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.

AIMCharacterization of the biliary disposition of GSK1325756, using a non-invasive bile sampling technique and spectrometric analyses, to inform the major routes of metabolic elimination and to enable an assessment of victim drug interaction risk. METHODSixteen healthy, elderly subjects underwent non-invasive bile capture using a peroral string device (Entero-Test ® ) prior to and following a single oral dose of GSK1325756 (100 mg). The device was swallowed by each subject and 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 analyzed for drug-related material using spectrometric and spectroscopic techniques following solvent extraction. RESULTSNuclear magnetic resonance spectroscopy (NMR) indicated that the O-glucuronide metabolite was the major metabolite of GSK1325756, representing approximately 80% of drug-related material in bile. As bile is the major clearance route for GSK1325756 (only 4% of the administered dose was excreted in human urine), this result indicates that uridine 5'-diphospho-glucuronosyltransferases (UGTs) are the major drug metabolizing enzymes responsible for drug clearance. The relatively minor contribution made by oxidative routes reduces the concern of CYP-mediated victim drug interactions. CONCLUSIONThe results from this study demonstrate the utility of deploying the Entero-Test® in early human studies to provide information on the biliary disposition of drugs and their metabolites. This technique can be readily applied in early clinical development studies to provide information on the risk of interactions for drugs that are metabolized and eliminated in bile. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Inhibition of a drug clearance mechanism by another co-administered drug can result in a victim drug interaction. Understanding the enzymes and transporters involved in the clearance of a drug, generally derived from in vitro systems, can help inform the drug interaction risk.• Knowledge of the drug and metabolite excretion profiles is required in human subjects to put mechanistic enzyme and transporter information into clinical context and this is generally limited to metabolic investigations of urine and faeces following a dose of radiolabelled drug during late clinical development. WHAT DOES THIS STUDY ADD?• This clinical study demonstrates that human bile samples collected for drug and metabolite analysis can be used to inform the risk of victim drug interactions for drugs in early clinical development.• Using non-invasive bile sampling technology the biliary disposition of GSK1325756, a drug being developed for the treatment of chronic obstructive pulmonary disease (COPD), was evaluated in healthy elderly subjects. This showed that an O-glucuronide was the major metabolite in bile, confirming that clearance of GSK1325756 is mediated predominately by UGT enzymes.• The relatively low levels of oxidative metabolites in human bile indicate a...

Abstract. Objective: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). Methods: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 – 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2. Results: Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively. Conclusions: GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2.

ABSTRACT:Preclinical information on the biliary metabolites of a drug candidate is typically obtained through the collection of bile after surgical cannulation of the bile duct. In this study, we describe a novel approach using the Entero-Test, a simple device that facilitates the noninvasive sampling of duodenal bile. The Entero-Test was used to collect bile from six fasted dogs that had been dosed either orally with simvastatin (SV) or intravenously with simvastatin hydroxy acid (SVA), compounds that have been previously reported to undergo extensive metabolism and biliary secretion in the dog. The devices, consisting of a weighted gelatin capsule containing 90 cm of a highly absorbent nylon string, were swallowed by each dog with the proximal end of the string taped to the animal's face. Once the weighted string had reached the duodenum, gallbladder contraction was stimulated to release bile. Each bile-stained string was then retrieved via the mouth and, after solvent extraction, samples were analyzed for drug-related material by ultraperformance liquid chromatography-mass spectrometry and NMR spectroscopy. Numerous metabolites of SV and SVA were observed, and, in general, the major metabolites have been reported previously from studies with bile duct-cannulated animals dosed with

ascending doses of GSK3335065 or matched placebo as a single intravenous bolus injection to assess safety, tolerability, pharmacokinetics and pharmacodynamics.GSK3335065 displayed an apparent volume of distribution between 20.6 L and 44.6 L, a clearance between 0.462 L/h and 0.805 L/hr and a terminal half-life between 31.3 and 34.5 hr. In the single subject who received 1.3 mg GSK3335065, changes in tryptophan pathway metabolites were observed consistent with the changes seen in preclinical species suggesting that KMO enzyme activity was partially inhibited. However, a broad complex ventricular tachycardia was observed in this subject, which was judged to be a Serious Adverse Event (SAE) and resulted in early termination of the study. While development of GSK3335065 was subsequently discontinued, significant confounding factors hinder a clear interpretation that the tachycardia was directly related to administration of the compound.