Complex formation of anti-VEGF-C with VEGF-C released during blood coagulation resulted in an artifact in its serum pharmacokinetics.

A phage-derived human monoclonal antibody against VEGF-C was developed as a potential anti-tumor therapeutic and exhibited fast clearance in preclinical species, with notably faster clearance in serum than in plasma. The purpose of this work was to understand the factors contributing to its fast clearance. In vitro incubations in animal and human blood, plasma, and serum were conducted with radiolabeled anti-VEGF-C to determine potential protein and cell-based interactions with the antibody as well as any matrix-dependent recovery dependent upon the matrix.

Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology.

We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue- and organ-level vascular volumes (V), interstitial volumes (V), and blood flow rates (Q) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements.

Balancing Blood Sample Volume with 3Rs: Implementation and Best Practices for Small Molecule Toxicokinetic Assessments in Rats.

Improved small molecule bioanalytical sensitivity and concomitant decreased sample volume requirements provide an opportunity to reconsider how toxicokinetic (TK) data are collected in rat toxicity studies. Often, satellite groups of rats are designated to separate procedural effects of TK blood collection from the primary toxicity evaluation. Blood microsampling (i.

45,X/46,XY Mosaicism and Possible Association With Hypothyroidism in Males.

Mosaicism has a wide phenotypic spectrum but frequently manifests as the normal male phenotype. Its association with short stature has been well recognized and appears to respond effectively to growth hormone therapy. We present 2 phenotypically normal males who both initially presented with short stature and were found to have hypothyroidism.

Postinjection Muscle Fibrosis from Lupron.

We describe the case of a 6.5-year-old girl with central precocious puberty (CPP), which signifies the onset of secondary sexual characteristics before the age of eight in females and the age of nine in males as a result of stimulation of the hypothalamic-pituitary-gonadal axis. Her case is likely related to her adoption, as children who are adopted internationally have much higher rates of CPP.

Comparative physiology of mice and rats: radiometric measurement of vascular parameters in rodent tissues.

A solid understanding of physiology is beneficial in optimizing drug delivery and in the development of clinically predictive models of drug disposition kinetics. Although an abundance of data exists in the literature, it is often confounded by the use of various experimental methods and a lack of consensus in values from different sources. To help address this deficiency, we sought to directly compare three important vascular parameters at the tissue level using the same experimental approach in both mice and rats.

Solvent-based formulations for intravenous mouse pharmacokinetic studies: tolerability and recommended solvent dose limits.

1. Modern high-throughput small molecule drug discovery requires rapid screening of the pharmacokinetic parameters of multiple candidate molecules in parallel. The mouse is often used for such screening, as are solvent-based intravenous formulations.

Vascular physiology and protein disposition in a preclinical model of neurodegeneration.

The development of clinically relevant preclinical models that mimic the hallmarks of neurodegenerative disease is an ongoing pursuit in early drug development. In particular, robust physiological characterization of central nervous system (CNS) disease models is necessary to predict drug delivery to target tissues and to correctly interpret pharmacodynamic responses to disease-modifying therapeutic candidates. Efficient drug delivery across the blood-CNS barrier is a particularly daunting task, prompting our strategy to evaluate the biodistribution of five distinct molecular probes in a well-characterized mouse model of neurodegeneration.

Evaluation of dried blood spot sampling following cassette dosing in drug discovery.

Background: Dried blood spot (DBS) sampling has received growing interest mainly in regulatory preclinical and clinical studies while not routinely used in exploratory discovery pharmacokinetic screening. An intravenous bolus cassette dose of six compounds in rats followed by hemolyzed blood sample (HBS) and DBS sampling was evaluated in this study.

Results: A sensitive liquid chromatography tandem mass spectrometry method was developed and qualified for the simultaneous determination of six compounds in rat whole blood using DBS or HBS techniques.

Effects of anti-VEGF on predicted antibody biodistribution: roles of vascular volume, interstitial volume, and blood flow.

Background: The identification of clinically meaningful and predictive models of disposition kinetics for cancer therapeutics is an ongoing pursuit in drug development. In particular, the growing interest in preclinical evaluation of anti-angiogenic agents alone or in combination with other drugs requires a complete understanding of the associated physiological consequences.

Methodology/principal Findings: Technescan™ PYP™, a clinically utilized radiopharmaceutical, was used to measure tissue vascular volumes in beige nude mice that were naïve or administered a single intravenous bolus dose of a murine anti-vascular endothelial growth factor (anti-VEGF) antibody (10 mg/kg) 24 h prior to assay.

Effect of immune complex formation on the distribution of a novel antibody to the ovarian tumor antigen CA125.

3A5 is a novel antibody that binds repeated epitopes within CA125, an ovarian tumor antigen that is shed into the circulation. Binding to shed antigen may limit the effectiveness of therapeutic antibodies because of unproductive immune complex (IC) formation and/or altered antibody distribution. To evaluate this possibility, we characterized the impact of shed CA125 on the in vivo distribution of 3A5.

Development and evaluation of a novel method for preclinical measurement of tissue vascular volume.

Identification of clinically predictive models of disposition kinetics for antibody therapeutics is an ongoing pursuit in drug development. To encourage translation of drug candidates from early research to clinical trials, clinical diagnostic agents may be used to characterize antibody disposition in physiologically relevant preclinical models. TechneScan PYP was employed to measure tissue vascular volumes (V(v)) in healthy mice.