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Background and Purpose: Cotadutide is a dual GLP‐1 and glucagon receptor agonist with balanced agonistic activity at each receptor designed to harness the advantages on promoting liver health, weight loss and glycaemic control. We characterised the effects of cotadutide on glucose, insulin, GLP‐1, GIP, and glucagon over time in a quantitative manner using our glucose dynamics systems model (4GI systems model), in combination with clinical data from a multiple ascending dose/Phase 2a (MAD/Ph2a) study in overweight and obese subjects with a history of Type 2 diabetes mellitus (NCT02548585). Experimental Approach: The cotadutide PK‐4GI systems model was calibrated to clinical data by re‐estimating only food related parameters. In vivo cotadutide efficacy was scaled based on in vitro potency. The model was used to explore the effect of weight loss on insulin sensitivity and predict the relative contribution of the GLP‐1 and glucagon receptor agonistic effects on glucose. Key Results: Cotadutide MAD/Ph2a clinical endpoints were successfully predicted. The 4GI model captured a positive effect of weight loss on insulin sensitivity and showed that the stimulating effect of glucagon on glucose production counteracts the GLP‐1 receptor‐mediated decrease in glucose, resulting in a plateau for glucose decrease around a 200‐μg cotadutide dose. Conclusion and Implications: The 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP‐1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds. [ABSTRACT FROM AUTHOR]

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) and dual GLP-1/glucagon receptor agonists improve glycaemic control and cause significant weight loss in patients with type 2 diabetes. 1 These effects are driven in part by augmenting glucose-stimulated insulin release (incretin effect), reducing caloric intake and delayed gastric emptying. We developed and externally validated a novel integrated quantitative systems pharmacology (QSP) model to gain quantitative insight into the relative contributions and mechanisms of drugs modulating glucose regulatory pathways. This model (4GI model) incorporates known feedback mechanisms among glucose, GLP-1, glucagon, glucose-dependent insulinotropic peptide (GIP), and insulin after glucose provocation (i.e., food intake) and drug intervention utilizing published nonpharmacological and pharmacological (liraglutide, a GLP-1RA) data. The resulting model accurately describes the aforementioned mechanisms and independently predicts the effects of the GLP-1RAs (dulaglutide and semaglutide) on system dynamics. Therefore, the validated 4GI model represents a quantitative decision-making tool to support the advancement of novel therapeutics and combination strategies modulating these pathways., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Methane-oxidizing bacteria (MOB) have a large potential as a microbial sink for the greenhouse gas methane as well as for biotechnological purposes. However, their application in biotechnology has so far been hampered, in part due to the relative slow growth rate of the available strains. To enable the availability of novel strains, this study compares the isolation of MOB by conventional dilution plating with miniaturized extinction culturing, both performed after an initial enrichment step. The extinction approach rendered 22 MOB isolates from four environmental samples, while no MOB could be isolated by plating. In most cases, extinction culturing immediately yielded MOB monocultures making laborious purification redundant. Both type I (Methylomonas spp.) and type II (Methylosinus sp.) MOB were isolated. The isolated methanotrophic diversity represented at least 11 different strains and several novel species based on 16S rRNA gene sequence dissimilarity. These strains possessed the particulate (100%) and soluble (64%) methane monooxygenase gene. Also, 73% of the strains could be linked to a highly active fast-growing mixed MOB community. In conclusion, miniaturized extinction culturing was more efficient in rapidly isolating numerous MOB requiring little effort and fewer materials, compared with the more widely applied plating procedure. This miniaturized approach allowed straightforward isolation and could be very useful for subsequent screening of desired characteristics, in view of their future biotechnological potential., (© 2011 The Authors. Microbial Biotechnology © 2011 Society for Applied Microbiology and Blackwell Publishing Ltd.)