7196 research outputs found
Sort by
Considerations for Human ADME Strategy and Design Paradigm Shift(s) - An Industry White Paper.
No full textThe human absorption, distribution, metabolism, and excretion (hADME) study is the cornerstone of the clinical pharmacology package for small molecule drugs, providing comprehensive information on the rates and routes of disposition and elimination of drug-related material in humans through the use of 14 C-labeled drug. Significant changes have already been made in the design of the hADME study for many companies, but opportunity exists to continue to re-think both the design and timing of the hADME study in light of the potential offered by newer technologies, that enable flexibility in particular to reducing the magnitude of the radioactive dose used. This paper provides considerations on the variety of current strategies that exist across a number of pharmaceutical companies and on some of the ongoing debates around a potential move to the so called "human first/human only" approach, already adopted by at least one company. The paper also provides a framework for continuing the discussion in the application of further shifts in the paradigm
Enzyme engineering enables inversion of substrate stereopreference of the halogenase WelO5*
No full textEnzymatic late-stage diversification of small molecules has the potential to rapidly generate diversity in compound libraries dedicated to drug discovery. In this context, freestanding Fe(II)/α-ketoglutarate-dependent halogenases have raised particular interest as this enzyme family allows the otherwise difficult regio- and stereoselective halogenation of unactivated C(sp3)-H bonds. Here, we report the development of two engineered variants of the halogenase WelO5* for the racemic resolution of a mixture of stereoisomers generated in the synthesis of a bioactive martinelline-derived fragment. By screening a 3-site combinatorial variant library, we could identify two variants exhibiting exquisite substrate selectivity towards the desired enantiomers. Strikingly, the inversion of substrate stereopreference between the halogenase variants was achieved by varying only three residues in the active site. Protein crystallization and subsequent structure elucidation of the wildtype enzyme and a WelO5* variant shed light on the factors governing substrate acceptance and selectivity
PLGA implants for controlled drug release: Impact of the diameter
No full textThe aim of this study was to better understand the importance of the diameter of poly(lactic-co-glycolic acid) (PLGA)-based implants on system performance, in particular the control of drug release. Different types of ibuprofen-loaded implants were prepared by hot melt extrusion using a Leistritz Nano 16 twin-screw extruder. Drug release was measured in well agitated phosphate buffer pH7.4 bulk fluid and in agarose gels in Eppendorf tubes or transwell plates. Dynamic changes in the implants' dry & wet mass, volume, polymer molecular weight as well as inner & outer morphology were monitored using gravimetric analysis, optical macroscopy, gel permeation chromatography and scanning electron microscopy. The physical states of the drug and polymer were determined by DSC. Also pH changes in the release medium were investigated. Irrespective of the type of experimental set-up, the resulting absolute and relative drug release rates decreased with increasing implant diameter (0.7-2.8 mm). Bi-phasic drug release was observed in all cases from the monolithic solutions (ibuprofen was dissolved in the polymer): A zero order release phase was followed by a final, rapid drug release phase (accounting for 80-90% of the total drug dose). The decrease in the relative drug release rate with increasing system diameter can be explained by the increase in the diffusion pathway lengths to be overcome. Interestingly, also the onset of the final rapid drug release phase was delayed with increasing implant diameter. This can probably be attributed to the higher mechanical stability of thicker devices, offering more resistance to substantial entire system swelling
Single cell RNA-seq analysis reveals temporally-regulated and quiescence-regulated gene expression in Drosophila larval neuroblasts
No full textThe mechanisms that generate neural diversity during development remains largely unknown. Here, we use scRNA-seq methodology to discover new features of the Drosophila larval CNS across several key developmental timepoints. We identify multiple progenitor subtypes - both stem cell-like neuroblasts and intermediate progenitors - that change gene expression across larval development, and report on new candidate markers for each class of progenitors. We identify a pool of quiescent neuroblasts in newly hatched larvae and show that they are transcriptionally primed to respond to the insulin signaling pathway to exit from quiescence, including relevant pathway components in the adjacent glial signaling cell type. We identify candidate "temporal transcription factors" (TTFs) that are expressed at different times in progenitor lineages. Our work identifies many cell type specific genes that are candidates for functional roles, and generates new insight into the differentiation trajectory of larval neurons
People of TM: Video of Danny Tuckwell
No full textThe video will be used for an external social media engagement campaign on platforms like linked-in, facebook etc. featruing stories of people in TM. No IP related content
JDQ443, a Structurally Novel, Pyrazole-Based, Covalent Inhibitor of KRASG12C for the Treatment of Solid Tumors.
No full textRapid emergence of tumor resistance via RAS pathway reactivation has been reported from clinical studies of covalent KRASG12C inhibitors. Thus, inhibitors with broad potential for combination treatment and distinct binding modes to overcome resistance mutations may prove beneficial. JDQ443 is an investigational covalent KRASG12C inhibitor derived from structure-based drug design followed by extensive optimization of two dissimilar prototypes. JDQ443 is a stable atropisomer containing a unique 5-methylpyrazole core and a spiro-azetidine linker designed to position the electrophilic acrylamide for optimal engagement with KRASG12C C12. A substituted indazole at pyrazole position 3 results in novel interactions with the binding pocket that do not involve residue H95. JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188)
Non-Human (NHP) husbandry and impact on NHP health: outcomes from a DruSafe/3Rs industrial benchmark survey
No full textThe presence of health issues (diarrhea, poor body condition) in non-human primates (NHPs) can impact animal welfare, confound toxicity study data, and lead to animal exclusion from studies. A working group cosponsored by DruSafe and 3Rs Translational and Predictive Sciences Leadership Groups of the IQ Consortium conducted a survey to benchmark quarantine, pre-study screening, husbandry, and veterinary care practices and their impact on NHP health. Nineteen companies participated in the survey providing separate responses for studies conducted in-house and at Contract Research Organizations (CROs) from 3 regions (North America (NA), Europe and Asia) for an aggregate of 33 responses. A majority of responding companies conducted studies at NA CROs (39%) or in-house (36%) using primarily Chinese (33%) or Cambodian (27%) and to a lesser extent Vietnam (18%) or Mauritian (15%) origin NHPs. Forty-Five percent of responses had pre-study health issues (fecal abnormalities, etc.) on ≥ 1 studies with the highest incidence observed in Vietnam origin NHPs (80%). The survey suggested variable pre-screening and quarantine practices across facilities. Husbandry practices including behavioral assessments, environmental enrichment and consistent diets were associated with a lower incidence of health issues. The survey also benchmarked approaches used to diagnose and manage abnormal feces in NHPs and has provided strategies to minimize impact on NHP health. The survey highlighted opportunities for harmonizing screening criteria across industryand for improving tracking and sharing of health screening results, leading to further refinement of NHP veterinary care practices, higher quality studies, and reduced NHP use
Tablet disintegration and dispersion under in vivo-like hydrodynamic conditions
No full textDisintegration and dispersion are functional properties of the tablet relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information about these complex processes and is considered for being not comparable with the biorelevant behaviour, e.g., due to the frequent appearance of high hydrodynamic forces. 3D tomographic laser-induced fluorescence imaging (3D Tomo-LIF) technique is applied to analyse tablet disintegration and dispersion by determination of disintegration time (DT) and time-resolved particle size distribution analysis in close proximity to the tablet in a continuously operated flow channel, adjustable to very low fluid velocities. A case study on tablets containing pharmaceutical polymers labelled with a fluorescence dye, a filler, disintegrants and different porosities is presented to demonstrate the functionality and precision of the novel method. DT results from 3D Tomo-LIF are compared with results from the SDT, confirming the analytical limitations of the pharmacopoeia disintegration test. Instead, the 3D Tomo-LIF method provides an in-depth understanding of the functional behaviour of the tablet material, composition and structural properties under in vivo-like hydrodynamic forces regarding disintegration and the temporal progress of dispersion. We are considering the 3D Tomo-LIF in vitro method as improved biorelevant and biopredictive in terms of hydrodynamic conditions in the human stomach
Pharmacokinetics of asciminib in the presence of CYP3A or P-gp inhibitors, CYP3A inducers, and acid-reducing agents.
No full textAsciminib is a first-in-class inhibitor of BCR::ABL1, specifically targeting the ABL myristoyl pocket. Asciminib is a substrate of CYP3A4 and P-glycoprotein (P-gp) and possesses pH-dependent solubility in aqueous solution. This report summarizes the results of two phase I studies in healthy subjects aimed at assessing the impact of CYP3A and P-gp inhibitors, CYP3A inducers and acid-reducing agents (ARAs) on the pharmacokinetics (PK) of asciminib (single dose of 40 mg). Asciminib exposure (area under the curve [AUC]) unexpectedly decreased by ~40% when administered concomitantly with the strong CYP3A inhibitor itraconazole oral solution, whereas maximum plasma concentration (Cmax ) decreased by ~50%. However, asciminib exposure was slightly increased in subjects receiving an itraconazole capsule (~3%) or clarithromycin (~35%), another strong CYP3A inhibitor. Macroflux studies showed that cyclodextrin (present in high quantities as excipient [40-fold excess to itraconazole] in the oral solution formulation of itraconazole) decreased asciminib flux through a lipid membrane by ~80%. The AUC of asciminib was marginally decreased by concomitant administration with the strong CYP3A inducer rifampicin (by ~13-15%) and the strong P-gp inhibitor quinidine (by ~13-16%). Concomitant administration of the ARA rabeprazole had little or no effect on asciminib AUC, with a 9% decrease in Cmax . The treatments were generally well tolerated. Taking into account the large therapeutic window of asciminib, the observed changes in asciminib PK following multiple doses of P-gp, CYP3A inhibitors, CYP3A inducers, or ARAs are not considered to be clinically meaningful. Care should be exercised when administering asciminib concomitantly with cyclodextrin-containing drug formulations
Crystal structure of 2-PG bound to BPGM
No full textRed blood cells contain the enzyme, 2,3, Bisphophateglycerate mutase, BPGM. This enzyme carries out 3 catalytic reactions. The phosphatase reaction degrades 2,3-phosphoglyderate forming 3-phosphoglyderate and inorganic phosphate. For decades, 2-phosphoglyceric has been known as an activator of this reaction; however, its mechanism of action has been unknown. The crystal structure of BPGM complexed with 2-PG reveals the mechanism of action of this activator