The integrated glucose-insulin (IGI) model is a previously published semimechanistic model that describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work was to use knowledge of physiology to improve the IGI model's description of glucose absorption and gastric emptying after tests with varying glucose doses. The developed model's performance was compared to empirical models. To develop our model, data from oral and intravenous glucose challenges in patients with type 2 diabetes and healthy control subjects were used together with present knowledge of small intestinal transit time, glucose inhibition of gastric emptying, and saturable absorption of glucose over the epithelium to improve the description of gastric emptying and glucose absorption in the IGI model. Duodenal glucose was found to inhibit gastric emptying. The performance of the saturable glucose absorption was superior to linear absorption regardless of the gastric emptying model applied. The semiphysiological model developed performed better than previously published empirical models and allows better understanding of the mechanisms underlying glucose absorption. In conclusion, our new model provides a better description and improves the understanding of dynamic glucose tests involving oral glucose.

Aim: Develop a population pharmacokinetic (PopPK) model to characterise the pharmacokinetics (PK) of anti-programmed cell death protein-1 (PD-1) antibody dostarlimab, identify covariates of clinical relevance, and investigate efficacy/safety exposure-response (ER) relationships.Methods: A PopPK model was developed using Phase 1 GARNET (NCT02715284) trial data for dostarlimab (1, 3 or 10 mg kg À1 every 2 wk; 500 mg every 3 wk or 1000 mg every 6 wk; 500 mg every 3 wk  4 then 1000 mg every 6 wk [recommended regimen]) serum concentrations over time. Concentration-time data were analysed using nonlinear mixed effects modelling with standard stepwise covariate modelling. ER was explored for treatment-related adverse events and overall response rate (ORR) using logistic regression. Results: PopPK model/adverse event ER analyses included 546 patients (ORR ER analysis n = 362). Dostarlimab PK was well described by a 2-compartment model with time-dependent linear elimination. Time-dependent clearance decreased over time to a maximum of 14.9%. At steady state, estimated dostarlimab geometric mean coefficient of variation % clearance was 0.179 (30.2%) L d À1 ; volume of distribution was 5.3 (14.2%) L; terminal elimination half-life was 23.5 (22.4%) days. Statistically significant covariates were age, body weight, sex, time-varying albumin and alanine aminotransferase for clearance; body weight, albumin and sex for volume of distribution of the central compartment. Hepatic or renal impairment did not affect PK. There were no clinically significant ER relationships. Conclusion: Dostarlimab PK parameters are similar to other anti-programmed cell death protein-1 antibodies. The clinical impact of covariates on exposure was limitedto-moderate, supporting recommended dostarlimab monotherapy therapeutic dosing. K E Y W O R D S clinical pharmacology (drug safety), oncology (anticancer drugs), pharmacokinetics, therapeutics The GARNET trial does not have a designated study PI.

Being able to scale preclinical pharmacodynamic response to clinical would be beneficial in drug development. In this work, the integrated glucose insulin (IGI) model, developed on clinical intravenous glucose tolerance test (IVGTT) data, describing dynamic glucose and insulin concentrations during glucose tolerance tests, was scaled to describe data from similar tests performed in healthy rats, mice, dogs, pigs, and humans. Several approaches to scaling the dynamic glucose and insulin were investigated. The theoretical allometric exponents of 0.75 and 1, for clearances and volumes, respectively, could describe the data well with some species‐specific adaptations: dogs and pigs showed slower first phase insulin secretion than expected from the scaling, pigs also showed more rapid insulin dependent glucose elimination, and rodents showed differences in glucose effectiveness. The resulting scaled IGI model was shown to accurately predict external preclinical IVGTT data and may be useful in facilitating translations of preclinical research into the clinic.

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism‐based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play an important role in glucose homeostasis by potentiating glucose-induced insulin secretion. Furthermore, GLP-1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP-1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP-1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP-1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP-1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.