R&D Centre, Celon Pharma SA, Marymoncka 15, 05-152, Kazun Nowy, Poland.
R&D Centre, Celon Pharma SA, Marymoncka 15, 05-152, Kazun Nowy, Poland.
Pulm Pharmacol Ther. 2022 Jun;73-74:102127. doi: 10.1016/j.pupt.2022.102127. Epub 2022 Apr 14.
Ketamine and its enantiomer esketamine have gained much attention in recent years as potent, fast-acting agents for the management of treatment-resistant depression. However, an alternative to oral ketamine administration is required to ensure adequate systemic exposure as the drug undergoes extensive first-pass metabolism. We propose dry powder inhalation as a new esketamine delivery route. Here, we examine the pharmacokinetics, pharmacodynamics, toxicology and safety of this novel esketamine administration method. Esketamine (10 mg/kg) and ketamine racemate (20 mg/kg) were administered to rats by dry powder inhalation, intravenous injection or intratracheal instillation and the pharmacokinetics of these treatments were compared. Analyte concentration of ketamine stereoisomers and their metabolites was assessed by LC-MS/MS method. Esketamine showed a clinically relevant pharmacokinetic profile, with high bioavailability (62%) and relatively low maximum concentration peaks. Esketamine exhibited high penetration of the blood-brain barrier, but pharmacodynamic examinations of brain homogenates showed no changes in selected protein phosphorylation or expression analyzed by the immunoblotting method. We conducted GLP-compliant 14-day and 28-day general toxicity studies in rats and dogs, respectively, subjected to dry esketamine powder inhalation. The maximum daily dosages were 46.5 mg/kg and 36.5 mg/kg, respectively. We also performed pharmacological safety studies. Esketamine inhaled as dry powder had an expected safety profile consistent with its known pharmacological action. None of its observed effects were considered toxicologically significant. The pharmacological safety studies confirmed that the observed effects were transient and that inhaled esketamine had a good safety profile. Hence, our preclinical studies demonstrated that dry powder inhalation is a highly efficacious and safe delivery route for esketamine and may be a viable alternative administration route meriting further clinical development.
氯胺酮及其对映异构体艾司氯胺酮近年来作为治疗抵抗性抑郁症的有效、快速作用药物受到广泛关注。然而，需要替代口服氯胺酮给药方式以确保足够的全身暴露，因为该药物会经历广泛的首过代谢。我们提出干粉吸入作为一种新的艾司氯胺酮给药途径。在此，我们研究了这种新型艾司氯胺酮给药方法的药代动力学、药效学、毒理学和安全性。通过干粉吸入、静脉注射或气管内滴注将氯胺酮（10mg/kg）和氯胺酮外消旋体（20mg/kg）给予大鼠，并比较这些治疗方法的药代动力学。通过 LC-MS/MS 方法评估氯胺酮立体异构体及其代谢物的分析物浓度。氯胺酮表现出具有临床相关性的药代动力学特征，具有高生物利用度（62%）和相对较低的最大浓度峰值。氯胺酮表现出对血脑屏障的高穿透性，但通过免疫印迹法分析脑匀浆的药效学检查显示，所选蛋白质磷酸化或表达没有变化。我们分别在大鼠和犬中进行了符合 GLP 的 14 天和 28 天的一般毒性研究，这些动物接受了干粉艾司氯胺酮吸入。最大日剂量分别为 46.5mg/kg 和 36.5mg/kg。我们还进行了药理学安全性研究。以干粉形式吸入的艾司氯胺酮具有与其已知药理学作用一致的预期安全性特征。其观察到的作用均不被认为具有毒理学意义。药理学安全性研究证实，观察到的作用是短暂的，吸入艾司氯胺酮具有良好的安全性。因此，我们的临床前研究表明，干粉吸入是一种高效且安全的艾司氯胺酮给药途径，可能是一种有前途的替代给药途径，值得进一步临床开发。
