Daprodustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated for treatment of anemia in chronic kidney disease. This phase 1, nonrandomized, 2-period, crossover study in 6 healthy men characterized the absorption, distribution, and excretion of daprodustat when administered as oral and intravenous (IV) doses of unlabeled and radiolabeled daprodustat ([ 14 C]-GSK1278863). Tolerability and pharmacokinetic properties of daprodustat, and its 6 metabolites in the systemic circulation, were also evaluated. The mean recovery of radiolabeled daprodustat was ≈95% by day 5, with the majority in feces and minor renal elimination, indicating that daprodustat and metabolites are primarily eliminated via hepatobiliary and fecal routes. Approximately 40% of total circulating radioactivity in plasma following both IV and oral administration was daprodustat; thus, 60% was attributed to metabolites. It was estimated that ≈80% of daprodustat was absorbed across the gastrointestinal tract, and ≈18% cleared by hepatic extraction. Pharmacokinetics were essentially dose proportional, with moderate (≈66%) oral tablet bioavailability. Following IV administration, daprodustat plasma clearance (19.3 L/h) and volume of distribution (14.6 L) were low, suggesting low tissue distribution outside systemic circulation with likely low penetration into tissues. Daprodustat was generally well tolerated, with no deaths or serious or significant adverse events reported.

Nalmefene blunts BOLD response in the mesolimbic system during anticipation of monetary reward and an alcohol infusion. This is consistent with nalmefene's actions on opioid receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.

AIMSTo compare gastric acid suppression by netazepide, a gastrin/CCK2 receptor antagonist, with that by a proton pump inhibitor (PPI), and to determine if netazepide can prevent the trophic effects of PPI-induced hypergastrinaemia. METHODSThirty healthy subjects completed a double-blind, randomized, parallel group trial of oral netazepide and rabeprazole, alone and combined, once daily for 6 weeks. Primary end points were: basal and pentagastrin-stimulated gastric acid and 24 h circulating gastrin and chromogranin A (CgA) at baseline, start and end of treatment, gastric biopsies at baseline and end of treatment and basal and pentagastrin-stimulated gastric acid and dyspepsia questionnaire after treatment withdrawal. RESULTSAll treatments similarly inhibited pentagastrin-stimulated gastric acid secretion. All treatments increased serum gastrin, but the combination and rabeprazole did so more than netazepide alone. The combination also reduced basal acid secretion. Rabeprazole increased plasma CgA, whereas netazepide and the combination reduced it. None of the biopsies showed enterochromaffin-like (ECL) cell hyperplasia. Withdrawal of treatments led neither to rebound hyperacidity nor dyspepsia. CONCLUSIONSNetazepide suppressed pentagastrin-stimulated gastric acid secretion as effectively as did rabeprazole. The reduction in basal acid secretion and greater increase in serum gastrin by the combination is consistent with more effective acid suppression. Despite our failure to show rabeprazole-induced ECL cell hyperplasia and rebound hyperacidity, the increase in plasma CgA after rabeprazole is consistent with a trophic effect on ECL cells, which netazepide prevented. Thus, netazepide is a potential treatment for the trophic effects of hypergastrinaemia and, with or without a PPI, is a potential treatment for acid-related conditions. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Gastrin controls gastric acid secretion and mucosal cell growth, especially of enterochromaffin-like (ECL) cells, which express gastrin/CCK2 receptors and release chromogranin A (CgA) into the circulation when stimulated by gastrin. • In non-clinical studies, acid suppression by a proton pump inhibitor (PPI) causes hypergastrinaemia which results in ECL cell growth and, after PPI withdrawal, rebound hyperacidity. Netazepide is an orally active, selective gastrin/CCK2 receptor antagonist, which suppresses acid production and prevents the trophic effects of PPI-induced hypergastrinaemia.• In healthy subjects, oral netazepide causes dose-dependent, persistent inhibition of gastric acid secretion, which leads to increased serum gastrin. WHAT THIS STUDY ADDS• In healthy subjects, netazepide and the PPI rabeprazole were similarly effective at suppressing pentagastrin-stimulated gastric acid secretion and increasing serum gastrin.• Rabeprazole increased plasma CgA, a sign of ECL cell hyperactivity, whereas netazepide reduced plasma CgA, a sign of ECL cell hypoactivity. Netazepide also prevented the increase in CgA resulting from rabeprazole-induced hyp...

Emodepside is an anthelmintic, originally developed for veterinary use. We investigated in healthy subjects the safety, and pharmacokinetics of a liquid service formulation (LSF) and immediate release (IR) tablet of emodepside in 2 randomised, parallel-group, placebo-controlled, Phase I studies.Methods: Seventy-nine subjects in 10 cohorts in the single ascending dose study and 24 subjects in 3 ascending-dose cohorts in the multiple ascending dose study were enrolled. Emodepside as LSF was administered orally as single 1-40-mg doses and for 10 days as 5 or 10 mg once daily and 10-mg twice daily doses, respectively.Pharmacokinetics and safety were assessed up to 21 and 30 days, respectively. In addition, IR tablets containing 5 or 20 mg emodepside were tested in the single ascending dose study.Results: Emodepside as LSF was rapidly absorbed under fasting conditions, with dose-proportional increase in plasma concentrations at doses from 1 to 40 mg.Terminal half-life was > 500 hours. In the fed state, emodepside was absorbed more slowly but overall plasma exposure was not significantly affected. Compared to the LSF, the rate and extent of absorption was significantly lower with the tablets.Conclusions: Overall, emodepside had acceptable safety and tolerability profiles, no major safety concerns, after single oral administration of 20 mg as LSF and after multiple oral administration over 10 days at 5 and 10 mg OD and at 10 mg twice daily. For further clinical trials, the development of a tablet formulation overcoming the limitations observed in the present study with the IR tablet formulation is considered.