Model averaging for robust assessment of QT prolongation by concentration-response analysis.

Assessing the QT prolongation potential of a drug is typically done based on pivotal safety studies called thorough QT studies. Model-based estimation of the drug-induced QT prolongation at the estimated mean maximum drug concentration could increase efficiency over the currently used intersection-union test. However, robustness against model misspecification needs to be guaranteed in pivotal settings. The objective of this work was to develop an efficient, fully prespecified model-based inference method for thorough QT studies, which controls the type I error and provides satisfactory test power. This is achieved by model averaging: The proposed estimator of the concentration-response relationship is a weighted average of a parametric (linear) and a nonparametric (monotonic I-splines) estimator, with weights based on mean integrated square error. The desired properties of the method were confirmed in an extensive simulation study, which demonstrated that the proposed method controlled the type I error adequately, and that its power was higher than the power of the nonparametric method alone. The method can be extended from thorough QT studies to the analysis of QT data from pooled phase I studies.

Maintaining knife sharpness in industrial meat cutting: A matter of knife or meat cutter ability.

Knife sharpness is imperative in meat cutting. The aim of this study was to compare the impact of knife blade steel quality with meat cutters' individual ability to maintain the cutting edge sharp in an industrial production setting. Twelve meat cutters in two different companies using three different knives during normal production were studied in this quasi-experimental study. Methods included were measuring knife cutting force before and after knife use, time knives were used, ratings of sharpness and discomfort and interviews. Results showed that the meat cutters' skill of maintaining sharpness during work had a much larger effect on knife sharpness during work than the knife steel differences. The ability was also related to feelings of discomfort and to physical exertion. It was found that meat cutters using more knives were more likely to suffer from discomfort in the upper limbs, which is a risk for developing MSD.

Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake.

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

Pharmacokinetics of budesonide controlled-release capsules when taken with omeprazole.

AIM: To investigate whether omeprazole affects the pharmacokinetics and systemic effects of budesonide controlled-release capsules when the two medications are taken together. METHODS: Thirteen healthy volunteers were enrolled into a randomized, double-blind, placebo-controlled, cross-over study. Participants received omeprazole, 20 mg/day, or placebo every morning for 5 days, with three 3-mg budesonide controlled-release capsules being given with omeprazole or placebo on day 5. After a 12-day washout period, participants were switched from omeprazole to placebo, or vice versa, and the trial was repeated. Blood samples for pharmacokinetic evaluation and urine samples for cortisol assessments were collected before and after the budesonide doses. RESULTS: No statistically significant differences were seen between omeprazole and placebo treatment with regard to any of the parameters analysed, including the maximum budesonide plasma concentration, time to concentration maximum, area under the concentration-time curve, mean residence time and urinary excretion of cortisol. Very few adverse events were reported during the trial, and the majority were of mild to moderate severity. CONCLUSION: Omeprazole treatment does not affect the pharmacokinetics or systemic effects of budesonide controlled-release capsules when the two medications are taken simultaneously.

Pharmacokinetics of budesonide controlled ileal release capsules in children and adults with active Crohn's disease.

BACKGROUND: Systemic glucocorticosteroid therapy is effective in Crohn's disease, but is associated with side-effects. Budesonide has high topical anti-inflammatory activity, but considerably lower systemic activity than other oral glucocorticosteroids. AIM: To evaluate the systemic exposure to budesonide (controlled ileal release capsules) in children and adults with active Crohn's disease, and to assess the suppression of plasma cortisol. METHODS: In an open label study, patients (eight children and six adults) with active Crohn's disease received 9 mg budesonide (Entocort capsules) orally once daily for 7 days. Plasma concentrations were determined on the seventh day of administration, and pharmacokinetic parameters were calculated. For reference, 0.5 mg budesonide was given intravenously separately. Plasma cortisol levels were compared with the pre-treatment baseline values. RESULTS: Systemic exposure to budesonide (AUC0-24 h) after 1 week of oral administration was 41 +/- 21 nmol/L x h (mean +/- s.d.) in children and 35 +/- 20 nmol/L x h in adults. The estimated systemic availability in children was 9 +/- 5% and in adults 11 +/- 7%. The mean plasma cortisol (AUC0-24 h) decreased by 64 +/- 18% in children and by 50 +/- 27% in adults. CONCLUSIONS: The systemic exposure, systemic availability and cortisol suppression after oral administration of 9 mg budesonide were similar in children and adults with active Crohn's disease. Budesonide was well tolerated and no clinically important safety-related findings were identified.

Comparisons of Analysis Methods for Proof-of-Concept Trials.

Drug development struggles with high costs and time consuming processes. Hence, a need for new strategies has been accentuated by many stakeholders in drug development. This study proposes the use of pharmacometric models to rationalize drug development. Two simulated examples, within the therapeutic areas of acute stroke and type 2 diabetes, are utilized to compare a pharmacometric model-based analysis to a t-test with respect to study power of proof-of-concept (POC) trials. In all investigated examples and scenarios, the conventional statistical analysis resulted in several fold larger study sizes to achieve 80% power. For a scenario with a parallel design of one placebo group and one active dose arm, the difference between the conventional and pharmacometric approach was 4.3- and 8.4-fold, for the stroke and diabetes example, respectively. Although the model-based power depend on the model assumptions, in these scenarios, the pharmacometric model-based approach was demonstrated to permit drastic streamlining of POC trials.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e23; doi:10.1038/psp.2012.24; advance online publication 16 January 2013.

Mechanistic modeling of a magnetic marker monitoring study linking gastrointestinal tablet transit, in vivo drug release, and pharmacokinetics.

Magnetic marker monitoring (MMM) is a new technique for visualizing transit and disintegration of solid oral dosage forms through the gastrointestinal (GI) tract. The aim of this work was to develop a modeling approach for gaining information from MMM studies using data from a food interaction study with felodipine extended-release (ER) formulation. The interrelationship between tablet location in the GI tract, in vivo drug release, and felodipine disposition was modeled. A Markov model was developed to describe the tablet's movement through the GI tract. Tablet location within the GI tract significantly affected drug release and absorption through the gut wall. Food intake decreased the probability of tablet transition from the stomach, decreased the rate with which released felodipine left the stomach, and increased the fraction absorbed across the gut wall. In conclusion, the combined information of tablet location in the GI tract, in vivo drug release, and plasma concentration can be utilized in a mechanistically informative way with integrated modeling of data from MMM studies.

Enzyme purification by genetically attached polycysteine and polyphenylalanine affinity tails.

Two novel affinity tails, polycysteine and polyphenylalanine, have been genetically attached to galactokinase (EC 2.7.1.6) and beta-galactosidase (EC 3.2.1.23) in order to facilitate their purification. A chemically synthesized DNA linker encoding four cysteine residues was thus fused in frame with the galactokinase gene. The gene product, cysteine galactokinase, was significantly retarded on a column of thiopropyl-Sepharose. Using pulse elution, cysteine galactokinase was eluted at 10 mM DTT. Under the condition used, native galactokinase did not bind to thiopropyl-Sepharose. Homopolymer tailing was employed to prepare a phenylalanine-modified beta-galactosidase. One of the obtained genetic transformants coding for a beta-galactosidase carrying 11 phenylalanine residues at the N-terminus of the enzyme was isolated. With the aid of hydrophobic interaction chromatography the modified enzyme could be purified to homogeneity on fast protein liquid chromatography using a phenyl-Superose column.