Pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of single and continuous intravenous infusion of SPT-07A in healthy volunteers.

purposeSPT-07A is an intravenous injection of (+)-2-borneol being developed for the treatment of acute ischemic stroke. This study aimed to investigate the pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of SPT-07A after sequentially administered single and multiple infusions of SPT-07A at 10 mg, 20 mg, or 40 mg.

methodsThis phase I, double-blind, randomized, placebo-controlled, dose-escalation study was conducted in 36 Chinese healthy volunteers. Each cohort enrolled 12 eligible subjects, who were 9:3 randomized to receive SPT-07A or matching placebo during the two study occasions, that is, an initial single-dose occasion followed by a 7-day multiple-dose occasion with a dosing interval of 12 h. Pharmacokinetic, pharmacodynamic assessments regarding effects on the central nervous system (CNS) were performed pre-dose and several times post-dose. Safety and tolerability were evaluated throughout the study for each cohort.

resultsFollowing single intravenous (i.v.) administration of 10 mg to 40 mg SPT-07A, the plasma SPT-07A concentration reached its peak by the end of infusion. Thereafter, the plasma concentration declined in a multiphase exponential manner with an average terminal elimination half-life of 3.85 to 8.93 h. The exposure parameters of SPT-07A increased dose proportionally. Steady state of SPT-07A was reached after 12-hourly i.v. administrations for 4 days with minimal accumulations. No significant difference of change-from-baseline was observed in the pharmacodynamic measurements between each of the three SPT-07A-treated groups and the placebo group. A total of 41 adverse events (AEs) were reported in 77.8% subjects at 10 mg (7/9), 20 mg (7/9), and 40 mg (7/9), respectively. The AE incidence in placebo group was also 77.8% (7/9). All AEs were mild or moderate in severity and self-limited. SPT-07A was mainly excreted in human urine in glucuronic acid conjugate forms. The total urine recovery rate approximated 84.69% of the administered dose.

conclusionsSPT-07A was safe and well tolerated after single and multiple intravenous administrations of SPT-07A in the range of 10 mg to 40 mg. SPT-07A presented linear pharmacokinetics in human. Based on plasma exposure, the doses of 10-40 mg twice daily resulted in exposure levels comparable with those obtained at doses demonstrating potential efficacy on AIS animal models and were thus recommended as therapeutic exploratory doses in the phase II clinical trial.