Preclinical pharmacokinetic characterization of (R)-ketamine injection, a novel antidepressant glutamatergic agent.

Abstract

<h4>Introduction</h4>Ketamine is a significant class of antidepressant drugs, and the pharmacokinetic and pharmacodynamic characteristics of its enantiomers exhibit differences. Among them, intravenous infusion of (R)-ketamine can effectively alleviate depressive symptoms in patients, offering the advantages of prolonged duration of action and minimal side effects. The extensive preclinical pharmacokinetic (PK) studies of (R)-ketamine were conducted to support its further development.<h4>Methods</h4>This study investigated the preclinical pharmacokinetic behavior of (R)-ketamine across different dose groups through single- and multiple-dose pharmacokinetic studies in rats and dogs, along with tissue distribution studies in Sprague-Dawley (SD) rats.<i>In vitro</i> metabolism study using microsomes from mice, rats, dogs, monkeys, and humans were conducted to evaluate metabolic stability and obtain metabolite profiles. The excretion studies in rats (7.5 mg/kg dose group) were performed to elucidate the primary elimination pathways of (R)-ketamine. The allometric scaling approach was employed to predict human plasma total clearance based on preclinical data.<h4>Results</h4>(R)-ketamine exhibits nonlinear pharmacokinetics in SD rats and Beagle dogs, with plasma exposure increasing disproportionately to dose after both single and multiple intravenous administrations. The highest tissue exposure to (R)-Ketamine was found in the fat and kidney of the rats. The (R)-ketamine concentration ratio of brain/plasma was 2.25 for the rats, indicating effective blood-brain barrier penetration and significant brain distribution of (R)-ketamine. (R)-ketamine undergoes rapid metabolism in liver microsomes from mice, rats, dogs, monkeys and humans. The predominant metabolite identified in human, monkey and mice liver microsomes was (R)-norketamine and demethylated and mono-oxidized metabolites in rats and dogs. (R)-ketamine is primarily excreted via bile, accounting for 3.613% of the dose within 72 h, significantly higher than in feces (0.327%) or urine (0.030%). The main elimination pathway may be metabolic elimination, and eventually excreted in the form of metabolites. The predicted human plasma total clearance of 29.93 mL/min/kg is close to reported value.<h4>Conclusion</h4>The preclinical pharmacokinetic characteristics of (R)-ketamine injection have been thoroughly investigated, and these findings can provide valuable information for predicting the first-in-human dose and designing Phase I clinical trials for (R)-ketamine injection.

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