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Immunogenicity against therapeutic proteins frequently causes attrition owing to its potential impact on pharmacokinetics, pharmacodynamics, efficacy, and safety. Predicting immunogenicity is complex because of its multifactorial drivers, including compound properties, subject characteristics, and treatment parameters. To integrate these, the Immunogenicity Simulator was developed using published, predominantly late‐stage trial data from 15 therapeutic proteins. This single‐blinded evaluation with subject‐level data from 10 further monoclonals assesses the Immunogenicity Simulator's credibility for application during the drug development process. [ABSTRACT FROM AUTHOR]

B Immunogenicity is a major challenge in drug development and patient care. For example, in combination therapies, the mechanism of action of one drug could influence the immune system or the population variability of immune system components in a way that influences the immune response to a second drug. In addition to population parameters already included in Simcyp, the IG Simulator uses human leukocyte antigen (HLA) allele frequencies and variability in the immune system as a function of age or disease will soon be included. This example virtual trial simulation ( B Figure b ) demonstrates that the IG Simulator is capable of simulating clinical population of interest, with accuracy sufficient to inform IG management. [Extracted from the article]

Objective Insulin resistance and hyperinsulinaemia precede the onset of obesity-induced DM2. The early adaptation of the β-cell during the initial phase of overfeeding and weight gain has only been partly elucidated. We studied the early changes in insulin clearance and β-cell responsivity during a positive and negative energy balance in lean healthy men. Design We studied in nine healthy lean men [age, 37 (27-43) years; BMI, 23·6 (20·6-25·6) kg/m2] insulin sensitivity, insulin clearance, insulin secretion and static and dynamic β-cell responsivity at baseline and after the hypercaloric and subsequent hypocaloric diet. Results Participants gained 7 [5·1-7·6]% of their initial body weight on the hypercaloric diet. Compared to baseline, insulin sensitivity and insulin clearance decreased, while glucose-stimulated insulin secretion was higher. The GLP-1 response to oral glucose did not change. The dynamic β-cell responsivity index increased but the basal and static responsivity indexes did not change. Total and static disposition indexes (DIs) in the hypercaloric state showed a trend towards a decrease. During the hypocaloric diet, insulin sensitivity, glucose-stimulated insulin secretion and insulin clearance returned to baseline. The responsivity and the DIs were not different in the hypocaloric phase compared to baseline. Conclusion A positive energy balance resulting in weight gain in lean men induces hyperinsulinaemia, which is explained by a combined effect on insulin clearance and insulin secretion. Increased insulin secretion was related to insulin resistance-induced higher glucose concentrations but also to increased dynamic β-cell responsivity. Glucose sensitivity of the β-cell did not change. These early adaptations are completely reversible during a negative energy balance after loss of the gained weight. [ABSTRACT FROM AUTHOR]