Bridging Sunitinib Exposure to Time-to-Tumor Progression in Hepatocellular Carcinoma Patients With Mathematical Modeling of an Angiogenic Biomarker.

Hepatocellular carcinoma (HCC) is third in cancer-related causes of death worldwide and its treatment is a significant unmet medical need. Sunitinib is a selective tyrosine kinase inhibitor of the angiogenic biomarker: soluble vascular endothelial growth factor receptor-2 (sVEGFR2 ). Sunitinib failed its primary overall survival endpoint in patients with advanced HCC in a phase III trial compared to sorafenib. In the present study, pharmacokinetic-pharmacodynamic modeling was used to link drug-exposure to tumor-growth-inhibition (TGI) and time-to-tumor progression (TTP) through sVEGFR2 dynamics. The results suggest that 1) active drug concentration (i.e., sunitinib and its metabolite) inhibits the release of sVEGFR2 and that such inhibition is associated with TGI, and 2) daily sVEGFR2 exposure is likely a reliable predictor for the TTP in HCC patients. Moreover, the model quantitatively links the dynamics of an angiogenesis biomarker to TTP and accurately predicts observed literature-reported results of placebo treatment.

Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis.

The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50 ) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data.

AMGET, an R-Based Postprocessing Tool for ADAPT 5.

ADAPT 5 is a powerful modeling software for population pharmacokinetic and pharmacodynamic systems analysis, but provides limited built-in functionality for creating pre- and post-analysis diagnostic plots. ADAPT 5 Model Evaluation Graphical Toolkit (AMGET), an external package written in the open source R programming language, was developed specifically to support efficient postprocessing of ADAPT 5 runs, as well as NONMEM and S-ADAPT runs. Using interactive navigational menus, users of AMGET are able to rapidly create informative diagnostic plots enriched by the display of numerical and graphical elements with a high degree of customization using a simple settings spreadsheet. This article describes each feature of the AMGET package and illustrates how it allows users to utilize the powerful numerical routines of the ADAPT 5 package in a more efficient manner through the use of a simulated dataset and a simple pharmacokinetic model optimized using the maximum likelihood expectation maximization (MLEM) algorithm of ADAPT 5.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e61; doi:10.1038/psp.2013.36; published online 31 July 2013.

Bridging Clinical Outcomes of Canakinumab Treatment in Patients With Rheumatoid Arthritis With a Population Model of IL-1ß Kinetics.

Canakinumab, an anti-interleukin-1ß (IL-1ß) monoclonal antibody, is approved for cryopyrin-associated periodic syndromes and is under investigation for the management of other inflammatory disorders. In this study, population-based pharmacokinetic-pharmacodynamic models were developed to understand responses to canakinumab in patients with rheumatoid arthritis (RA). Total canakinumab and total IL-1ß concentrations were obtained from four clinical trials (n = 472). In contrast to traditional models, free IL-1ß concentrations were calculated and used to link canakinumab to changes in C-reactive protein (CRP) concentrations and American College of Rheumatology (ACR) scores of 20, 50, and 70% improvement. Temporal patterns of total canakinumab, total IL-1ß, CRP, and ACR scores were all well described. Simulations confirmed that 150 mg every 4 weeks improved ACR scores in patients with RA, but no additional benefit was provided by higher doses or more frequent administration. Integrating predicted endogenous free ligand concentrations with biomarkers and clinical outcomes could be extended to new therapies of anti-inflammatory diseases.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e5; doi:10.1038/psp.2012.6; advance online publication 26 September 2012.