Use of Entero‐Test, a simple approach for non‐invasive clinical evaluation of the biliary disposition of drugs

Abstract

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT• Biliary secretion is often a major route of elimination of drugs and metabolites. Knowledge of the biliary disposition of a drug in man is important in understanding the contribution of this route to overall clearance and the potential for drug-drug interactions which may have clinical consequences. • Current methods for collecting human bile as part of drug disposition studies are invasive and complex, requiring intubation of the duodenum. As a result, limited data exist regarding the biliary elimination of many drugs and their metabolites. WHAT THIS STUDY ADDS• This proof of utility study clearly demonstrates that bile samples for drug and metabolite analysis can be collected simply, safely and cost-effectively from subjects using non-invasive technology.• Using such technology, the biliary disposition of simvastatin was evaluated successfully in healthy subjects. Qualitative metabolite data compared favourably with reported biliary data derived from intubated patients dosed with radiolabelled simvastatin.• This technique has substantial utility for early clinical evaluation of biliary disposition of drugs. AIMTo evaluate the non-invasive collection of bile from healthy human subjects for the qualitative characterization of the biliary disposition of a drug, using spectrometric techniques. METHODSTwenty subjects underwent non-invasive bile capture using a peroral string test (Entero-Test) device prior to and following a single oral dose of simvastatin (80 mg). The device, consisting of a weighted gelatin capsule containing a highly absorbent nylon string, was swallowed by each subject with the proximal end of the string taped to the face. Once the weighted string was judged to have reached the duodenum, gallbladder contraction was stimulated in order to release bile. The string was then retrieved via the mouth, and bile samples were analysed for drug-related material using spectrometric and spectroscopic techniques following solvent extraction. RESULTSNumerous metabolites of simvastatin were detected, and the major metabolites were consistent with those reported from studies where bile was collected using invasive techniques from patients dosed with [ 14 C]-simvastatin. CONCLUSIONSThe results from this study demonstrate the utility of deploying the Entero-Test in human studies to provide structural information on biliary metabolites. This can be readily applied in drug development studies, including those in the target patient population and may eliminate the need for more invasive sampling techniques.

Assessment of potential drug interactions by characterization of human drug metabolism pathways using non‐invasive bile sampling

“…Owing to the considerable investment and enabling studies required to support a human radiolabel study [19,20], these studies are often conducted too late in clinical development to impact on the co-medication strategy. Also bile is typically not collected in these studies thereby missing a potential key route of drug elimination [7]. Biliary elimination can sometimes be inferred by the drug-related material in faeces.…”

“…A simple method for the collection of duodenal bile in human subjects has been previously reported by Guiney et al [7] and has demonstrated that the Entero-Test®, a commercially available device, could be used reliably to collect human duodenal bile in order to determine metabolites of the lipid lowering drug simvastatin. The work described herein demonstrates a further application of the Entero-Test® technique to aid the assessment of victim drug interaction risk by characterization of the biliary disposition of GSK1325756.…”

Investigation of Metabolism and Disposition of GSK1322322, a Peptidase Deformylase Inhibitor, in Healthy Humans Using the Entero-Test for Biliary Sampling

“…Recently, GSK pioneered its use in metabolism studies. The device has proven useful in sampling bile from both dogs and human subjects in nonradiolabeled metabolism studies (Guiney et al, 2011;Bloomer et al, 2012), but it has never been tested in a conventional human radiolabel study where its application could be fully evaluated.…”

Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions--an Industry Perspective

“…It is also possible to get qualitative information into metabolic pathways of orally administered drugs in bile with the use of recent techniques such as Entero-Test (Guiney et al, 2011;Bloomer et al, 2013), although this has not yet been widely adopted. Identification of human-specific metabolic pathways along with any saturable pathways (as indicated by nonlinear PK) guides further refinement of victim DDI potential at FIH stage.…”

“…Recent advances in clinical devices as Entero-Test (Guiney et al, 2011;Bloomer et al, 2013) have enabled direct assessment of drugs and metabolites excreted into the bile of humans. This method can be applied in early clinical development to provide qualitative information on the risk of interactions for drugs that are metabolized and eliminated in bile.…”