KBP Biosciences Co., Ltd., Jinan, China.
KBP Biosciences USA, Inc., Princeton, New Jersey, USA
Antimicrob Agents Chemother. 2020 May 21;64(6). doi: 10.1128/AAC.00488-20.
KBP-7072 is a semisynthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens, including multidrug-resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (i.v.) administrations of single and multiple doses were investigated in animal models, including during fed and fasted states, and the protein binding and excretion characteristics were also evaluated. In Sprague-Dawley (SD) rats, beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after the administration of single oral and i.v. and multiple oral doses. The oral bioavailability ranged from 12% to 32%. The mean time to maximum concentration () ranged from 0.5 to 4 h, and the mean half-life ranged from approximately 6 to 11 h. The administration of oral doses in the fed state resulted in marked reductions in the maximum plasma concentration () and the area under the concentration-time curve (AUC) compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5-mg/kg oral dose of KBP-7072 in SD rats, the cumulative excretion in feces was 64% and that in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single- and multiple-ascending-dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once-daily oral and i.v. administration in clinical studies.
KBP-7072 是一种半合成氨甲基环素，对革兰氏阳性和革兰氏阴性病原体具有广谱活性，包括多药耐药菌株。在动物模型中，包括在进食和禁食状态下，研究了 KBP-7072 单次和多次口服和静脉（i.v.）给药后的药代动力学（PK），并评估了其蛋白结合和排泄特征。在 Sprague-Dawley（SD）大鼠、比格犬和 CD-1 小鼠中，KBP-7072 单次口服和 i.v.以及多次口服给药后表现出线性 PK 特征。口服生物利用度范围为 12%至 32%。达峰时间（Tmax）范围为 0.5 至 4 小时，半衰期（t1/2）范围约为 6 至 11 小时。与禁食动物相比，在进食状态下给予口服剂量会导致最大血浆浓度（Cmax）和浓度-时间曲线下面积（AUC）显著降低。KBP-7072 在小鼠、大鼠、狗、猴子和人血浆中的平均结合分数分别为 77.5%、69.8%、64.5%、69.3%和 69.2%。在 SD 大鼠单次给予 22.5mg/kg 的 KBP-7072 后，粪便中的累积排泄量为给药剂量的 64%，尿液中的累积排泄量为 2.5%。动物模型中的 PK 结果与健康志愿者的单次和多次递增剂量研究一致，并证实 KBP-7072 适合在临床研究中进行每日一次口服和 i.v.给药。
