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Background and purpose: Sorafenib tosylate (SFN), a potent multikinase inhibitor, is used for the treatment of various cancers. However, it shows limited therapeutic applications due to its poor biopharmaceutical properties. The aim of the present investigation is to develop surface solid dispersion (SSD) of SFN using adsorbent to improve its solubility, bioavailability and therapeutic efficacy. Experimental approach: The SFN-SSD was prepared by modified solvent evaporation technique using Neusilin US2 (magnesium alumino­metasilicate) as an adsorbent and sodium dodecyl sulphate as a surfactant. SFN-SSD was optimized by adopting the design of experiment (DOE) using 32 factorial designs and characterized in terms of in-vitro and in-vivo efficacy. Key results: The obtained SFN-SSD showed more than 20-fold improvement in SFN solubility. The FTIR depicted hydrogen bonding between SFN and Neusilin. Further, PXRD and DSC indicated the molecular dispersion of SFN to be amorphous. SFN-SSD and SFN immediate release tablets reflected cumulative release of 97.13 and 29.93 % in 1 h. The pharmacokinetics study of SFN-SSD showed 2 and 6.5-fold improvement in maximum concentration (Cmax,) and area under the curve (AUC0-t) as compared to pure SFN due to faster drug release at the absorption site. Conclusion: The study concluded that the SSD could be a scalable formulation approach and more industry-friendly technology to improve the biopharmaceutical properties of SFN.

Background and Objectives: Gemcitabine has been used to treat various solid cancers, including, since 1997, metastatic pancreatic cancer. Here, we developed an HPLC-UV method to determine serum gemcitabine levels and use it in pharmacokinetic studies. Materials and Methods: The analysis was performed after a single protein precipitation step on a reversed-phase column, isocratically eluted with sodium phosphate buffer and methanol. For the pharmacokinetic study, NOD/SCID mice received a single dose of gemcitabine at 100 mg/kg by either subcutaneous (SC) or intraperitoneal (IP) administration. Blood samples were collected at 5, 15, and 30 min and 1, 2, 4, and 6 h after the administration of gemcitabine for further analysis. Results: The duration of the analysis was ~12.5 min. The calibration curve was linear (r2 = 0.999) over the range of 1–400 μM. The mean recovery of GEM was 96.53% and the limit of detection was 0.166 μΜ. T1/2, Tmax, Cmax, AUC0–t, and clearance were 64.49 min, 5.00 min, 264.88 μmol/L, 9351.95 μmol/L*min, and 0.0103(mg)/(μmol/L)/min, respectively, for the SC administration. The corresponding values for the IP administration were 59.34 min, 5.00 min, 300.73 μmol/L, 8981.35 μmol/L*min and 0.0108(mg)/(μmol/L)/min (not statistically different from the SC administration). Conclusions: A simple, valid, sensitive, and inexpensive method for the measurement of gemcitabine in serum has been developed. This method may be useful for monitoring gemcitabine levels in cancer patients as part of therapeutic drug monitoring.

In the pharmacokinetic analysis of ethanol after oral administration, only single- or two-compartment models are used, but their precision in estimating pharmacokinetic parameters might be insufficient. In a recent study, pharmacokinetic analysis using a modified Norberg three-compartment model was performed after oral administration of differently sweetened alcoholic solutions and compared to pharmacokinetic analysis using the classic Widmark model. On three occasions, eight male volunteers consumed differently sweetened alcoholic solutions: non-sweetened, sweetened with sucrose, and sweetened with steviol glycoside. Blood ethanol concentration was determined from samples obtained at t = 15, 30, 60, 90, 120, 180 min after consumption. Pharmacokinetic analysis was performed model independently, using the classic Widmarks model and using the modified Norberg model. Results showed that estimated pharmacokinetic parameters depend on the type of model used. The classic Widmark model in particular overestimated the fraction of absorbed ethanol from the gastrointestinal system to systemic circulation. Furthermore, the type of sweetener also affected pharmacokinetic parameters, although the difference was not statistically significant. In conclusion, the novel pharmacokinetic model, while being more physiological, fits experimental data better and hence is more suitable for modelling real-life alcohol consumption. In addition, the effect of natural non-caloric sweetener steviol glycoside on ethanol pharmacokinetics, analysed for the first time in the current research, might be different when compared to the common-used sweetener sucrose.

N-(4-hydroxyphenyl) retinamide (4-HPR, or fenretinide) has promising in vitro and in vivo antiviral activity against a range of flaviviruses and an established safety record, but there are challenges to its clinical use. This study evaluated the in vivo exposure profile of a 4-HPR dosage regime previously shown to be effective in a mouse model of severe dengue virus (DENV) infection, comparing it to an existing formulation for human clinical use for other indications and developed/characterised self-emulsifying lipid-based formulations of 4-HPR to enhance 4-HPR in vivo exposure. Pharmacokinetic (PK) analysis comprising single-dose oral and IV plasma concentration-time profiles was performed in mice; equilibrium solubility testing of 4-HPR in a range of lipids, surfactants and cosolvents was used to inform formulation approaches, with lead formulation candidates digested in vitro to analyse solubilisation/precipitation prior to in vivo testing. PK analysis suggested that effective plasma concentrations could be achieved with the clinical formulation, while novel lipid-based formulations achieved > 3-fold improvement. Additionally, 4-HPR exposure was found to be limited by both solubility and first-pass intestinal elimination but could be improved through inhibition of cytochrome P450 (CYP) metabolism. Simulated exposure profiles suggest that a b.i.d dosage regime is likely to maintain 4-HPR above the minimum effective plasma concentration for anti-DENV activity using the clinical formulation, with new formulations/CYP inhibition viable options to increase exposure in the future.

Voxtalisib, is a specific, effective, and reversible dual inhibitor, which inhibits both pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR). To date, voxtalisib has been studied in trials for melanoma, lymphoma, glioblastoma, breast cancer, and other cancers. In this study, a highly sensitive and rapid ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) technology was applied to the quantitative methodology and pharmacokinetic analysis of voxtalisib in rat plasma. After protein precipitation of the analyte by acetonitrile, the chromatographic separation was performed by gradient elution on an Acquity BEH C18 column (2.1 mm × 50 mm, 1.7 μm) with acetonitrile (solvent A) and 0.1% formic acid (solvent B) as the mobile phase. In the positive ion mode, the mass transfer detection of the analyte and IS was m/z 270.91 > 242.98 and m/z 572.30 > 246.10, respectively. In the concentration range of 1–2000 ng/ml, a good linear relationship of voxtalisib was successfully established by the UPLC-MS/MS technology, and the lower limit of quantification (LLOQ) of the analyte was identified as 1 ng/ml. Intra-day and inter-day precisions for voxtalisib were 7.5–18.7% and 13.0–16.6%, respectively, and the accuracies were in the ranges of −14.0–2.0% and −7.2–3.1%, respectively. The matrix effect, extraction recovery, carryover and stability of the analyte were all in compliance with the acceptance criteria of bioassays recommended by FDA. Finally, the pharmacokinetic profile of the analyte had been availably studied by the UPLC-MS/MS bio-analytical method after rats were treated by intragastric administration with voxtalisib (5 mg/kg). The results indicated that the UPLC-MS/MS technology can effectively and quickly quantify the analyte, and this method can also be used for the pharmacokinetic study of voxtalisib, which can provide reference for the optimization of clinical drug management in the later period.

Immunoglobulin G therapy for chronic inflammatory demyelinating polyneuropathy (CIDP) often requires individual dose adjustments because of the heterogeneity of pathogenesis and varying catabolic rates. However, currently available pharmacokinetic studies of immunoglobulin G therapy do not consider individual differences. We conducted a pharmacokinetic study of both intravenous immunoglobulin and subcutaneous immunoglobulin in a single patient with CIDP who was dependent on high-dose immunoglobulin treatment. This patient—a 77-year-old man with symmetrical limb weakness, diffuse demyelination determined by a nerve conduction study, and lacking autoantibodies—was treated with intravenous immunoglobulin and experienced severe fluctuations in symptoms. We transitioned him to subcutaneous immunoglobulin: his serum immunoglobulin G levels stabilised and he experienced symptomatic relief. Monitoring of serum immunoglobulin G concentrations revealed volatile changes following intravenous immunoglobulin administration which stabilised following subcutaneous immunoglobulin treatment. This suggests that subcutaneous immunoglobulin is a preferable long-term treatment option, especially for high-dose immunoglobulin-dependent patients with CIDP.

Abstract Background Cancer of the breast is known to be among the top spreading diseases on the globe. Triple-negative breast cancer is painstaking the most destructive type of mammary tumor because it spreads faster to other parts of the body, with high chances of early relapse and mortality. This research would aim at utilizing computational methods like quantitative structure–activity relationship (QSAR), performing molecular docking studies and again to further design new effective molecules using the QSAR model parameters and to analyze the pharmacokinetics “drug-likeliness” properties of the new compounds before they could proceed to pre-clinical trials. Results The QSAR model of the derivatives was highly robust as it also conforms to the least minimum requirement for QSAR model from the statistical assessments of (R 2) = 0.6715, (R 2 adj) = 0.61920, (Q 2) = 0.5460 and (R 2pred) of 0.5304, and the model parameters (AATS6i and VR1_Dze) were used in designing new derivative compounds with higher potency. The molecular docking studies between the derivative compounds and Maternal Embryonic Leucine Zipper Kinase (MELK) protein target revealed that ligand 2, 9 and 17 had the highest binding affinities of − 9.3, − 9.3 and − 8.9 kcal/mol which was found to be higher than the standard drug adriamycin with − 7.8 kcal/mol. The pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test and also the Lipinski rule of five. Conclusions The results obtained from the QSAR mathematical model of parthenolide derivatives were used in designing new derivatives compounds that were more effective and potent. The molecular docking result of parthenolide derivatives showed that compounds 2, 9 and 17 had higher docking scores than the standard drug adriamycin. The compounds would serve as the most promising inhibitors (MELK). Furthermore, the pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test (ADME and other physicochemical properties) and they also adhered to the Lipinski rule of five. This gives a great breakthrough in medicine in finding the cure to triple-negative breast cancer (MBA-MD-231 cell line).

Abstract Introduction Worldwide, cancer of the breast is the most commonly diagnosed disease and the second leading cause of cancer-related mortality amongst women yearly (Miller et al., 2016). Computer-aided drug discovery (CADD) is a fundamental shortcut in drug discovery arena. CADD tools ascertain key molecule for testing, predicting the effectiveness, the possible side effect, and also assist in upgrading drug-likeliness of drug molecules (Leelananda and Lindert, 2016). The propose of carrying out this research is to design new 2-anilinopyrimidine derivative compounds based on the interaction of the derivative compounds (ligand) and thyroid hormone receptor (TRβ1), and also analyze their pharmacokinetic properties as drug compounds that would be used by the pharmaceuticals against triple-negative breast cancer (MDA-MB-468 cell line). Results Three compounds (12, 17, and 18) had the highest docking score ranging from − 7.3 to − 7.4 kcal/mol. This showed that the compounds (ligands) bind tightly with the active site of the thyroid hormone receptor (TRβ1). Based on their tight interactions with the receptor, the compounds were chosen as lead compounds in the design of fourteen new compounds by incorporating some fragments found to bind intensely with the active site of the thyroid hormone receptor (TRβ1). All the newly designed compounds passed the pharmacokinetic analysis (adsorption, distribution, metabolism, excretion, and other physicochemical test) passed the drug-likeness test, and they also adhered to the Lipinski rule of five. Conclusions New derivative compounds of 2-anilinopyrimidine against MDA-MB-468 cell line were designed based on the information obtained from the molecular docking studies. Furthermore, the pharmacokinetics analysis (adsorption, distribution, metabolism, excretion (ADME) and other physicochemical properties) carried out on the newly designed compounds showed this compounds can be made into oral drugs for patients with triple-negative breast cancer (MBA-MD-468 cell line) as they serve as most promising inhibitors against thyroid hormone receptor (TRβ1).

This prospective study investigated the impact of cabozantinib exposure on proteinuria and muscle toxicity, in a cohort of 14 Japanese patients with unresectable hepatocellular carcinoma (uHCC). We measured the trough concentration of cabozantinib (Ctrough) weekly for 6 weeks after starting treatment. Although the initial dose was less than 60 mg in most cases, dose interruption occurred in 79%, primarily because of proteinuria and/or malaise. The median and coefficient of variation of maximum Ctrough at 7–42 d were 929.0 ng/mL and 59.2%, respectively. The urinary protein-to-creatinine ratio (UPCR), serum creatine kinase, and serum aldolase values were all significantly elevated following treatment. Moreover, maximum changes in serum creatine kinase and aldolase were significantly associated with maximum Ctrough (r = 0.736, p < 0.01; r = 0.798, p < 0.001; respectively). Receiver operating characteristic (ROC) curve analysis showed that changes in serum creatine kinase ≥70.5 U/L and aldolase ≥6.1 U/L from baseline relatively accurately predicted inclusion in the high-maximum Ctrough (≥929.0 ng/mL) group, with an area under the ROC of 0.929 and 0.833, respectively. Measurement of serum creatine kinase and aldolase may increase the clinical usefulness of cabozantinib treatment for uHCC and help alleviate difficulties with dose adjustments.

This prospective, Phase 3, open-label, study (EudraCT: 2016-001631-12) evaluated pharmacokinetic (PK) characteristics of 3-/4-weekly Privigen® (IgPro10, CSL Behring, King of Prussia, PA, USA) in Japanese patients with PID. PK parameters including serum trough immunoglobulin (IgG) level before next infusion during the wash-in/wash-out phase (Ctrough), area under the concentration-time curve from time point zero to the last time point with quantifiable concentration (AUC0–last), dose-adjusted AUC0–last (dAUC), lowest and highest observed IgG levels (Cmin, Cmax), time to reach Cmax (Tmax), and total clearance (CL) were analyzed for both regimens of Privigen® (dose: 138–554 mg/kg body weight). Ten patients were included in this analysis (3-/4-weekly: n = 2/n = 8). Ctrough levels achieved ranged 7.96–10.05 g/L. Cmax was observed approximately 1 h after the start of the infusion in both regimens. Mean (SD [not applicable for 3-weekly data]) PK parameters: Cmax, 16.60 and 14.20 (5.53) g/L; Cmin, 10.60 and 8.53 (3.89) g/L; AUC0–last, 5971 and 6591 (2633) g*h/L; dAUC, 0.41 and 0.46 (0.19) g*h/L/mg; CL, 2.53 and 2.53 (1.00) mL/h and median Tmax was 1.19 and 1.14 h, for 3-/4-weekly dosing regimens, respectively. Privigen® PK characteristics in Japanese patients were similar between dosing regimens and to previously-reported results in non-Japanese patients with PID.

Introduction: Two most common pharmaceutical formulation of tacrolimus (Tac) used after kidney transplantation (Tx) are immediate-release one, administered twice-daily (TacTD), and prolonged-release one, administered once-daily (Tac-OD). Aim: The aim of this study was to compare daily doses, trough concentrations (C0 ) and dose-adjusted trough concentrations (C0 /D) of Tac between patients who administered different drug formulations, Tac-TD or Tac-OD, during the first year after Tx. Additionally, the aim of the study was to compare the distribution of C0 within and beyond the target therapeutic range (8-12 ng/mL for the first 90 days and 6-10 ng/mL afterwards) after the administration of different drug formulations. Subjects and Methods: A retrospective pharmacokinetic study included 84 patients (56 on Tac-TD and 28 on Tac-OD), with a follow-up period between the first and twelfth month post-transplantation. Following pharmacokinetic data were used: daily dose, daily dose according to patient's body weight, concentration C0 and C0 /D of Tac. Results: The results of the study showed that patients on Tac-OD formulation had higher daily doses and higher C0 during 4-6 months (p

Purpose: Glioma tumor segmentation is an essential step in clinical decision making. Recently, computer-aided methods have been widely used for rapid and accurate delineation of the tumor regions. Methods based on image feature extraction can be used as fast methods, while segmentation based on the physiology and pharmacokinetic of the tissues is more accurate. This study aims to compare the performance of tumor segmentation based on these two different methods. Materials and Methods: Nested Model Selection (NMS) based on Extended-Toft’s model was applied to 190 Dynamic Contrast-Enhanced MRI (DCE-MRI) slices acquired from 25 Glioblastoma Multiforme (GBM) patients in 70 time-points. A model with three pharmacokinetic parameters, Model 3, is usually assigned to tumor voxel based on the time-contrast concentration signal. We utilized Deep-Net as a CNN network, based on Deeplabv3+ and layers of pre-trained resnet18, which has been trained with 17288 T1-Contrast MRI slices with HGG brain tumor to predict the tumor region in our 190 DCE MRI T1 images. The NMS-based physiological tumor segmentation was considered as a reference to compare the results of tumor segmentation by Deep-Net. Dice, Jaccard, and overlay similarity coefficients were used to evaluate the tumor segmentation accuracy and reliability of the Deep tumor segmentation method. Results: The results showed a relatively high similarity coefficient (Dice coefficient: 0.73±0.15, Jaccard coefficient: 0.66±0.17, and overlay coefficient: 0.71±0.15) between deep learning tumor segmentation and the tumor region identified by the NMS method. The results indicate that the deep learning methods may be used as accurate and robust tumor segmentation. Conclusion: Deep learning-based segmentation can play a significant role to increase the segmentation accuracy in clinical application, if their training process is completely automatic and independent from human error.

Abstract An HPLC-DAD method combined with second-order calibration based on the alternating trilinear decomposition (ATLD) algorithm with the aid of region selection was developed to simultaneously and quantitatively characterize the synergistic relationships and cumulative excretion of the four bioactive ingredients of Radix Gentianae Macrophyllae in vivo. Although the analytes spectra substantially overlapped with that of the biological matrix, the overlapping profiles between analytes and co-eluting interferences can be successfully separated and accurately quantified by the ATLD method on the basis of the strength of region selection. The proposed approach not only determined the content change but also revealed the synergistic relationships and the cumulative excretion in vivo of the four ingredients in urine and feces samples collected at different excretion time intervals. In addition, several statistical parameters were employed to evaluate the accuracy and precision of the method. Quantitative results were confirmed by HPLC-mass spectrometry. Satisfactory results indicated that the proposed approach can be utilized to investigate the pharmacokinetics of Radix Gentianae Macrophyllae excretion in vivo. Graphical Abstract

This study was performed to evaluate the plasma vitamin kinetic behavior following oral vitamin supplement administration in pigs, and to determine the bioavailability of vitamins. A total of 36 pigs (fitted with jugular catheters) with an average body weight of 25 ± 2.24 kg were divided into three treatment groups: (1) placebo, (2) non-microencapsulated multivitamins supplement, or (3) lipid matrix microencapsulated multivitamins supplement. The blood samples were obtained starting pre-meal until 72 h post-meal for plasma vitamin analysis. Pharmacokinetic parameters were modeled with a non-compartmental method. The AUC (Area under the curve) from the time of dosing to the time of the last observation, Cmax (Maximum observed concentration), and MRT (Mean residence time) of α-tocopherol from oral non-microencapsulated supplement were significantly lower than oral microencapsulated supplement (p < 0.01). The average relative bioavailability of vitamin A (VA) and vitamin E (VE) from microencapsulated supplement was greater than that from non-microencapsulated supplement, but relative bioavailability of vitamin K3 (VK3) and water-soluble vitamins from microencapsulated supplement was lower than non-microencapsulated supplement. The AUC and Cmax of menadione, thiamine, and riboflavin from microencapsulated supplement were significantly lower than these parameters from oral non-microencapsulated supplement. Lipid matrix microencapsulation was able to delay absorption and improved the bioavailability of VE, whereas there were limited effects of microencapsulation on vitamin D (VD), VK3, and water-soluble vitamins.

In this study, chlorogenic acid (CGA), a phenolic compound widely distributed in fruits and vegetables, was encapsulated into chitosan nanoparticles by ionic gelation method. The particles exhibited the size and zeta potential of 210 nm and 33 mV respectively. A regular, spherical shaped distribution of nanoparticles was observed through scanning electron microscopy (SEM) and the success of entrapment was confirmed by FTIR analysis. The encapsulation efficiency of CGA was at about 59% with the loading efficiency of 5.2%. In vitro ABTS assay indicated that the radical scavenging activity of CAG was retained in the nanostructure and further, the release kinetics study revealed the burst release of 69% CGA from nanoparticles at the end of 100th hours. Pharmacokinetic analysis in rats showed a lower level of Cmax, longer Tmax, longer MRT, larger AUC0–t and AUC0–∞ for the CGA nanoparticles compared to free CGA. Collectively, these results suggest that the synthesised nanoparticle with sustained release property can therefore ease the fortification of food-matrices targeted for health benefits through effective delivery of CGA in body.