EXTH-15. DRUG SCREENING ON PATIENT GBM CELL CULTURES IDENTIFIES OMACETAXINE MEPESUCCINATE AS A POTENT ANTI-GLIOMA AGENT WITH THE ABILITY TO CROSS THE BLOOD-BRAIN-BARRIER
Ioannis NtafoulisStijn L.W. KoolenChelsea W. J. den HollanderJie JuTrisha V. KersThierry P. P. van den BoschKranthi M. PanthLaura MezzanotteDana A. M. MustafaAndrew StubbsClemens M.F. DirvenSieger LeenstraMartine L.M. Lamfers
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Abstract INTRODUCTION Little progress has been made in the development of effective new therapies for glioblastoma (GBM) the past decades. Fresh patient-derived GBM cell culture models have become the gold standard for GBM drug discovery and development. One of the major obstacles in identifying novel candidate drugs against GBM remains the blood-brain barrier (BBB). Therefore, it is crucial to select drugs with favourable physicochemical properties to cross BBB and reach the tumour tissue in therapeutically effective concentrations. In current drug repurposing approach, we evaluated available anti-cancer agents in our patient-derived drug screening platform against GBM. METHODS The FDA-approved Oncology Drug Set II library was tested on 45 primary GBM cell cultures. We developed a drug shortlisting pipeline combining efficacy data with pharmacodynamic and pharmacokinetic characteristics of each compound. The therapeutic efficacy of the selected agent was assessed in an orthotopic mouse PDX model, while penetration into the CNS by LC/MS/MS. RESULTS Omacetaxine mepesuccinate (OMA) was ranked as one of the most promising candidates applying our drug selection approach. In vitro, OMA revealed anti-tumour activity at IC50 values well-below reported Cmax plasma values in approximately 80% of GBM cultures. NanoString nCounter analysis, revealed DNA damage repair as the main pathway involved in OMA’s anti-tumour effect. Activation of caspase 3/7 activity and decrease of glioma cell invasiveness were also linked to its anti-tumour effect. In vivo, 1mg/kg dose of OMA was found to reach the brain tumour tissue in concentrations similar to the reported IC50 values in vitro. No adverse reactions were noted and a survival benefit was observed in a proportion of the treated mice. CONCLUSIONS At 1 mg/kg, OMA reaches the tumour brain tissue in therapeutically effective concentrations in mice while a moderate therapeutic benefit was observed. Additional in vivo experiments are ongoing investigating higher dosages of OMA and longer exposure.Keywords:
Drug repositioning
Many pharmacokinetic studies of paclitaxel formulations with or without Cremophor (CrEL) have been performed on experimental animals. However, limited studies describe the different pharmacokinetic behaviors of paclitaxel in animals. The different distribution of drug in blood fractions may have great effect on its pharmacokinetic behaviors. Our present study was designed to study the characteristics of paclitaxel distribution in human, rabbit and rat blood, by measuring plasma-to-blood ratio (PBR) of paclitaxel in vitro and in vivo, and analyzing the results of equilibrium dialysis of paclitaxel with erythrocyte, plasma and hemoglobin. It was demonstrated that the paclitaxel PBR values in rat, unlike those in rabbit, are most significantly different from those in human, which may be due to distinct affinity of paclitaxel to blood fractions among different species. The effect of CrEL on increasing paclitaxel plasma concentration and in vitro & in vivo correlation in animal PBR values were observed. The findings in this study are of significance in the evaluation of the newly developed formulations of paclitaxel.
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The aim of this study was to elucidate the inhibition mechanism of 18β‐glycyrrhetic acid (GLY) on cytochrome P450 (CYP) activity and in vivo pharmacokinetic consequences of single GLY dose in rats. An in vitro CYP inhibition study in rat liver microsomes (RLM) was conducted using probe substrates for CYPs. Then, an in vivo pharmacokinetics of intravenous and oral buspirone (BUS), a probe substrate for CYP3A, was studied with the concurrent administration of oral GLY in rats. In the in vitro CYP inhibition study, CYP3A was involved in the metabolism of GLY. Moreover, GLY inhibited CYP3A activity with an IC 50 of 20.1 ± 10.7 μM via a mixed inhibition mechanism. In the in vivo rat pharmacokinetic study, single oral GLY dose enhanced the area under plasma concentration–time curve (AUC) of intravenous and oral BUS, but the extent of increase in AUC was only minimal (1.12–1.45 fold). These results indicate that GLY can inhibit the in vitro CYP3A‐mediated drug metabolism in RLM via a mixed inhibition mechanism. However, the impact of single oral GLY dose on the pharmacokinetics of BUS in rats was limited, showing that GLY could function as merely a weak inhibitor for CYP3A‐mediated drug metabolism in vivo . Copyright © 2015 John Wiley & Sons, Ltd.
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This is a comparative pharmacokinetics study of linezolid (Lzd), and two novel oxazolidinone antibacterial agents-PH027 and PH051-in rabbits to determine if the discrepancy between the in vitro and in vivo activities of the novel compounds is due to pharmacokinetic factors. The pharmacokinetics after IV and oral administration, plasma protein binding and tissue distribution for the three compounds were compared. The elimination half-lives were 52.4 ± 6.3, 68.7 ± 12.1 and 175 ± 46.1 min for Lzd, PH027 and PH051, respectively. The oral bioavailability for Lzd, PH027 and PH051 administered as suspension were 38.7%, 22.1% and 4.73%, which increased significantly when administered as microemulsion to 51.7%, 72.9% and 13.9%. The plasma protein binding were 32-34%, 37-38% and 90-91% for Lzd, PH027 and PH051. The tissue distribution for PH027 and PH051 in all investigated tissues were higher than that for Lzd. It can be concluded that the lower bioavailability of PH027 and PH051 compared to Lzd when administered as suspension is the main cause of their lower in vivo activity, despite their comparable in vitro activity. Differences in the other pharmacokinetic characteristics cannot explain the lower in vivo activity. The in vivo activity of the novel compounds should be re-evaluated using formulations with good oral bioavailability.
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1. AMG 232 is a novel inhibitor of the p53–MDM2 protein–protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data.2. AMG 232 exhibited low clearance (<0.25 × Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74 × Qh) and low oral exposure in dogs (18%).3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered 14C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species.4. The in vitro–in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.
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Objective The single-dose and multi-dose pharmacokinetics of two sustained-release tablet formulations of metformin hydrochloride in fed, 40 healthy volunteers were compared, and their in vitro-in vivo correlations were evaluated. Methods Self-made and imported (Glucophage XP) sustained-release tablets of metformin hydrochloride were administered orally in a single-dose, 1000 mg/d for two times with a 6-day interval, or the multi-dose regimen of 1000 mg/d for two blocks of five-consecutive days with a 14-day interval. The plasma concentrations and pharmacokinetics of metformin hydrochloride were analyzed after administration. The in vivo drug release rate was compared with in vivo Absorption percentage calculated from Wagner-Nelson method for getting the in vitro-in vivo correlation. Result and Conclusion The two formulations have similar phamarcokinetics and bioequivalent, and their in vitro-in vivo correlations are good.
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The taccalonolides are microtubule stabilizers that covalently bind tubulin and circumvent clinically relevant forms of resistance to other drugs of this class. Efforts are under way to identify a taccalonolide with optimal properties for clinical development. The structurally similar taccalonolides AF and AJ have comparable microtubule-stabilizing activities in vitro, but taccalonolide AF has excellent in vivo antitumor efficacy when administered systemically, while taccalonolide AJ does not elicit this activity even at maximum tolerated dose. The hypothesis that pharmacokinetic differences underlie the differential efficacies of taccalonolides AF and AJ was tested. The effects of serum on their in vivo potency, metabolism by human liver microsomes and in vivo pharmacokinetic properties were evaluated. Taccalonolides AF and AJ were found to have elimination half-lives of 44 and 8.1 min, respectively. Furthermore, taccalonolide AJ was found to have excellent and highly persistent antitumor efficacy when administered directly to the tumor, suggesting that the lack of antitumor efficacy seen with systemic administration of AJ is likely due to its short half-life in vivo. These results help define why some, but not all, taccalonolides inhibit the growth of tumors at systemically tolerable doses and prompt studies to further improve their pharmacokinetic profile and antitumor efficacy.
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OBJECTIVE To determine pharmacokinetic and relative bioavailability of diclofence sodium sustained release micropellets(DS?SRMP) in vivo.METHODS UV method was established for assaying serum diclofence sodium concentrations in rabbits. To study theabsorptive kinetics and bioavailability of DS?SRMP. RESULTS The absorption rate of DS?SRMP in vivo was found to conform apparent zero orderkinetics(Ka 0= 12.14% /h)during the first 8 h .CONCLUSIONS The studies of pharmacokinetics in vivo indicated DS SRMP had sustained release effect.The drug concentration in blood was steady after oral administration, it could last longer and reduce the times of adminstration. The preparation release stability, bioavailability and safty.
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AIM:To estabalish the methodology of microdialysis technique in pharmacokinetic(PK) reseach of anticancer drugs in vivo. METHODS:Gemcitabine(GEM) was injected into mice's tail vein.The microdialysate samples from blood were collected after dosing in gemcitabine-treated mices.The concentration of GEM was detected real-time continuously and pharmacokinetic parameters were evaluated.RESULTS:The recovery rate of GEM in vivo was(11.9±2.0)%.It showed that the pharmacokinetics of gemcitabine was two-compartment model in vivo and the elimination and distribution of GEM meets the first kinetics.There were no serious side effects in model mice.CONCLUSION:Microdialysis can be successfully employed in living body to detect the concentration of GEM continuously,which prompts it is possible to study the PK of anticancer drugs in malignant tissues in vivo.
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