目的:Omadacycline(PTK-0796)是一种治疗成人社区获得性细菌性肺炎(CABP)及易感病原菌引起的急性细菌性皮肤和皮肤结构感染(ABSSSI)的一流氨基甲环素。我们研究了奥马环素的药代动力学(PK)和药效学(PD)谱,考虑到协变量的影响,特别是种族,并确定给药方案的PK/PD截断值。
方法:利用非线性混合效应建模,我们汇集了11项临床试验的数据用于PopPK分析.NONMEM中的一阶条件估计与交互(FOCEI)方法促进了模型参数估计。采用逐步模型选择策略,正向添加(P<0.01)和反向删除(P<0.001),我们评估了协变量对omadacyclinePK的潜在影响,包括基线年龄,体重,性别,种族,身体质量指数,体表面积,基线白蛋白,肌酸清除率,和配方。在通过各种方法验证模型后,最终的PopPK模型进行了蒙特卡洛模拟,以生成中国人口的PK概况.这使得AUC计算和评估各种给药方案和细菌菌株的目标达成概率(PTA)和累积响应分数(CFR)成为可能。
结果:Omadacycline的PK可以通过三室模型充分表征。体重,性别,种族,和药物配方对其PK有统计学影响。亚洲人和非亚洲人在静脉输注后表现出相似的暴露,但是口服给药的暴露量要比非亚洲人高得多。蒙特卡罗模拟表明,仅IV或IV/PO序贯治疗方案可为所有导致ABSSSI和CABP的主要病原体提供足够的治疗。PK/PD截止值通常高于中国近期临床分离株的MIC90值。
结论:结论:在中国获得批准的治疗方案对通常与这些感染相关的所有病原体均达到了足够的目标.在亚洲人中观察到的较高的口服暴露可能会增强疗效,而不会影响安全性或耐受性。
OBJECTIVE: Omadacycline (PTK-0796) is a first-in-class aminomethylcycline for adult patients with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible pathogens. We investigated the pharmacokinetic (PK) and pharmacodynamic (PD) profile of omadacycline, considering the impact of covariates, particularly ethnicity, on PK and determined the PK/PD cutoff values for dosing regimens.
METHODS: Utilizing nonlinear mixed-effects modeling, we pooled data from 11 clinical trials for PopPK analysis. The first-order conditional estimation with interaction (FOCEI) method in NONMEM facilitated model parameter estimation. Employing a stepwise model selection strategy, with forward addition (P < 0.01) and backward deletion (P < 0.001), we assessed the potential impacts of covariates on omadacycline PK, including baseline age, body weight, sex, race, body mass index, body surface area, baseline albumin, creatine clearance, and formulation. After validating the model through various methods, the final PopPK model underwent Monte Carlo simulations to generate the PK profile for the Chinese population. This enabled AUC calculation and assessment of the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for various dosing regimens and bacterial strains.
RESULTS: Omadacycline\'s PK can be adequately characterized by a three-compartment model. Body weight, sex, race, and drug formulation statistically influenced its PK. Asians and non-Asians exhibit similar exposure after intravenous infusion, but oral dosing results in much higher exposures than in non-Asians. Monte Carlo simulation indicates that IV-only or IV/PO sequential therapy regimens provide adequate attainment for all major pathogens causing ABSSSI and CABP. PK/PD cutoffs were generally above the MIC90 value of recent clinical isolates from China.
CONCLUSIONS: In conclusion, the approved regimen for China achieved adequate target attainment for all pathogens typically associated with these infections. The higher oral exposure observed in Asians may enhance efficacy without affecting safety or tolerability.