Effects of HM30181, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of loperamide in healthy volunteers.

AIMS: HM30181 is a third generation P-glycoprotein (P-gp) inhibitor currently under development. The objectives of this study were to evaluate the effects of a single dose of HM30181 on the pharmacodynamics and pharmacokinetics of loperamide, a P-gp substrate, and to compare them with those of quinidine. METHODS: Eighteen healthy male subjects were administered loperamide alone (period 1) or with loperamide plus quinidine or HM30181 in period 2 or 3, respectively. In period 3, subjects randomly received one of three HM30181 doses: 15, 60 or 180 mg. Changes in pupil size, alertness, oxygen saturation and the oral bioavailability of loperamide were assessed in each period. In addition, the pharmacokinetics of HM30181 were determined. RESULTS: Pupil size, alertness and oxygen saturation did not change over time when loperamide alone or loperamide plus HM30181 was administered while HM30181 significantly increased the systemic exposure to loperamide, i.e. the geometric mean ratio (90% confidence interval) of AUC(0,tlast ) for loperamide with and without HM30181 was 1.48 (1.08, 2.02). Co-administered quinidine significantly increased the systemic exposure to loperamide 2.2-fold (1.53, 3.18), which also markedly reduced pupil size, resulting in a decrease of 24.7 mm h in the area under the effect curve of pupil size change from baseline compared with loperamide alone. CONCLUSIONS: HM30181 inhibits P-gp mainly in the intestinal endothelium, which can be beneficial because pan-inhibition of P-gp, particularly in the brain, could lead to detrimental adverse events. Further studies are warranted to investigate adequately the dose-exposure relationship of HM30181, along with its duration of effect.

Eflapegrastim versus Pegfilgrastim for Chemotherapy-Induced Neutropenia in Korean and Asian Patients with Early Breast Cancer: Results from the Two Phase III ADVANCE and RECOVER Studies.

PURPOSE: We investigated the consistent efficacy and safety of eflapegrastim, a novel long-acting granulocyte-colony stimulating factor (G-CSF), in Koreans and Asians compared with the pooled population of two global phase 3 trials. Materials and Methods: Two phase 3 trials (ADVANCE and RECOVER) evaluated the efficacy and safety of fixed-dose eflapegrastim (13.2 mg/0.6 mL [3.6 mg G-CSF equivalent]) compared to pegfilgrastim (6 mg based on G-CSF) in breast cancer patients who received neoadjuvant or adjuvant docetaxel/cyclophosphamide. The primary objective was to demonstrate non-inferiority of eflapegrastim compared to pegfilgrastim in mean duration of severe neutropenia (DSN) in cycle 1, in Korean and Asian subpopulations. RESULTS: Among a total of 643 patients randomized to eflapegrastim (n=314) or pegfilgrastim (n=329), 54 Asians (29 to eflapegrastim and 25 to pegfilgrastim) including 28 Koreans (14 to both eflapegrastim and pegfilgrastim) were enrolled. The primary endpoint, DSN in cycle 1 in the eflapegrastim arm was non-inferior to the pegfilgrastim arm in Koreans and Asians. The DSN difference between the eflapegrastim and pegfilgrastim arms was consistent across populations: -0.120 days (95% confidence interval [CI], -0.227 to -0.016), -0.288 (95% CI, -0.714 to 0.143), and -0.267 (95% CI, -0.697 to 0.110) for pooled population, Koreans and Asians, respectively. There were few treatment-related adverse events that caused discontinuation of eflapegrastim (1.9%) or pegfilgrastim (1.5%) in total and no notable trends or differences across patient populations. CONCLUSION: This study may suggest that eflapegrastim showed non-inferior efficacy and similar safety compared to pegfilgrastim in Koreans and Asians, consistently with those of pooled population.

Structural characterization of immunoglobulin G using time-dependent disulfide bond reduction.

Time-dependent reduction of the disulfide bonds of immunoglobulin G (IgG) using dithiothreitol (DTT) was used to characterize the structure of IgG. After treatment with DTT, gel electrophoresis was used to separate the resulting IgG fragments, which were subsequently quantified. Using this approach, the disulfide bond between a light chain and a heavy chain was determined to be cleaved faster than the disulfide bonds between two heavy chains.

Phase 1 Studies of Poziotinib, an Irreversible Pan-HER Tyrosine Kinase Inhibitor in Patients with Advanced Solid Tumors.

PURPOSE: Poziotinib, a pan-human epidermal growth factor receptor 2 (HER) tyrosine kinase inhibitor, has shown potent activity againstwild type of epidermal growth factorreceptor(EGFR) family kinases including EGFR, HER2, and HER4 and EGFR-mutant cells in vitro. Two phase I studies were conducted to determine the maximum tolerated dose (MTD), pharmacokinetics, safety, and antitumor activity against advanced solid tumors. MATERIALS AND METHODS: Standard 3+3 dose escalation scheme using two different dosing schedules were studied: once daily, 14-day on, and 7-day off (intermittent schedule); and once daily continuous dosing with food effect. Additional patients were enrolled in an expansion cohort. RESULTS: A total of 75 patients were enrolled in the two studies. The most common drug-related treatment-emergent adverse eventswere diarrhea,rash, stomatitis, pruritus, and anorexia. Doselimiting toxicities were grade 3 diarrhea in the intermittent schedule and grade 3 anorexia and diarrhea in the continuous dosing schedule. The MTDs were determined as 24 mg/day in the intermittent dosing schedule and 18 mg/day in the continuous dosing schedule. Eight (16%) and 24 (47%) of 51 evaluable patients in the intermittent schedule achieved partial response (PR) and stable disease (SD), respectively. Four (21%) and six (32%) of 19 evaluable patients in continuous dosing schedule achieved PR and SD, respectively. Patients with PR (n=7) or SD ≥ 12 weeks (n=7) had HER2 amplification (n=7; breast cancer, 5; and stomach cancer, 2) and EGFR amplification (n=1, squamous cell lung cancer). CONCLUSION: Poziotinib was safe and well tolerated in patients with advanced solid tumors. It showed an encouraging activity against EGFR-mutant and HER2-amplified cancers.

A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma Who Have Acquired Resistance to EGFR-Tyrosine Kinase Inhibitors.

PURPOSE: We examined the efficacy of poziotinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with activating EGFR mutations, who developed acquired resistance (AR) to EGFR-TKIs. MATERIALS AND METHODS: This single-arm phase II study included EGFR-mutant lung adenocarcinoma with AR to erlotinib or gefitinib based on the Jackman criteria. Patients received poziotinib 16 mg orally once daily in a 28-day cycle. The primary endpoint was progression-free survival (PFS). Prestudy tumor biopsies and blood samples were obtained to determine resistance mechanisms. RESULTS: Thirty-nine patients were treated. Tumor genotyping was determined in 37 patients; 19 EGFR T790M mutations and two PIK3CA mutations were detected in the prestudy tumors, and seven T790M mutations were detected in the plasma assay. Three (8%; 95% confidence interval [CI], 2 to 21) and 17 (44%; 95% CI, 28 to 60) patients had partial response and stable disease, respectively. The median PFS and overall survival were 2.7 months (95% CI, 1.8 to 3.7) and 15.0 months (95% CI, 9.5 to not estimable), respectively. A longer PFS was observed for patients without T790M or PIK3CA mutations in tumor or plasma compared to those with these mutations (5.5 months vs. 1.8 months, p=0.003). The most frequent grade 3 adverse events were rash (59%), mucosal inflammation (26%), and stomatitis (18%). Most patients required one (n=15) or two (n=15) dose reductions. CONCLUSION: Low activity of poziotinib was detected in patients with EGFR-mutant non-small cell lung cancer who developed AR to gefitinib or erlotinib, potentially because of severe-toxicityimposed dose limitation.

An optimised method for the accurate determination of zeranol and diethylstilbestrol in animal tissues using isotope dilution-liquid chromatography/mass spectrometry.

Isotope dilution-liquid chromatography/mass spectrometry (ID-LC/MS) has been established as a candidate reference method for the accurate determination of growth promoters (zeranol, taleranol, and diethylstilbesterol) in raw meat samples. Sample preparation processes including an enzymatic hydrolysis, extraction, and SPE clean-up were optimised. The sensitivity difference of trans- and cis-diethylstilbestrol (isomerizing in sample preparation processes) by the LC/MS was measured by running a trans/cis mixture (ratio measured by a quantitative NMR) with and without sample matrices, and applied for the determination of total diethylstilbestrol. Validity, repeatability, and reproducibility of the analytical method were tested by measuring gravimetrically fortified samples (chicken breast, bovine muscles, and porcine muscle) in a number of different time periods. Measurement results agreed with the fortified values within their uncertainties. The method provided accurate results of the target analytes in the range of 0.05-15 µg/kg with the relative expanded uncertainty of 2-15%.