A tutorial on model informed approaches to cardiovascular safety with focus on cardiac repolarisation.

Drugs can affect the cardiovascular (CV) system either as an intended treatment or as an unwanted side effect. In both cases, drug-induced cardiotoxicities such as arrhythmia and unfavourable hemodynamic effects can occur, and be described using mathematical models; such a model informed approach can provide valuable information during drug development and can aid decision-making. However, in order to develop informative models, it is vital to understand CV physiology. The aims of this tutorial are to present (1) key background biological and medical aspects of the CV system, (2) CV electrophysiology, (3) CV safety concepts, (4) practical aspects of development of CV models and (5) regulatory expectations with a focus on using model informed and quantitative approaches to support nonclinical and clinical drug development. In addition, we share several case studies to provide practical information on project strategy (planning, key questions, assumptions setting, and experimental design) and mathematical models development that support decision-making during drug discovery and development.

Comparison of the exposure-response relationship of dapagliflozin in adult and paediatric patients with type 2 diabetes mellitus.

AIMS: To quantitatively compare the exposure-response relationship of dapagliflozin in adult and paediatric patients with type 2 diabetes mellitus (T2DM) and to assess the potential impact of covariate effects. METHODS: Data from three clinical studies of single-dose (2.5, 5 and 10 mg), orally administered dapagliflozin in adult (NCT00162305, NCT00538174) and paediatric (NCT01525238) patients with T2DM were analysed to examine the relationship between dapagliflozin exposure (area under concentration-time curve) and response [24-h urinary glucose excretion (UGE)] using a sigmoidal maximum effect model. Baseline fasting plasma glucose (FPG), estimated glomerular filtration rate (eGFR), baseline 24-h UGE, sex and race were evaluated as covariates. RESULTS: Data from 63 predominantly white or Asian (92.4%) adult and 20 paediatric (45.8% white; 45.8% black) patients were included. The model appeared robust, with predictions fitting well with observed data. Baseline eGFR, FPG and sex were significant covariates in both populations; race was a significant covariate in the paediatric population only. Model-predicted UGE response was higher in paediatric (47.4, 67.5 and 85.9 g/24 h for 2.5, 5 and 10 mg) than in adult (31.2, 43.5 and 54.3 g/24 h for 2.5, 5 and 10 mg) patients, which may be associated with the higher eGFR values in paediatric patients. CONCLUSIONS: After a single oral dose of dapagliflozin, adult and paediatric patients with T2DM had similar exposure-response relationships after accounting for significant covariates. These results support the planned dosage strategy for a phase III dapagliflozin safety and efficacy study in paediatric patients with T2DM, for whom treatment options are currently limited.

Good Practices in Model-Informed Drug Discovery and Development: Practice, Application, and Documentation.

This document was developed to enable greater consistency in the practice, application, and documentation of Model-Informed Drug Discovery and Development (MID3) across the pharmaceutical industry. A collection of "good practice" recommendations are assembled here in order to minimize the heterogeneity in both the quality and content of MID3 implementation and documentation. The three major objectives of this white paper are to: i) inform company decision makers how the strategic integration of MID3 can benefit R&D efficiency; ii) provide MID3 analysts with sufficient material to enhance the planning, rigor, and consistency of the application of MID3; and iii) provide regulatory authorities with substrate to develop MID3 related and/or MID3 enabled guidelines.

Longitudinal model-based meta-analysis in rheumatoid arthritis: an application toward model-based drug development.

Summary-level longitudinal data on the clinical efficacy of drugs for rheumatoid arthritis (RA) are available in the literature. This information can be used to optimize the clinical development of new drugs for RA. The aim of this study was twofold: first, to quantify the time course of the ACR20 score across approved drugs and patient populations, and second, to apply this knowledge in the decision-making process for a specific compound, canakinumab. The integrated analysis included data from 37 phase II-III studies describing 13,474 patients. It showed that, with the tested doses/regimens of canakinumab, there was only a low probability that this drug would be better than the most effective current treatments. This finding supported the decision not to continue with clinical development of canakinumab in RA. This paper presents the first longitudinal model-based meta-analysis of ACR20. The framework can be applied to any other compound targeting RA, thereby supporting internal and external decision making at all clinical development stages.

Models for plasma glucose, HbA1c, and hemoglobin interrelationships in patients with type 2 diabetes following tesaglitazar treatment.

Pharmacokinetic (PK) pharmacodynamic (PD) modeling was applied to understand and quantitate the interplay between tesaglitazar (a peroxisome proliferator-activated receptor alpha/gamma agonist) exposure, fasting plasma glucose (FPG), hemoglobin (Hb), and glycosylated hemoglobin (HbA1c) in type 2 diabetic patients. Data originated from a 12-week dose-ranging study with tesaglitazar. The primary objective was to develop a mechanism-based PD model for the FPG-HbA1c relationship. The secondary objective was to investigate possible mechanisms for the tesaglitazar effect on Hb. Following initiation of tesaglitazar therapy, time to new FPG steady state was approximately 9 weeks, and tesaglitazar potency in females was twice that in males. The model included aging of red blood cells (RBCs) using a transit compartment approach. The RBC life span was estimated to 135 days. The transformation from RBC to HbA1c was modeled as an FPG-dependent process. The model indicated that the tesaglitazar effect on Hb was caused by hemodilution of RBCs.

Pharmacokinetics and metabolism of tesaglitazar, a novel dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, after a single oral and intravenous dose in humans.

The pharmacokinetics of tesaglitazar (GALIDA), a novel dual-acting peroxisome proliferator-activated receptor alpha and gamma agonist, were studied in eight healthy male subjects. The subjects initially received either a single oral or intravenous (i.v.) dose of 1 mg of [(14)C]tesaglitazar. After a washout period, they received 1 mg of nonlabeled tesaglitazar via the alternative administration route. Serial blood samples and complete urine and feces were collected until 336 h postdose. Tesaglitazar absorption was rapid, with maximum plasma concentration (C(max)) at approximately 1 h postdose, and the absolute bioavailability was approximately 100%, suggesting no, or negligible, first-pass metabolism. Mean plasma clearance was 0.16 l/h and the volume of distribution at steady state was 9.1 liters. After either route of administration, the plasma concentration-time profiles of radioactivity and tesaglitazar were virtually identical, indicating low systemic metabolite concentrations and formation rate limitation of metabolite elimination. The elimination half-life of radioactivity and tesaglitazar was approximately 45 h. Radioactivity recovery was complete in all subjects, with mean values of 99.9% (i.v.) and 99.6% (oral). Tesaglitazar was mainly metabolized before excretion, and most radioactivity (91%) was recovered in urine. Approximately 20% of the dose was recovered unchanged after either administration route, resulting in a renal clearance of 0.030 l/h. Most of the radioactivity in urine was identified as acyl glucuronide of tesaglitazar. Plasma protein binding of tesaglitazar was high ( approximately 99.9%), and the mean blood-plasma partitioning ratio was 0.66, suggesting low affinity for red blood cells. There was no indication of partial inversion of the (S)-enantiomer to the corresponding (R)-form. Tesaglitazar was well tolerated.