Absorption, distribution, metabolism, excretion (ADME), drug-drug interaction potential and prediction of human pharmacokinetics of SUVN-G3031, a novel histamine 3 receptor (H3R) inverse agonist in clinical development for the treatment of narcolepsy.

SUVN-G3031 is a potent and selective inverse agonist of Histmine-3 (H3) receptor that is being investigated for the treatment of narcolepsy. SUVN-G3031 has high passive permeability, not a substrate for P-glycoprotein, has high plasma unbound fractions and was equally distributed between blood and plasma. Major routes of metabolism in vitro were cyclization (Metabolite A) in microsomes and dealkylation (Metabolite D) in hepatocytes. Intrinsic clearance in liver microsomes and hepatocytes was low as monitored by metabolite formation approach. CYP3A4 and MAO-A were the major enzymes involved in the formation of metabolite A and metabolite D respectively. The human hepatic clearance estimated by well-stirred model from hepatocytes was low (2.7 L.h -1) illustrating the importance of metabolite formation kinetics for prediction of human clearance for SUVN-G3031. Renal clearance in humans (9.7 L.h -1) was predicted from dog renal clearance and accounts for ~78% of the total clearance. SUVN-G3031 was neither an inhibitor nor inducer of the P450 enzymes at clinically relevant concentrations. SUVN-G3031 did not inhibit the major uptake transporters and was not a substrate for the uptake transporters. The potential of SUVN-G3031 as a victim and perpetrator of drug-drug interactions is remote. The predicted human pharmacokinetic parameters were consistent with those observed in the first-in-human study.