A model-based approach to predict individual weight loss with semaglutide in people with overweight or obesity.

Aims: To determine the relationship between exposure and weight-loss trajectories for the glucagon-like peptide-1 analogue semaglutide for weight management.

Materials And Methods: Data from one 52-week, phase 2, dose-ranging trial (once-daily subcutaneous semaglutide 0.05-0.

Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are used for the treatment of type 2 diabetes. Whether clinically important responses and adverse events (AEs) are dependent on the route of administration has not been determined. We demonstrate that nearly identical exposure-response pharmacodynamic relationships are determined by plasma semaglutide levels achieved through oral versus injectable administration for changes in HbA, body weight, biomarkers of cardiovascular risk, and AEs such as nausea and vomiting.

Clinical Pharmacokinetics of Oral Semaglutide: Analyses of Data from Clinical Pharmacology Trials.

Objective: The absorption, distribution and elimination of oral semaglutide, the first oral glucagon-like peptide-1 receptor agonist for treating type 2 diabetes, was investigated using a population pharmacokinetic model based on data from clinical pharmacology trials.

Methods: A previously developed, two-compartment pharmacokinetic model, based on subcutaneous and intravenous semaglutide, was extended to include data from six oral semaglutide trials conducted in either healthy volunteers or subjects with renal or hepatic impairment. Five trials employed multiple doses of oral semaglutide (5-10 mg) and one was a single-dose (10 mg) trial.

Optimal Monitoring of Weekly IGF-I Levels During Growth Hormone Therapy With Once-Weekly Somapacitan.

Context: Somapacitan is a long-acting growth hormone (GH) in development for once-weekly treatment of GH deficiency (GHD). Optimal monitoring of insulin-like growth factor-I (IGF-I) levels must account for weekly IGF-I fluctuations following somapacitan administration.

Objective: To develop and assess the reliability of linear models for predicting mean and peak IGF-I levels from samples taken on different days after dosing.

Impact of dose-escalation schemes and drug discontinuation on weight loss outcomes with liraglutide 3.0 mg: A model-based approach.

Aims: To investigate the impact on weight loss of the treatment changes in overweight or obese people that may be needed in case of gastrointestinal (GI) tolerability issues during escalation of the glucagon-like peptide-1 analogue liraglutide.

Materials And Methods: The individual longitudinal body weight data from the main trial periods of three phase II/III trials in overweight or obese patients (56-week treatment with once-daily liraglutide 1.2, 1.

Optimizing Dose-Finding Studies for Drug Combinations Based on Exposure-Response Models.

Combinations of pharmacological treatments are increasingly being investigated for potentially higher clinical benefit, especially when the combined drugs are expected to act via synergistic interactions. The clinical development of combination treatments is particularly challenging, particularly during the dose-selection phase, where a vast range of possible combination doses exists. The purpose of this work was to evaluate the added value of using optimal design for guiding the dose allocation in drug combination dose-finding studies as compared with a typical drug-combination trial.

Population Pharmacokinetics of Semaglutide for Type 2 Diabetes.

Introduction: The aim of the present analysis was to characterise the absorption, distribution and elimination of semaglutide by means of population pharmacokinetic (PK) models using data from nine clinical pharmacology trials conducted in both healthy subjects and those with type 2 diabetes.

Methods: Data were obtained from trials with subcutaneous and intravenous administration of semaglutide that utilised frequent PK sampling and included a total of 353 subjects with 10,573 concentration values.

Results: Semaglutide PK properties across trials, drug product strengths and populations were well characterised by a two-compartment model with first-order absorption and elimination.

Impact on HbA1c and body weight of switching from other GLP-1 receptor agonists to semaglutide: A model-based approach.

Aims: Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. The impact of switching treatment from another GLP-1 receptor agonist (GLP-1RA) to semaglutide was investigated by analyses of exposure-response models.

Methods: HbA1c and body weight time-course models were developed, using up to 30 weeks of observations from four trials in the semaglutide phase 3 programme.

Semaglutide s.c. Once-Weekly in Type 2 Diabetes: A Population Pharmacokinetic Analysis.

Introduction: Semaglutide, a new treatment option approved for the treatment of patients with type 2 diabetes mellitus, is a glucagon-like peptide-1 receptor agonist to be injected subcutaneously once weekly. This analysis used a population pharmacokinetic model of semaglutide to identify clinically relevant covariates for exposure.

Methods: A total of 1612 patients with up to seven pharmacokinetic observations each were included in the analysis.

Exposure-response analysis for evaluation of semaglutide dose levels in type 2 diabetes.

Aims: To evaluate dose levels for semaglutide, a glucagon-like peptide-1 analogue approved for the treatment of type 2 diabetes, by examining the effects of demographic factors on efficacy and safety in an exposure-response analysis.

Methods: We analysed data from 1552 adults from four randomized phase III trials of 30 to 56 weeks' duration, investigating once-weekly semaglutide doses 0.5 and 1.

Feasibility of Exposure-Response Analyses for Clinical Dose-Ranging Studies of Drug Combinations.

The exposure-response relationship of combinatory drug effects can be quantitatively described using pharmacodynamic interaction models, which can be used for the selection of optimal dose combinations. The aim of this simulation study was to evaluate the reliability of parameter estimates and the probability for accurate dose identification for various underlying exposure-response profiles, under a number of different phase II designs. An efficacy variable driven by the combined exposure of two theoretical compounds was simulated and model parameters were estimated using two different models, one estimating all parameters and one assuming that adequate previous knowledge for one drug is readily available.

Pharmacokinetics and Pharmacodynamics of Once-Weekly Somapacitan in Children and Adults: Supporting Dosing Rationales with a Model-Based Analysis of Three Phase I Trials.

Background: Somapacitan, a long-acting growth hormone (GH) derivative, has been well-tolerated in children with GH deficiency (GHD) and adults (healthy and adult GHD), in phase I, single- and multiple-dose trials, respectively, and has pharmacokinetic and pharmacodynamic properties supporting a once-weekly dosing regimen.

Objective: In the absence of a multiple-dose phase I trial in children with GHD, the aim was to develop a pharmacokinetic/pharmacodynamic model to predict somapacitan exposure and insulin-like growth factor-I (IGF-I) response after once-weekly multiple doses in both children and adults with GHD.

Methods: Pharmacokinetic/pharmacodynamic models were developed from pharmacokinetic and IGF-I profiles in three phase I trials of somapacitan (doses: healthy adults, 0.

Liraglutide 3.0 mg for Weight Management: A Population Pharmacokinetic Analysis.

Background And Objectives: This analysis used a population pharmacokinetic approach to identify covariates that influence plasma exposure of liraglutide 3.0 mg, a glucagon-like peptide-1 (GLP-1) receptor agonist approved for weight management in overweight and obese individuals.

Methods: Samples for pharmacokinetic analysis were drawn at weeks 2, 12 and 28 of the phase IIIa SCALE Obesity and Prediabetes (N = 2339) and SCALE Diabetes (N = 584) trials.

Anti-NKG2D monoclonal antibody (NNC0142-0002) in active Crohn's disease: a randomised controlled trial.

Objective: Anti-NKG2D (NNC0142-0002) is an antagonising human immunoglobulin G4 monoclonal antibody that binds to natural killer group 2 member D (NKG2D) receptors, which are expressed by T cells and innate lymphoid cells, and may be linked to mucosal damage in Crohn's disease (CD).

Design: Seventy-eight patients (aged ≥18 and ≤75 years) with CD for ≥3 months, Crohn's Disease Activity Index (CDAI) ≥220 and ≤450 and either C-reactive protein ≥10 mg/L or endoscopic evidence of inflammation, were randomised 1:1 to a single subcutaneous (SC) dose of 2 mg/kg anti-NKG2D or placebo. Primary endpoint was change in CDAI (ΔCDAI) from baseline to week 4.

Clinical pharmacokinetics of the anti-interleukin-20 monoclonal antibody NNC0109-0012 in healthy volunteers and patients with psoriasis or rheumatoid arthritis.

Introduction: NNC0109-0012, a novel human monoclonal antibody that binds to and neutralizes the activity of interleukin-20, was investigated as a potential treatment for inflammatory diseases. Pharmacokinetic (PK) modeling was performed using data from four completed clinical phase 1/2 trials to better understand the clinical PK of NNC0109-0012.

Methods: The populations included were patients with rheumatoid arthritis (RA), chronic plaque psoriasis, and healthy volunteers.

Ethnic differences in insulin sensitivity, β-cell function, and hepatic extraction between Japanese and Caucasians: a minimal model analysis.

Context: Ethnic differences have previously been reported for type 2 diabetes.

Objective: We aimed at assessing the potential differences between Caucasian and Japanese subjects ranging from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and to type 2 diabetes.

Design: This was a cross-sectional study with oral glucose tolerance tests to assess β-cell function, hepatic insulin extraction, and insulin sensitivity.

Pharmacokinetics of an anti-TFPI monoclonal antibody (concizumab) blocking the TFPI interaction with the active site of FXa in Cynomolgus monkeys after iv and sc administration.

Introduction: Concizumab (mAb 2021) is a monoclonal IgG4 antibody (mAb) that binds to the Kunitz-type protease inhibitor (KPI) 2 domain of TFPI thereby blocking the interaction of this domain with the active site of FXa. The objective of the present study was to characterize the pharmacokinetics of concizumab in Cynomolgus monkeys after intravenous (iv) and subcutaneous (sc) administration.

Methods: Data from two studies were included in the modelling, all in all data from 52 monkeys distributed into 9 groups.

Body composition is the main determinant for the difference in type 2 diabetes pathophysiology between Japanese and Caucasians.

OBJECTIVE This cross-sectional clinical study compared the pathophysiology of type 2 diabetes in Japanese and Caucasians and investigated the role of demographic, genetic, and lifestyle-related risk factors for insulin resistance and β-cell response. RESEARCH DESIGN AND METHODS A total of 120 Japanese and 150 Caucasians were enrolled to obtain comparable distributions of high/low BMI values across glucose tolerance states (normal glucose tolerance, impaired glucose tolerance, and type 2 diabetes), which were assessed by oral glucose tolerance tests. BMI in the two cohorts was distributed around the two regional cutoff values for obesity.

An integrated disease/pharmacokinetic/pharmacodynamic model suggests improved interleukin-21 regimens validated prospectively for mouse solid cancers.

Interleukin (IL)-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses.

Mechanism-based population modelling for assessment of L-cell function based on total GLP-1 response following an oral glucose tolerance test.

GLP-1 is an insulinotropic hormone that synergistically with glucose gives rise to an increased insulin response. Its secretion is increased following a meal and it is thus of interest to describe the secretion of this hormone following an oral glucose tolerance test (OGTT). The aim of this study was to build a mechanism-based population model that describes the time course of total GLP-1 and provides indices for capability of secretion in each subject.

Predictive performance for population models using stochastic differential equations applied on data from an oral glucose tolerance test.

Several articles have investigated stochastic differential equations (SDEs) in PK/PD models, but few have quantitatively investigated the benefits to predictive performance of models based on real data. Estimation of first phase insulin secretion which reflects beta-cell function using models of the OGTT is a difficult problem in need of further investigation. The present work aimed at investigating the power of SDEs to predict the first phase insulin secretion (AIR (0-8)) in the IVGTT based on parameters obtained from the minimal model of the OGTT, published by Breda et al.

Population stochastic modelling (PSM)--an R package for mixed-effects models based on stochastic differential equations.

The extension from ordinary to stochastic differential equations (SDEs) in pharmacokinetic and pharmacodynamic (PK/PD) modelling is an emerging field and has been motivated in a number of articles [N.R. Kristensen, H.

A matlab framework for estimation of NLME models using stochastic differential equations: applications for estimation of insulin secretion rates.

The non-linear mixed-effects model based on stochastic differential equations (SDEs) provides an attractive residual error model, that is able to handle serially correlated residuals typically arising from structural mis-specification of the true underlying model. The use of SDEs also opens up for new tools for model development and easily allows for tracking of unknown inputs and parameters over time. An algorithm for maximum likelihood estimation of the model has earlier been proposed, and the present paper presents the first general implementation of this algorithm.

Pharmacodynamic model of interleukin-21 effects on red blood cells in cynomolgus monkeys.

Interleukin-21 (IL-21) is a novel cytokine that is currently under clinical investigations as a potential anti-cancer agent. Like many other anti-cancer agents, including other interleukins, IL-21 is seen to produce a broad range of biological effects that may be related to both efficacy and safety of treatment. The present analysis investigates the observed pharmacodynamics effects on red blood cells following various treatment schedules of human IL-21 administrated to cynomolgus monkeys.

PKPD model of interleukin-21 effects on thermoregulation in monkeys--application and evaluation of stochastic differential equations.

Purpose: To describe the pharmacodynamic effects of recombinant human interleukin-21 (IL-21) on core body temperature in cynomolgus monkeys using basic mechanisms of heat regulation. A major effort was devoted to compare the use of ordinary differential equations (ODEs) with stochastic differential equations (SDEs) in pharmacokinetic pharmacodynamic (PKPD) modelling.

Methods: A temperature model was formulated including circadian rhythm, metabolism, heat loss, and a thermoregulatory set-point.