Merck & Co., Inc., Rahway, New Jersey, USA.
Cognigen Corporation, a Simulations Plus Company, Buffalo, New York, USA.
J Clin Pharmacol. 2023 Feb;63(2):166-171. doi: 10.1002/jcph.2149. Epub 2022 Oct 2.
ASPECT-NP, a phase 3 trial of ceftolozane/tazobactam in hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), excluded patients with end-stage renal disease (ESRD). A modeling/simulation approach was undertaken to inform optimal dosing in this population, using previously developed ceftolozane and tazobactam population pharmacokinetic models informed by data from 16 clinical studies. Stochastic simulations were performed using NONMEM to support dose justification. Probability of target attainment (PTA) simulations in plasma and epithelial lining fluid were conducted using a 14-day treatment, with hemodialysis every other weekday for a high-dose (4X), middle-dose (3X), or low-dose (2X) regimen, where X was the recommended dose in patients with complicated intra-abdominal infection/complicated urinary tract infection and ESRD (500 mg/250 mg ceftolozane/tazobactam loading dose and 100 mg/50 mg ceftolozane/tazobactam maintenance dose administered by 1-hour infusion every 8 hours). PTA was determined using established pharmacokinetic/pharmacodynamic targets: ceftolozane, 30% of the interdose interval (8 hours) in which free ceftolozane concentration exceeded the minimum inhibitory concentration value of 4 µg/mL; tazobactam, 20% of the interdose interval in which free tazobactam concentration exceeded 1 µg/mL. Plasma PTA was >90% for both agents for all 3 regimens. Plasma ceftolozane exposures at the high-dose regimen exceeded those from phase 3 study experience. Epithelial lining fluid PTA was >90% for high- and middle-dose regimens but was <80% for tazobactam on dialysis days at the low-dose regimen. For patients with HABP/VABP and ESRD requiring intermittent hemodialysis, the middle-dose regimen of 1.5 g/0.75 g ceftolozane/tazobactam loading + 300 mg/150 mg maintenance every 8 hours by 1-hour infusion is recommended.
ASPECT-NP 是一项关于头孢他洛酯/他唑巴坦治疗医院获得性/呼吸机相关性细菌性肺炎（HABP/VABP）的 3 期临床试验，排除了终末期肾病（ESRD）患者。采用建模/模拟方法，利用先前开发的头孢他洛酯和他唑巴坦群体药代动力学模型，对来自 16 项临床研究的数据进行了信息补充，以此来确定最佳剂量。采用 NONMEM 进行随机模拟，以支持剂量合理性。采用 14 天治疗方案，每周 2 次在非透析日进行血液透析，模拟高剂量（4X）、中剂量（3X）和低剂量（2X）方案的血药浓度和肺泡上皮衬液中的药物浓度。其中 X 为头孢他洛酯/他唑巴坦在复杂性腹腔感染/复杂性尿路感染和 ESRD 患者中的推荐剂量（500mg/250mg 头孢他洛酯/他唑巴坦负荷剂量和 100mg/50mg 头孢他洛酯/他唑巴坦维持剂量，每 8 小时 1 小时输注）。采用既定的药代动力学/药效学目标确定了目标达到概率（PTA）：头孢他洛酯，游离头孢他洛酯浓度在 8 小时的间隔时间内超过最低抑菌浓度值 4μg/ml 的 30%；他唑巴坦，游离他唑巴坦浓度在 8 小时的间隔时间内超过 1μg/ml 的 20%。对于所有 3 种方案，两种药物的血药浓度 PTA 均>90%。高剂量方案的血药浓度暴露量超过了 3 期研究的经验。高剂量和中剂量方案的肺泡上皮衬液 PTA 均>90%，但低剂量方案透析日时的他唑巴坦 PTA<80%。对于需要间歇性血液透析的 HABP/VABP 和 ESRD 患者，建议使用头孢他洛酯/他唑巴坦 1.5g/0.75g 负荷剂量+300mg/150mg 维持剂量，每 8 小时 1 小时输注，每 8 小时 1 小时输注。
