AstraZeneca, Waltham, Massachusetts, USA.
Quantitative Solutions, Raleigh, North Carolina, USA.
Clin Transl Sci. 2019 Mar;12(2):151-163. doi: 10.1111/cts.12585. Epub 2018 Sep 28.
Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Population pharmacokinetic (PopPK) models were built to incorporate pharmacokinetic (PK) data from five phase III trials in patients with complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), or nosocomial (including ventilator-associated) pneumonia. Ceftazidime and avibactam pharmacokinetics were well-described by two-compartment disposition models, with creatinine clearance (CrCL) the key covariate determining clearance variability. Steady-state ceftazidime and avibactam exposure for most patient subgroups differed by ≤ 20% vs. healthy volunteers. Probability of PK/pharmacodynamic (PD) target attainment (free plasma ceftazidime > 8 mg/L and avibactam > 1 mg/L for ≥ 50% of dosing interval) was ≥ 94.9% in simulations for all patient subgroups, including indication and renal function categories. No exposure-microbiological response relationship was identified because target exposures were achieved in almost all patients. These modeling results support the approved ceftazidime-avibactam dosage regimens (2000-500 mg every 8 hours, adjusted for CrCL ≤ 50 mL/min).
头孢他啶-阿维巴坦是一种新型β-内酰胺/β-内酰胺酶抑制剂复方制剂，用于治疗由耐药革兰氏阴性病原体引起的严重感染。构建了群体药代动力学（PopPK）模型，以纳入 5 项关于复杂性腹腔内感染（cIAI）、复杂性尿路感染（cUTI）或医院获得性（包括呼吸机相关性）肺炎患者的 III 期临床试验中的药代动力学（PK）数据。头孢他啶和阿维巴坦的药代动力学通过双室分布模型得到了很好的描述，肌酐清除率（CrCL）是决定清除率变异性的关键协变量。对于大多数患者亚组，稳态头孢他啶和阿维巴坦的暴露与健康志愿者相比差异≤20%。在所有患者亚组的模拟中（包括适应证和肾功能类别），PK/药效学（PD）目标达标率（游离血浆头孢他啶>8mg/L 和阿维巴坦>1mg/L，占给药间隔的≥50%）≥94.9%。由于几乎所有患者均达到了目标暴露，因此未确定暴露-微生物反应关系。这些建模结果支持批准的头孢他啶-阿维巴坦剂量方案（每 8 小时 2000-500mg，根据 CrCL≤50mL/min 进行调整）。
