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DISSOLUTION AND TRANSLATIONAL MODELING STRATEGIES ENABLING PATIENT-CENTRIC PRODUCT DEVELOPMENT M-CERSI WORKSHOP SUMMARY REPORT
No full textAbstract
On May 15th -17th 2017, the US Food and Drug Administration (FDA) and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) held a workshop at the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), Baltimore campus to discuss the role of dissolution testing and translational modeling and simulation in enabling patient-centric drug product development. This three-day event was attended by roughly 120 scientists from international regulatory agencies, major global pharmaceutical companies and academia. The recognition of patient-centric drug product development by the FDA and the scientific community is not a new concept, and yet, the number of submissions containing data that link product quality attributes to in vivo performance in order to enhance drug product understanding appears stagnant. In this regard, one of the areas of focus of the workshop was to discuss the gaps in knowledge and challenges that the scientific community is facing to establish this in vitro-in vivo link.
The first day of the meeting focused on the role of dissolution testing to guide formulation candidate selection, to assess and to mitigate biopharmaceutics risks, and as a quality control tool. On the second day, approaches to establish a link between in vitro testing and in vivo drug product performance were presented. Overall success rates and challenges in establishing in vitro – in vivo correlations (IVIVC) via traditional and modern physiologically based pharmacokinetic (PBPK) modeling and simulation approaches were discussed. Day 3 provided an opportunity for regulatory agencies and industry to discuss their expectations for establishing clinically relevant drug product specifications. After the morning presentations, afternoon breakout sessions served as platforms for the discussion of key and controversial topics.
The meeting concluded with a commitment to continue the dialogue between regulators, industry and academia to advance overall product quality understanding
Photoredox Iridium-Nickel Dual Catalyzed Decarboxylative Arylation Cross-Coupling: From Batch to Continuous Flow via Self-Optimizing Segmented Flow Reactor
No full textPhotoredox decarboxylative arylation cross-coupling via Iridium-Nickel dual catalysis has emerged as a valuable method for Csp2—Csp3 bond formation and the demand for finding scalable continuous flow conditions is high. Herein, we describe the application of the segmented flow (“microslug”) reactor equipped with a newly designed photochemistry module for material-efficient reaction screening and optimization. The study utilized Cbz-protected proline and 4’-bromoacetophenone as the model substrates to validate the chemistry on the fully automated system. Through the deployment of a self-optimizing algorithm, we were able to develop optimal flow conditions for the model reaction, simultaneously accounting for the effects of continuous variables (temperature and time), and discrete variables (base and catalyst). The optimized conditions identified at microscale were found to directly transfer to Vapourtec® UV-150 continuous flow photoreactor, enabling predictable scale-up operation at hundreds of milligrams per hour scale. This optimization approach was expanded to other halide coupling partners that were low-yielding in batch reactions, highlighting the practical application of this optimization platform when developing conditions for photochemical synthesis in continuous flow
Digital Therapeutics—An Integral Component of Digital Innovation in Drug Development
No full textDigital therapeutics represent a new treatment modality in which digital systems such as smartphone apps are used as regulatory-approved, prescribed therapeutic interventions to treat medical conditions. In this paper, we provide a critical overview of the rationale for investing into such novel modalities, including the unmet medical needs addressed by digital therapeutics and the potential for reducing current costs of medical care. We also discuss emerging pathways to regulatory approval and how innovative business models are enabling further growth in the development of digital therapeutics. We conclude by providing some recent examples of digital therapeutics that have gained regulatory approval and highlight opportunities for the near future
Loss of PRMT5 promotes PDGFRa degradation during oligodendrocyte differentiation and myelination
No full textPlatelet derived growth factor receptor α (PDGFRα) signaling is required for proliferation, commitment and maintenance of oligodendrocyte (OL) precursor cells (OPCs). PDGFRα signaling promotes OPC homeostasis and its attenuation signals OPC differentiation and maturation triggering the onset of myelination of the central nervous system (CNS). The initial steps of how PDGFRα signaling is attenuated are still poorly understood. Herein we show that decreased Protein Arginine MethylTransferase5 (PRMT5) expression, as occurs during OPC differentiation, is involved in the down-regulation of PDGFRα by modulating its cell surface bioavailability leading to its degradation in a Cbl-dependent manner. Mechanistically, loss of arginine methylation at R554 of the PDGFRα intracellular domain reveals a masked Cbl binding site at Y555. Physiologically, depletion of PRMT5 in OPCs results in severe CNS myelination defects. We propose that decreased PRMT5 activity initiates PDGFRα degradation to promote OL differentiation. More broadly, inhibition of PRMT5 may be used therapeutically to manipulate PDGFRα bioavailability
Ranking Itraconazole Formulations Based on the Flux through Artificial Lipophilic Membrane
No full textPurpose: The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature. Method: Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane. In addition to the flux evaluations, changes in solid state as a function of time were investigated to gain further insight into the flux changes observed over time for the solid dispersion formulations. Results: Initial flux values from Sporanox®, the nanosuspension and the micronized ITZ showed ratios of 52/4/1 with a decreasing flux from nanosuspension and both solid dispersions after 2.5–3 h. Although the initial flux from the Soluplus® formulation was 2.2 times lower than the one observed for Sporanox®, the decrease in flux observed was milder and became ~ 2 times higher than Sporanox® after approximately 2.5 h. The total amounts of ITZ in the receiver compartment after 240 min showed the same rank order as the rodent AUCs of these formulations reported in literature. Conclusions: It was demonstrated that in vitro flux measurements using lipophilic artificial membranes could correctly reproduce the rank order of PK results for ITZ formulations. The drop in flux over time for solid dispersions could be backed by experimental indications of crystallization
Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases
No full textObjective: Use of the frailty index to measure an accumulation of deficits has been proven a valuable method for identifying elderly people at risk for increased vulnerability, disease, injury, and mortality. However, complementary molecular frailty biomarkers or ideally biomarker panels have not yet been identified. We conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. Methods: Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, AnAge, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. Factors broadly expressed, related to several “hallmark of aging” pathways as well as used or predicted as biomarkers in other disease settings, particularly age-related pathologies, were identified. This set of biomarkers was further expanded according to the expertise and experience of the authors. In the next step, biomarkers were assigned to six “hallmark of aging” pathways, namely (1) inflammation, (2) mitochondria and apoptosis, (3) calcium homeostasis, (4) fibrosis, (5) NMJ (neuromuscular junction) and neurons, (6) cytoskeleton and hormones, or (7) other principles and an extensive literature search was performed for each candidate to explore their potential and priority as frailty biomarkers. Results: A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. Conclusion: Biomarker panels for frailty would be of high value and better than single markers. Based on our search we would propose a core panel of frailty biomarkers consisting of (1) CXCL10 (C-X-C motif chemokine ligand 10), IL-6 (interleukin 6), CX3CL1 (C-X3-C motif chemokine ligand 1), (2) GDF15 (growth differentiation factor 15), FNDC5 (fibronectin type III domain containing 5), vimentin (VIM), (3) regucalcin (RGN/SMP30), calreticulin, (4) PLAU (plasminogen activator, urokinase), AGT (angiotensinogen), (5) BDNF (brain derived neurotrophic factor), progranulin (PGRN), (6) α-klotho (KL), FGF23 (fibroblast growth factor 23), FGF21, leptin (LEP), (7) miRNA (micro Ribonucleic acid) panel (to be further defined), AHCY (adenosylhomocysteinase) and KRT18 (keratin 18). An expanded panel would also include (1) pentraxin (PTX3), sVCAM/ICAM (soluble vascular cell adhesion molecule 1/Intercellular adhesion molecule 1), defensin α, (2) APP (amyloid beta precursor protein), LDH (lactate dehydrogenase), (3) S100B (S100 calcium binding protein B), (4) TGFβ (transforming growth factor beta), PAI-1 (plasminogen activator inhibitor 1), TGM2 (transglutaminase 2), (5) sRAGE (soluble receptor for advanced glycosylation end products), HMGB1 (high mobility group box 1), C3/C1Q (complement factor 3/1Q), ST2 (Interleukin 1 receptor like 1), agrin (AGRN), (6) IGF-1 (insulin-like growth factor 1), resistin (RETN), adiponectin (ADIPOQ), ghrelin (GHRL), growth hormone (GH), (7) microparticle panel (to be further defined), GpnmB (glycoprotein nonmetastatic melanoma protein B) and lactoferrin (LTF). We believe that these predicted panels need to be experimentally explored in animal models and frail cohorts in order to ascertain their diagnostic, prognostic and therapeutic potential
Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses
No full textPancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelinredirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-α and IL-2 (Ad5/3-E2F-D24-TNFa-IRES-IL2, or OAd-TNFa-IL2) would improve efficacy. OAd-TNFa-IL2 enhanced the antitumor efficacy of meso-CAR T cells in human-PDA-xenograft immunodeficient mice and efficacy was associated with robustly increased tumor-infiltrating lymphocytes (TILs), enhanced and prolonged T cell function. Mice treated with parental OAd combined with meso-CAR T developed tumor metastasis to the lungs even if primary tumors were controlled. However, no mice treated with combined OAd-TNFa-IL2 and meso-CAR T died of tumor metastasis. We also evaluated this approach in a syngeneic mouse tumor model by combining adenovirus expressing murine TNF-α and IL-2 (Ad-mTNFa-mIL2) and mouse CAR T cells. This approach induced significant tumor regression in mice engrafted with highly aggressive and immunosuppressive PDA tumors. Ad-mTNFa-mIL2 increased both CAR T cell and host T cell infiltration to the tumor and altered host tumor immune status with M1 polarization of macrophages and increased dendritic cell maturation. These findings indicate that combining cytokine-armed oncolytic adenovirus to enhance the efficacy of CAR T cell therapy is a promising approach to overcome the immunosuppressive TME for the treatment of PDA
Association of somatic driver alterations with prognosis in postmenopausal, hormone receptor-positive, HER2-negative early breast cancer - A secondary analysis of the BIG 1-98 randomized clinical trial
No full textImportance:
A range of somatic driver alterations have been described in estrogen receptor positive, HER2-negative (ER+/HER2-) early breast cancer (BC), however the clinical relevance is unknown.
Objective:
To investigate associations of driver alterations with prognosis and the role of PIK3CA mutations in prediction of benefit to endocrine therapy in postmenopausal patients with ER+/HER2- early BC treated with tamoxifen or letrozole.
Design, setting, participants, and interventions:
The BIG 1-98 trial randomized 8,010 post-menopausal patients with hormone receptor-positive operable invasive BC to monotherapy with letrozole or tamoxifen, or a sequential strategy for 5 years. Driver alterations were characterized using next generation sequencing in primary tumors from a subset of 764 patients from 7329 eligible ER+/HER2- patients, with 841 distant recurrences after 8.1 years median follow-up. To correct for the over-sampling of distant recurrences, weighted analysis methods were used.
Main outcomes and measures:
We analyzed the prevalence of driver alterations, associations with 5 clinicopathological factors, distant recurrence-free interval, and treatment interactions. Multivariable analyses were performed to adjust for clinicopathological factors
Considerations from the IQ Induction Working Group in Response to Drug-Drug Interaction Guidances from Regulatory Agencies: Focus on CYP3A4 mRNA in vitro response thresholds, variability, and clinical relevance
No full textHere the IQ induction working group presents an assessment of best practice for data interpretation of in vitro induction, specifically, response thresholds, variability, application of controls and translation to clinical risk assessment with focus on CYP3A4 mRNA. Single concentration control data and Emax/EC50 data for prototypical CYP3A4 inducers were compiled from many human hepatocyte donors, repeated over time, in different laboratories. Clinical CYP3A induction and in vitro data were gathered for 51 compounds, 16 of which were proprietary from IQ member companies. A large degree of variability was observed in both the clinical and in vitro induction responses gathered, yet analysis confirmed in vitro data are able to predict clinical induction risk. Following extensive examination of this large dataset, the following recommendations are proposed:
• CYP induction should continue to be evaluated in three separate human donors in vitro.
• In light of empirically divergent responses in rifampicin control and most test inducers, normalization of data to percent positive control appears to be of limited benefit.
• Two-fold induction, with concentration dependence, is an acceptable threshold for positive identification of in vitro CYP3A4 mRNA induction.
• To reduce the risk of false positives, in the absence of a concentration dependent response, induction ≥ 2-fold should be observed in more than one donor to classify a compound as an in vitro inducer.
• If qualifying a compound as negative for CYP3A4 mRNA induction, the magnitude of maximal rifampicin response in that donor should be ≥10-fold.
• Inclusion of a negative control adds no value beyond that of the vehicle control
Copper-Catalyzed Oxidative Cleavage of Electron-Rich Olefins in Wa-ter at Room Temperature
No full textA copper-catalyzed oxidative cleavage of electron-rich olefins into their corresponding carbonyl derivatives is described as an alternative to ozonolysis. The scope includes various precursors to aryl ketone derivatives, as well as oxida-tions of enol ethers bearing atypical alkyl and dialkyl substitution, the first of their kind among such metal catalyzed alkene cleavage reactions. The use of an inexpensive copper salt, room temperature conditions, an aerobic atmosphere, and water as the global reaction medium highlight the green features of this new method. Associated mechanistic investigations are also presented