Wang Kun, Zhu Yusong, Xu Fengyan, Liu Lucy, Liu Lichuan, Shi Mengling, Nie Jing, Reinhart Harald, Liu Jing, Gao Yuying, Pu Xia
Shanghai Qiangshi Information Technology Co., Ltd., Shanghai, China.
Zai Laboratory (Shanghai) Co., Ltd., Shanghai, China.
Eur J Pharm Sci. 2024 Apr 1;195:106713. doi: 10.1016/j.ejps.2024.106713. Epub 2024 Feb 1.
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.
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.
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 MIC value of recent clinical isolates from China.
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.
奥马环素（PTK-0796）是首个用于治疗由易感病原体引起的社区获得性细菌性肺炎（CABP）及急性细菌性皮肤和皮肤结构感染（ABSSSI）的成年患者的氨甲基环素类药物。我们研究了奥马环素的药代动力学（PK）和药效学（PD）特征，考虑协变量尤其是种族对PK的影响，并确定给药方案的PK/PD截止值。
利用非线性混合效应模型，我们汇总了11项临床试验的数据用于群体药代动力学（PopPK）分析。NONMEM中的带交互作用的一阶条件估计（FOCEI）方法有助于模型参数估计。采用逐步模型选择策略，通过向前加入（P<0.01）和向后剔除（P<0.001），我们评估了协变量对奥马环素PK的潜在影响，包括基线年龄、体重、性别、种族、体重指数、体表面积、基线白蛋白、肌酐清除率和剂型。通过多种方法验证模型后，最终的PopPK模型进行蒙特卡洛模拟以生成中国人群的PK特征。这使得能够计算曲线下面积（AUC）并评估各种给药方案和细菌菌株的达标概率（PTA）和累积反应分数（CFR）。
奥马环素的PK可用三室模型充分表征。体重、性别、种族和药物剂型对其PK有统计学影响。亚洲人和非亚洲人静脉输注后的暴露情况相似，但口服给药后的暴露量比非亚洲人高得多。蒙特卡洛模拟表明，仅静脉给药或静脉/口服序贯治疗方案对引起ABSSSI和CABP的所有主要病原体均能充分达标。PK/PD截止值通常高于中国近期临床分离株的最低抑菌浓度（MIC）值。
总之，中国获批的方案对所有通常与这些感染相关的病原体均能充分达标。亚洲人观察到的较高口服暴露量可能会提高疗效而不影响安全性或耐受性。
