Assessment of the safety, pharmacokinetics and pharmacodynamics of GSK3335065, an inhibitor of kynurenine monooxygenase, in a randomised placebo-controlled first-in-human study in healthy volunteers.

GSK3335065 is an inhibitor of kynurenine monooxygenase (KMO) being developed for the treatment of acute pancreatitis. Healthy male volunteers were administered 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.

Understanding the interplay of drug transporters involved in the disposition of rosuvastatin in the isolated perfused rat liver using a physiologically-based pharmacokinetic model.

The role of hepatic uptake (Oatp1a1 and Oatp1b4) and efflux (Bcrp and Mrp2) transporters in the disposition of rosuvastatin were investigated using the isolated perfused rat liver (IPRL). A simple physiologically-based pharmacokinetic model was developed to quantitatively determine the interplay between the individual transporters. Uptake and elimination of rosuvastatin in the IPRL was rapid and extensive. In the presence of rifamycin (an equipotent inhibitor of both Oatp1a1 and Oatp1a4) the perfusate clearance of rosuvastatin was reduced, but rifampicin (a potent inhibitor of Oatp1a4) had no effect upon the perfusate clearance. This might indicate a limited role for Oatp1a4, but it is possible that Oatp1a1 (or other uptake transporters) may have redundancy in their affinity for rosuvastatin. In the presence of GF120918 (a potent inhibitor of Bcrp) and in the Wistar TR- rat (a naturally occurring mutant not expressing Mrp2) the biliary clearance was reduced and virtually abolished in the TR- pre-incubated GF120918. Bcrp and Mrp2 appear to represent the primary efflux mechanisms for rosuvastatin in the rat. Rosuvastatin disposition in the IPRL is mediated in part by Oatp1a1 and efflux is almost entirely by Mrp2 and Bcrp. Other uptake processes may be involved.