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Use of PBPK Modeling for Predicting Drug-Food Interactions: An Industry Perspective
No full textThe effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low (> 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here
Scale up synthesis of IID572: A new β-lactamase inhibitor
No full textThe new potentially best-in-class β-lactamase inhibitor IID572 was discovered by a late stage functionalization approach. An alternative scalable synthesis was developed to satisfy the short-term need for tox studies. The two key features were an intramolecular azomethine ylide [2+3] cycloaddition that allowed the quick formation of molecular complexity from cheap starting material and an efficient enzymatic resolution that resulted in high optical purity of a key intermediate
Bimagrumab for treatment of sarcopenia in community-dwelling older adults: a phase II, randomized, controlled trial
No full textBackground: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown.
Objective: To confirm the safety and efficacy of bimagrumab on skeletal muscle mass, strength, and physical function in community-dwelling older adults with sarcopenia.
Design: Randomized, double-blind, placebo-controlled.
Setting: 38 sites in 13 countries.
Participants: 180 community-dwelling, men and women aged ≥70 years meeting gait speed and skeletal muscle criteria for sarcopenia.
Intervention: Bimagrumab 700 mg (n=113) or placebo (n=67) monthly for 6-months with appropriate diet and home-based exercise.
Measurements: Short Physical Performance Battery (SPPB), 6-minute walk distance (6MWD), gait speed, handgrip strength, total lean body mass (LBM), and standard safety parameters.
Results: 159/180 (88.3%) participants (mean age: 79.1 years; 60.6% women) completed the study. Bimagrumab was safe, well-tolerated and increased LBM by 6.0% over placebo (P<0.001). The mean SPPB score increased by 1.34 (0.90–1.77, mean, 95%CI) with bimagrumab versus 1.03 (0.53–1.52) with placebo (P=0.134); 6MWD increased by 24.60 m (7.65–41.56 m) versus 14.30 m (−4.64–33.23 m; P=0.163); and gait speed increased by 0.14 m/s (0.09–0.18 m/s) versus 0.11 m/s (0.05–0.16 m/s; P=0.161). Handgrip strength did not change.
Limitation: Powered only for key functional endpoints.
Conclusion: Bimagrumab treatment over 6-months was safe, well-tolerated and increased LBM in community-dwelling older adults with sarcopenia. Appropriate nutrition and exercise improved physical performance in this vulnerable population; bimagrumab did not significantly enhance this effect. At the completion of the study, a majority of participants in both treatment groups no longer met sarcopenia criteria. Sarcopenia, an increasing cause of disability in the elderly, is reversible with proper diet and exercise.
ClinicalTrials.gov identifier: NCT02333331
Keywords: bimagrumab; sarcopenia; muscle; lean body mass; SPPB; gait speed;
6-minute walk tes
Development of the first reference panel for qualification and validation of cytokine release assay platforms - Report of an international collaborative study
No full textImmunomodulatory therapeutics such as monoclonal antibodies (mAb) carry an inherent risk of undesired immune reactions. One such risk is cytokine release syndrome (CRS), a rapid systemic inflammatory response characterized by the secretion of pro-inflammatory cytokines from immune cells. It is crucial for patient safety to correctly identify potential risk of CRS prior to first-in-human dose administration. For this purpose, a variety of in vitro cytokine release assays (CRA) are routinely used as part of the preclinical safety assessment of novel therapeutic mAbs. One of the challenges for the development and comparison of CRA performance is the lack of availability of standard positive and negative control mAbs for use in assay qualification. To address this issue, the National Institute for Biological Standards and Control (NIBSC) developed a reference panel of lyophilised mAbs known to induce CRS in the clinic: human anti-CD52, mouse anti-CD3 and human superagonistic (SA) anti-CD28 mAb manufactured according to the respective published sequences of Campath-1H® (alemtuzumab, IgG1) , Orthoclone OKT-3® (muromonab, IgG2a) and TGN1412 (theralizumab, IgG4), as well as three isotype matched negative controls (human IgG1, mouse IgG2a and human IgG4, respectively). The relative capacity of these control mAbs to stimulate the release of IFN-, IL-2, TNF- and IL-6 in vitro was evaluated in eleven laboratories in an international collaborative study mediated through the HESI Immuno-safety Technical Committee Cytokine Release Assay Working Group. Participants tested the NIBSC mAbs in a variety of CRA platforms established at each institution. This paper presents the results from the centralised cytokine quantification on all the plasma/supernatants corresponding to the stimulation of immune cells in the different CRA platforms by a single concentration of each mAb. Each positive control mAb induced cytokine release in the different CRA tested which was ≥ 3-fold above levels observed with its negative control mAb. There was a high inter-laboratory variability in the levels of cytokines produced, but similar patterns of response were observed across laboratories that replicated the cytokine release patterns previously published for the respective clinical therapeutic mAbs. Therefore, the positive and negative mAbs are suitable as a reference panel for the qualification and validation of CRAs, comparison of different CRA platforms (e.g. solid vs aqueous phase), and intra- and inter-laboratory comparison of CRA performance. Thus, the use of this panel of positive and negative control mAbs will increase the confidence in the robustness of a CRA platform to identify a potential CRS risk for novel immunomodulatory therapeutic candidates
Biocatalysis: Enzymatic Synthesis for Industrial Applications
No full textBiocatalysis has found numerous applications in various fields as an alternative to chemical catalysis. The use of enzymes in organic synthesis, especially to make chiral compounds for pharmaceuticals as well for the flavors and fragrance industry, are the most prominent examples. In addition, biocatalysts are also used on large scale to make specialty and even bulk chemicals. This review intends to give illustrative examples in this field with a special focus on scalable chemical production using enzymes. It also discusses the opportunities and limitations of enzymatic syntheses at distinct examples and provides an outlook on emerging enzyme classes with potential for industrial applications
An ABSINTH-Based Protocol for Predicting Binding Affinities Between Proteins and Small Molecules
No full textThe core task in computational drug discovery is to accurately predict binding free energies in receptor-ligand systems for large libraries of putative binders. Here, the ABSINTH implicit solvent model and force field is extended to describe small, organic molecules and their interactions with proteins. We show that an automatic pipeline based on partitioning arbitrary molecules into substructures corresponding to model compounds with known free energies of solvation can be combined with the CHARMM general force field into a method that is successful at the two important challenges a scoring function faces in virtual screening work flows: it ranks known binders with correlation values rivaling that of comparable state-of-the-art methods, and it enriches true binders in a set of decoys. Our protocol introduces innovative modifications to common virtual screening workflows, notably the use of explicit ions as competitors and the integration over multiple protein and ligand species differing in their protonation states. We demonstrate the value of modifications to both the protocol and to ABSINTH itself. We conclude by discussing limitations of high-throughput implicit methods like the one proposed here
Two distinct immunopathological profiles in autopsy lungs of COVID-19
No full textCoronavirus Disease 19 (COVID-19) is a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has grown to a worldwide pandemic with substantial mortality. Immune mediated damage has been proposed as a pathogenic factor, but immune responses in lungs of COVID-19 patients remain poorly characterized. Here we show transcriptomic, histologic and cellular profiles of post mortem COVID-19 (n = 34 tissues from 16 patients) and normal lung tissues (n = 9 tissues from 6 patients). Two distinct immunopathological reaction patterns of lethal COVID-19 are identified. One pattern shows high local expression of interferon stimulated genes (ISGhigh) and cytokines, high viral loads and limited pulmonary damage, the other pattern shows severely damaged lungs, low ISGs (ISGlow), low viral loads and abundant infiltrating activated CD8+ T cells and macrophages. ISGhigh patients die significantly earlier after hospitalization than ISGlow patients. Our study may point to distinct stages of progression of COVID-19 lung disease and highlights the need for peripheral blood biomarkers that inform about patient lung status and guide treatment
Dixon's Q-test and Student's t-test to assess analog internal standard response in nonregulated LC-MS/MS bioanalysis
No full textAim: In bioanalytical assays, analyte response is normalized to an internal standard response. When the internal standard works well, it compensates for processing and detection variability. However, in case the internal standard introduces additional variability, due to addition errors or other issues, scientists need to identify this. Results: A new method, using a Q-test for outliers and a t-test to compare internal standard response from different sample types, is applied to 15 cases. The results show that the Q-test/t-test, which uses confidence level rather than arbitrary cut-points, is more discerning of deviations compared with widely used methods. Conclusion: This work may improve the quality of and rationale for the internal standard response monitoring method
Inhibition of IL-1β by canakinumab may be effective against diverse molecular subtypes of lung cancer: An exploratory analysis of the CANTOS trial
No full textIn the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), inhibition of the IL1β inflammatory pathway by canakinumab has been shown to significantly reduce lung cancer incidence and mortality. Here we performed molecular characterization of CANTOS patients who developed lung cancer during the study, including circulating tumor DNA (ctDNA) and soluble inflammatory biomarker analysis. Catalogue of Somatic Mutations in Cancer (COSMIC) database ctDNA mutations were detected in 65% (46/71) of the CANTOS patients with lung cancer, with 51% (36/71) having detectable ctDNA at the time point closest to lung cancer diagnosis and 43% (29/67) having detectable ctDNA at trial randomization. Mutations commonly found in lung cancer were observed with no evidence of enrichment in any mutation following canakinumab treatment. Median time to lung cancer diagnosis in patients with (n = 29) versus without (n = 38) detectable COSMIC ctDNA mutations at baseline was 407 days versus 837 days (P = 0.011). For serum inflammatory biomarker analysis, circulating levels of C-reactive protein (CRP), IL6, IL18, IL1 receptor antagonist, TNFα, leptin, adiponectin, fibrinogen, and plasminogen activator inhibitor-1 were determined. Patients with the highest level of baseline CRP or IL6, both downstream of IL1β signaling, trended toward a shorter time to lung cancer diagnosis. Other inflammation markers outside of the IL1β pathway at baseline did not trend with time to lung cancer diagnosis. These results provide further evidence for the importance of IL1β-mediated protumor inflammation in lung cancer and suggest canakinumab's effect may be mediated in part by delaying disease progression of diverse molecular subtypes of lung cancer