Applied Pharmacology, Non-clinical Regulatory Science, Applied Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.
Applied Drug Metabolism & Pharmacokinetics, Non-clinical Regulatory Science, Applied Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.
J Pharmacol Sci. 2023 Apr;151(4):171-176. doi: 10.1016/j.jphs.2023.02.003. Epub 2023 Feb 15.
ASP8062 is an orally available GABA receptor positive allosteric modulator (PAM). This study assessed the potential of ASP8062 for treating opioid use disorder (OUD). Three rhesus monkeys were pretreated with ASP8062 (0.3, 1 or 3 mg/kg) by oral administration 1 h prior to a 2-h morphine self-administration session (0.03 mg/kg, iv, per injection) under a fixed-ratio 5 schedule. We further examined the potential worsening of morphine-induced respiratory suppression by ASP8062 after coadministration of morphine (10 mg/kg, sc) and ASP8062 (10 mg/kg, po) in cynomolgus monkeys using a custom-made whole-body plethysmograph. Plasma concentrations of ASP8062 (3 or 10 mg/kg, po) were assessed in cynomolgus monkeys using liquid chromatography-tandem mass spectroscopy (LC-MS/MS). ASP8062 at 3 mg/kg, po decreased the morphine self-administrations with significant differences from the vehicle-treated group (IC = 0.97 ± 0.36 mg/kg). Exposure levels at 3 mg/kg observed in monkeys were comparable to the clinical exposure levels which positive pharmacodynamic effects were previously shown. Further, ASP8062 did not potentiate morphine-induced respiratory suppression up to exposure levels higher than the clinically relevant dose. ASP8062 may reduce opioid use in OUD patients without affecting respiratory system, providing justification for further ASP8062 development as a potential treatment option for OUD.
ASP8062 是一种口服有效的 GABA 受体正变构调节剂（PAM）。本研究评估了 ASP8062 治疗阿片类药物使用障碍（OUD）的潜力。三只恒河猴通过口服预先用 ASP8062（0.3、1 或 3mg/kg）预处理 1 小时，然后进行 2 小时的吗啡自我给药（0.03mg/kg，iv，每次注射），固定比率为 5。我们进一步使用定制的全身测压仪，在给予吗啡（10mg/kg，sc）和 ASP8062（10mg/kg，po）后，检查 ASP8062 对吗啡引起的呼吸抑制的潜在恶化。在食蟹猴中，使用液相色谱-串联质谱法（LC-MS/MS）评估 ASP8062（3 或 10mg/kg，po）的血浆浓度。ASP8062 以 3mg/kg，po 减少了吗啡的自我给药，与载体处理组相比有显著差异（IC=0.97±0.36mg/kg）。在猴子中观察到的 3mg/kg 暴露水平与先前显示阳性药效学作用的临床暴露水平相当。此外，ASP8062 没有增强吗啡引起的呼吸抑制，直到暴露水平高于临床相关剂量。ASP8062 可能会减少 OUD 患者对阿片类药物的使用，而不会影响呼吸系统，为进一步开发 ASP8062 作为 OUD 的潜在治疗选择提供了依据。
