Can in vitro/in silico tools improve colonic concentration estimations for oral extended-release formulations? A case study with upadacitinib.

Upadacitinib, classified as a highly soluble drug, is commercially marketed as RINVOQ®, a modified-release formulation incorporating hydroxypropyl methylcellulose as a matrix system to target extended release throughout the gastrointestinal (GI) tract. Our study aimed to explore how drug release will occur throughout the GI tract using a plethora of in vitro and in silico tools. We built a Physiologically-Based Pharmacokinetic (PBPK) model in GastroPlus™ to predict the systemic concentrations of the drug when administered using in vitro dissolution profiles as input to drive luminal dissolution. A series of in vitro dissolution experiments were gathered using the USP Apparatus I, III and IV in presence of biorelevant media, simulating both fasted and fed state conditions. A key outcome from the current study was to establish an in vitro-in vivo correlation (IVIVC) between (i) the dissolution profiles obtained from the USP I, III and IV methods and (ii) the fraction absorbed of drug as deconvoluted from the plasma concentration-time profile of the drug. When linking the fraction dissolved as measured in the USP IV model, a Level A IVIVC was established. Moreover, when using the different dissolution profiles as input for PBPK modeling, it was also observed that predictions for plasma Cmax and AUC were most accurate for USP IV compared to the other models (based on predicted versus observed ratios). Furthermore, the PBPK model has the utility to extract the predicted concentrations at the level of the colon which can be of utmost interest when working with specific in vitro assays.

Utility of Single-Photon Emission Computed Tomography/Computed Tomography in Suspected Unilateral Condylar Hyperplasia: A Histopathologic Validation Study.

PURPOSE: The purpose of this study is to evaluate the utility of hybrid single-photon emission computed tomography (SPECT) and computed tomography (CT) with technetium-99m methylene diphosphonate in patients with suspected active unilateral condylar hyperplasia (UCH) using histopathology as the reference standard. METHODS: Twenty-four patients with suspected active UCH prospectively underwent technetium-99m methylene diphosphonate planar bone scintigraphy with SPECT/CT of the mandible. Qualitative and quantitative readings for growth activity were performed by 3 nuclear medicine physicians and the final diagnosis was derived from postoperative histopathological examination. Readings were reported as positive, equivocal, or negative. Total, maximum, and mean counts were recorded for each condyle on SPECT/CT images. The uptake of the index (suspected) condyle was expressed as a count ratio (Rtotal, Rmean, Rmax), a percentage uptake (Ptotal, Pmean, Pmax), background-corrected counts (Btotal, Bmean, Bmax), as well as CT-based condylar diameters (RCT,PCT) relative to the contralateral condyle. RESULTS: Interobserver agreement was 0.79 and 0.83 for planar bone scintigraphy and SPECT/CT, respectively, with a total of 5 and 1 equivocal readings from the respective modalities. Surgery was performed in 22 patients; all of them had pathologically proven UCH. SPECT/CT was slightly more sensitive than planar bone scintigraphy (91 vs 78%) with identical specificity (96%). Rtotal, Rmean, Ptotal, and Pmean demonstrated area under the curve between 84% and 86%. Metrics based on CT diameters and background-corrected counts were not associated with UCH diagnosis. CONCLUSIONS: Quantitative approaches based on total or mean count ratio or relative count percentage were equally predictive for UCH diagnosis; however, they were slightly less sensitive compared with qualitative technetium-99m methylene diphosphonate SPECT/CT evaluation. SPECT/CT evaluation has the potential to decrease the equivocal readings.

The correlation between speckle tracking echocardiography and coronary artery disease in patients with suspected stable angina pectoris.

BACKGROUND: To examine the value of speckle tracking echocardiography to detect the presence, extent and severity of coronary artery affection in patients with suspected stable angina pectoris. METHODS: Two hundred candidates with suspected stable angina pectoris and normal resting conventional echocardiography were subjected to speckle tracking echocardiography and coronary angiography. Global and segmental longitudinal peak systolic strain were assessed and were correlated to the results of coronary angiography for each patient. RESULTS: There was a statistically significant difference in the mean of global longitudinal peak systolic strain between normal coronaries and different degrees of coronary artery disease (CAD) (-20.11±0.8 for normal, -18.34±2.52 for single vessel, -16.14±2.85 for two vessels, -14.81±2.12 for three vessels, -13.01±2.92 for left main disease). GLPSS showed high sensitivity for the diagnosis of single vessel CAD (90%, specificity 95.1%, cutoff value: -18.44, AUC: 0.954); two vessels disease (90%, sensitivity 88.9%, cutoff value -17.35, AUC: 0.906) and for three vessels CAD (cutoff value -15.33, sensitivity 63% and specificity 72.2% AUC 0.681) segmental LPSS also showed statistical significance for localization of the affected vessel for left anterior descending, left circumflex and right coronary artery (ρ=0.001) and inverse correlation with syntax score that was significant with high and intermediate score (ρ=0.001) and insignificant for low syntax score (ρ value 0.05). CONCLUSION: Two-dimensional speckle tracking echocardiography has good sensitivity and specificity to predict the presence, extent and severity of CAD.