Deciphering the Pharmacokinetics of SPH3127: Insights from Nonclinical Studies and Human Predictions

The text describes a study on SPH3127, a new oral medication intended to manage blood pressure and fluid balance through the renin-angiotensin-aldosterone system. The drug is currently undergoing a phase I clinical trial in China. The research aimed to gather comprehensive pharmacokinetic data and forecast human pharmacokinetic parameters.

The methodology included in vivo studies in rats, dogs, and monkeys to examine SPH3127's exposure, absorption, clearance, distribution, and metabolism following both intravenous and oral administration. A pharmacokinetics/pharmacodynamics study in monkeys was also conducted to explore the relationship between the drug's effect and concentration. Human pharmacokinetic characteristics were estimated using allometric scaling from non-clinical species data. Additional in vitro studies were performed, such as CYP enzyme phenotyping, inhibition and induction studies, and analysis of Caco-2 cell permeation and metabolite profiles.

Results indicated that SPH3127 displayed high clearance and volume of distribution with a short half-life after intravenous administration in rats and monkeys. Oral bioavailability was found to be between 11.5-24.5% for rats and 3.3-11.3% for monkeys, with a short peak time. The drug exhibited low permeability across Caco-2 cell membranes and was identified as a substrate of p-gp with efflux characteristics. After oral dosing in rats, it was primarily distributed to the gastrointestinal tract, liver, kidney, pancreas, and lung, with concentrations rapidly declining to 1% of the peak within 12 hours. The drug showed low plasma protein binding across all species. Excretion studies suggested that SPH3127 undergoes significant metabolism after oral dosing, with fecal, urine, and bile excretion accounting for approximately 15% of the administered dose. CYP3A4 was identified as the primary enzyme involved in the drug's metabolism, with key metabolites being N-hydroxylation, mono-oxidation-dehydrogenation, and mono-oxidation. The in vitro CYP inhibition study showed weak effects on CYP3A4. Monkey pharmacokinetic/pharmacodynamic data indicated favorable safety margins when compared to the effect dose and the NOAEL level. The four-species allometric scaling method was used to predict human plasma clearance and volume of distribution, and to simulate the oral human plasma concentration-time profile, which correlated well with phase I clinical trial data.

The conclusion of the study is that SPH3127 possesses suitable pharmacokinetic properties for further clinical investigation.