intermediate endpoints. This review summarises key results in this field and provides a hypothesis concerning the mechanism by which IGF physiology influences risk of common epithelial cancers including those of breast, prostate, lung and colon.