National Center for Advancing Translational Sciences, Bethesda, MD, United States.
Covance Laboratories, Inc., 3301 Kinsman Blvd., Madison, WI, United States.
Regul Toxicol Pharmacol. 2019 Nov;108:104433. doi: 10.1016/j.yrtph.2019.104433. Epub 2019 Jul 27.
PF614, a novel trypsin activated abuse protection (TAAP) prodrug of oxycodone, is being studied as chronic pain analgesic with extended release and abuse resistant properties. A series of nonclinical safety studies were conducted to support PF614 introduction to clinical trials. Ames assays (PF614 and its metabolites), comet assay (PF614 ≤ 50 mg/kg/day oral gavage in rats) and micronucleus assay (PF614 ≤ 175 mg/kg/day oral gavage in rats) were negative. hERG assay IC for PF614 was ≥300 μM. PF614 (0.1 and 10 μM) showed a low permeability in Caco-2 cells (≤1.17 x 10-6 cm/s) and was not a P-gp or BCRP substrate or inhibitor. The mean percent unbound PF614 among all concentrations in plasma ranged from 91.2 to 98.4, 79.4 to 100, and 52.9-79.9% in rat, dog, and human, respectively. Also, PF614 was metabolically stable in rat, dog, and human hepatocytes with no metabolites identified. Safety pharmacology study in dog indicated moderately lower heart rate at ≥ 2 mg/kg oral gavage doses. Toxicity studies of PF614 in rat and dog with daily oral doses of 25 and 18 mg/kg, respectively, for 14 Days were well tolerated with favorable safety profile supporting its further clinical evaluation.
PF614 是一种新型的胰蛋白酶激活的滥用保护（TAAP）羟考酮前药，作为具有延长释放和抗滥用特性的慢性疼痛治疗药物正在进行研究。进行了一系列非临床安全性研究，以支持 PF614 引入临床试验。Ames 测定（PF614 及其代谢物）、彗星试验（PF614 在大鼠中每天口服灌胃≤50mg/kg）和微核试验（PF614 在大鼠中每天口服灌胃≤175mg/kg）均为阴性。hERG 测定 PF614 的 IC 为≥300µM。PF614（0.1 和 10µM）在 Caco-2 细胞中的渗透性低（≤1.17x10-6cm/s），不是 P-糖蛋白或 BCRP 的底物或抑制剂。在所有浓度的血浆中未结合的 PF614 的平均百分比在大鼠、狗和人中分别为 91.2-98.4%、79.4-100%和 52.9-79.9%。此外，PF614 在大鼠、狗和人肝细胞中代谢稳定，未鉴定出代谢物。狗的安全药理学研究表明，口服剂量≥2mg/kg 时心率中度降低。在大鼠和狗中进行的 PF614 毒性研究，每天口服剂量分别为 25 和 18mg/kg，连续 14 天，耐受性良好，安全性良好，支持进一步的临床评估。
