Steen H. Ingwersen

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. RESULTS Insulin sensitivity was higher in Japanese compared with Caucasians, as indicated by the homeostatic model assessment of insulin resistance and Matsuda indices, whereas β-cell response was higher in Caucasians, as measured by homeostatic model assessment of β-cell function, the insulinogenic indices, and insulin secretion ratios. Disposition indices were similar for Japanese and Caucasians at all glucose tolerance states, indicating similar β-cell response relative to the degree of insulin resistance. The main determinants for differences in metabolic indices were measures of body composition, such as BMI and distribution of adipose tissue. Differences in β-cell response between Japanese and Caucasians were not statistically significant following adjustment by differences in BMI. CONCLUSIONS Our study showed similar disposition indices in Japanese and Caucasians and that the major part of the differences in insulin sensitivity and β-cell response between Japanese and Caucasians can be explained by differences in body composition.

Using stochastic differential equations for PK/PD model development.

A method for PK/PD model development based on stochastic differential equation models is proposed. The new method has a number of advantages compared to conventional methods. In particular, the new method avoids the exhaustive trial-and-error based search often conducted to determine the most appropriate model structure, because it allows information about the appropriate model structure to be extracted directly from data. This is accomplished through quantification of the uncertainty of the individual parts of an initial model, by means of which tools for performing model diagnostics can be constructed and guidelines for model improvement provided. Furthermore, the new method allows time-variations in key parameters to be tracked and visualized graphically, which allows important functional relationships to be revealed. Using simulated data, the performance of the new method is demonstrated by means of two examples. The first example shows how, starting from a simple assumption of linear PK, the method can be used to determine the correct nonlinear model for describing the PK of a drug following an oral dose. The second example shows how, starting from a simple assumption of no drug effect, the method can be used to determine the correct model for the nonlinear effect of a drug with known PK in an indirect response model.

Halothane anesthesia enhances the effect of dopamine uptake inhibition on interstitial levels of striatal dopamine

The anesthetic, isoflurane, has been shown to potentiate the ability of the dopamine (DA)-uptake inhibitor, nomifensine, to increase the brain interstitial dopamine level ([DA]e). Since the effect of the more commenly used anesthetic, halothane, on this system is unknown, we determined [DA]e by microdialysis in the striatum of rats, conscious or anesthetized with halothane, in the presence of the more selective DA uptake inhibitor, vanoxerine (GBR 12909), or the DA releaser, d-amphetamine. Basal [DA]e was not changed by halothane. However, in halothane-anesthetized rats, the vanoxerine (3 mg/kg i.v.)-induced DA response increased severalfold compared to the response in conscious rats. The initial peak response to d-amphetamine (1 mg/kg i.v.) did not change, but the late response (1–3 h after injection) was augmented in anesthetized rats. Halothane is believed to increase firing of DA neurons in the substantia nigra and, hence, to release striatal DA. We hypothesize that [DA]e, is maintained at a normal level during the increased firing by equally increased activity of the DA transporter. However, when the DA transporter is blocked by vanoxerine, the increased DA release is unimpaired and [DA]e rises.

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. PARTICIPANTS PARTICIPANTS included 120 Japanese and 150 Caucasian subjects. MAIN OUTCOMES Measures of β-cell function, hepatic extraction, and insulin sensitivity were assessed using C-peptide, glucose, and insulin minimal models. RESULTS Basal β-cell function (Φ(b)) was lower in Japanese compared with Caucasians (P < .01). In subjects with IGT, estimates of the dynamic (Φ(d)) and static (Φ(s)) β-cell responsiveness were significantly lower in the Japanese compared with Caucasians (P < .05). In contrast, values of insulin action showed higher sensitivity in the Japanese IGT subjects. Hepatic extraction was similar in NGT and IGT groups but higher in Japanese type 2 diabetic subjects (P < .01). Despite differences in insulin sensitivity, β-cell function, and hepatic extraction, the disposition indices were similar between the 2 ethnic groups at all glucose tolerance states. Furthermore, the overall insulin sensitivity and β-cell responsiveness for all glucose tolerance states were similar in Japanese and Caucasians after accounting for differences in body mass index. CONCLUSION Our study provides evidence for a similar ability of Japanese and Caucasians to compensate for increased insulin resistance.

Population Pharmacokinetics of Liraglutide, a Once‐Daily Human Glucagon‐Like Peptide‐1 Analog, in Healthy Volunteers and Subjects With Type 2 Diabetes, and Comparison to Twice‐Daily Exenatide

The once‐daily human glucagon‐like peptide‐1 (GLP‐1) analog, liraglutide, was recently shown to provide improved glycemic control in subjects with type 2 diabetes (T2D) compared with exenatide. The aim of this work is to estimate the population pharmacokinetics of liraglutide and make a comparison to the pharmacokinetic profile of exenatide. Pharmacokinetic data from 5 published studies of subcutaneous and intravenous administration of liraglutide to healthy volunteers (HV) and subjects with T2D were used to develop a population pharmacokinetic model in NONMEM. Exenatide data came from a published study in T2D. Liraglutide pharmacokinetics were adequately described using a 1‐compartment model with sequential zero‐ and first‐order absorption. The pharmacokinetic profile of once‐daily liraglutide showed considerably smaller peak‐to‐trough fluctuations compared with twice‐daily exenatide. A small difference in the estimates of absorption parameters was found between HV and subjects with T2D but was not clinically relevant. It was concluded that pharmacokinetic profiles estimated by modeling showed that liraglutide has pharmacokinetic properties consistent with once‐daily dosing in humans and provides better pharmacokinetic coverage in comparison with twice‐daily exenatide. Furthermore, no clinically relevant differences were found in liraglutide pharmacokinetics between HV and subjects with T2D.

Pharmacokinetic and pharmacodynamic properties of insulin aspart and human insulin

The preferred approach to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of insulin analogues is the euglycemic glucose clamp. Currently, non-compartmental data analytical approaches are used to analyze data. The purpose of the present study is to propose a novel compartmental-model for analysis of data from glucose clamp studies. Data used in this trial only involved 18 of the 20 originally treated subjects. Data was obtained from a crossover trial where 18 healthy subjects each received a single subcutaneous (sc) dose of 1.2 nmol/kg (body weight) insulin aspart (IAsp) or 1.2 nmol/kg human insulin (HI) during a euglycemic glucose clamp after overnight fast. Serum insulin and glucose concentrations were measured and the glucose infusion rate (GIR) was adjusted after dosing, to maintain blood glucose near basal levels. Individual model parameters were estimated for IAsp, HI, and the corresponding glucose and GIR data. We found statistically significant differences between most of the HI and IAsp pharmacokinetic parameters, including the sigmoidicity of the time course of absorption (1.5 for HI vs. 2.1 for IAsp (unit less), P=0.0005, Wilcoxon Signed-rank test), elimination rate constant (0.010 min−1 for HI vs. 0.016 min−1 for IAsp (P=0.002)). The PD model parameters were mostly not different, except for the rate of insulin action (0.012 min−1 for HI vs. 0.017 min−1 for IAsp (P=0.03)). The model may provide a framework to account for different PK properties when estimating the PD properties of insulin and insulin analogues in glucose clamp experiments.

Comparison of sandwich enzyme-linked immunoadsorbent assay and radioimmunoassay for determination of exogenous glucagon-like peptide-1(7-36)amide in plasma.

A sensitive sandwich enzyme-linked immunoadsorbent assay (ELISA) for determination of exogenous glucagon-like peptide-1(7-36)amide (GLP-1(7-36)amide) in plasma samples from pharmacokinetic studies is described. The assay employs an N-terminally directed antibody and a C-terminally directed antibody. The ELISA has a working range from 10 to 500 pmol l-1, and can be applied to plasma samples from humans, dogs, pigs, minipigs, cats, rabbits, and rats. The assay was compared to a validated radioimmunoassay (RIA), employing an antibody directed against the mid-region of GLP-1. After s.c. administration of GLP-1(7-36)amide, the plasma immunoreactivity of GLP-1 (P-GLP-1-IR) measured by ELISA was markedly lower than P-GLP-1-IR measured by RIA. After HPLC fractionation of plasma samples with subsequent RIA and ELISA analyses of the fractions, this difference was shown to be due to cross reaction with biologically inactive fragments of GLP-1(7-36)amide in the RIA but not in the ELISA.

Dosing Rationale for Liraglutide in Type 2 Diabetes Mellitus: A Pharmacometric Assessment

The glucagon‐like peptide‐1 (GLP‐1) receptor agonist liraglutide was approved in 2010 by the US Food and Drug Administration (FDA) as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. This article provides insights into the use of pharmacometric analyses for regulatory review with a focus on the dosing recommendations. The assessment was based on the totality of exploratory and confirmatory analysis of dose‐finding and pivotal clinical data and was structured around a set of key questions in accordance with current FDA review practice. For the pharmacometric review of liraglutide, the key questions focused on exposure‐response relationships for effects on fasting plasma glucose, hemoglobin A1c, and calcitonin and on variability in exposure across demographic subgroups of patients. The importance of conducting exploratory exposure‐response analysis and population pharmacokinetic studies in clinical drug development to support dosing recommendations is highlighted.

Establishing Good Practices for Exposure-Response Analysis of Clinical Endpoints in Drug Development.

This tutorial aims at promoting good practices for exposure–response (E‐R) analyses of clinical endpoints in drug development. The focus is on practical aspects of E‐R analyses to assist modeling scientists with a process of performing such analyses in a consistent manner across individuals and projects and tailored to typical clinical drug development decisions. This includes general considerations for planning, conducting, and visualizing E‐R analyses, and how these are linked to key questions.

Preserved pharmacokinetic exposure and distinct glycemic effects of insulin degludec and liraglutide in IDegLira, a fixed‐ratio combination therapy

Insulin degludec/liraglutide (IDegLira) is a novel fixed‐ratio combination of the basal insulin insulin degludec (IDeg) and liraglutide, a glucagon‐like peptide‐1 analog. The pharmacokinetics (PK) and pharmacodynamics of IDegLira were assessed versus its components. A single‐dose, randomized, 4‐period crossover clinical pharmacology study in healthy subjects compared the bioavailability of IDegLira with its monocomponents. Dose proportionality, covariate effects on exposure, and exposure–response for change in glycated hemoglobin were analyzed based on data from a randomized treat‐to‐target phase 3 study in subjects with type 2 diabetes. Overall, the PK properties of IDeg and liraglutide were preserved for IDegLira. Liraglutide exposure was lower when dosed as IDegLira but met the criterion for equivalence. No relevant deviations from dose proportionality for the IDegLira components were observed. Covariate effects on exposure were consistent with previous results. Glycemic response to IDegLira was larger than with IDeg or liraglutide alone, reflecting their distinct glucose‐lowering effects throughout the dose/exposure range.