MARS: bringing the automation of small-molecule bioanalytical sample preparations to a new frontier.

Background: In recent years, there has been a growing interest in automating small-molecule bioanalytical sample preparations specifically using the Hamilton MicroLab(®) STAR liquid-handling platform. In the most extensive work reported thus far, multiple small-molecule sample preparation assay types (protein precipitation extraction, SPE and liquid-liquid extraction) have been integrated into a suite that is composed of graphical user interfaces and Hamilton scripts. Using that suite, bioanalytical scientists have been able to automate various sample preparation methods to a great extent.

Assessment of exposure of metabolites in preclinical species and humans at steady state from the single-dose radiolabeled absorption, distribution, metabolism, and excretion studies: a case study.

The exposure of a drug candidate and its metabolites in humans and preclinical species during drug development needs to be determined to ensure that the safety of drug-related components in humans is adequately assessed in the standard toxicology studies. The in vivo radiolabeled studies in preclinical species and human volunteers provide the total fate of the drug-derived radioactivity including the relative abundance of metabolites. Here, we describe how the single-dose radiolabeled human studies could provide the exposure of circulating metabolites at steady state using a case study of an extensively metabolized drug, lixivaptan.

AAPS workshop report: strategies to address therapeutic protein-drug interactions during clinical development.

Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction.

Human radiolabeled mass balance studies: objectives, utilities and limitations.

The determination of metabolic pathways of a drug candidate through the identification of circulating and excreted metabolites is vitally important to understanding its physical and biological effects. Knowledge of metabolite profiles of a drug candidate in animals and humans is essential to ensure that animal species used in toxicological evaluations of new drug candidates are appropriate models of humans. The recent FDA final guidance recommends that human oxidative metabolites whose exposure exceeds 10% of the parent AUC at steady-state should be assessed in at least one of the preclinical animal species used in toxicological assessment.

Preclinical pharmacokinetics of a novel HIV-1 attachment inhibitor BMS-378806 and prediction of its human pharmacokinetics.

BMS-378806 is a prototype of novel HIV attachment inhibitors that block the gp120 and CD4 interaction, the first step of HIV-1 entry into cells. The present work investigated the pharmacokinetics of BMS-378806 in rats, dogs and monkeys and assessed its in vitro permeability and metabolism. BMS-378806 exhibited species-dependent oral bioavailability which was 19%-24% in rats and monkeys and 77% in dogs.