Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; and.
Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Ther Drug Monit. 2023 Oct 1;45(5):697-701. doi: 10.1097/FTD.0000000000001058.
Gentamicin is used to treat severe infections and has a small therapeutic window. This study aimed to optimize the dosing strategy of gentamicin in intermittently hemodialyzed patients by simulating concentration-time profiles during pre- and postdialysis dosing, based on a published pharmacokinetic model.
Pharmacokinetic simulations were performed with virtual patients, including septic patients, who were treated with gentamicin and received weekly hemodialysis with an interval of 48 h-48 h-72 h. The following dosing regimens were simulated: for nonseptic patients, 5 mg/kg gentamicin was given 1 h or 2 h before dialysis or a starting dose of 2.5 mg/kg and a maintenance dose of 1.5 mg/kg immediately after dialysis were given; for septic patients, 6 mg/kg gentamicin was given 1 h or 2 h before dialysis or a starting dose of 3 mg/kg and a maintenance dose of 1.8 mg/kg immediately were given after dialysis. The mean maximum concentration (C max ), area under the curve (AUC) 24 h , and target attainment (TA) of pharmacodynamic targets were calculated and compared. The following targets were adopted from the literature: C max >8 mg/L and <20 mg/L and AUC 24 h >70 mg·h/L and <120 mg·h/L.
In nonseptic patients, postdialysis dosing resulted in a TA of 35% for C max of >8 mg/L, 100% for <20 mg/L and AUC 24 h >70 mg·h/L, and 45% for <120 mg·h/L. Dosing 2 h before dialysis resulted in a TA of 100% for C max of >8 mg/L, 40% for <20 mg/L, 65% for AUC 24 h >70 mg·h/L, and 77% for <120 mg·h/L. Simulations of septic patients resulted in comparable outcomes with higher TAs for C max <20 mg/L (96%), AUC 24 h >70 mg·h/L (90%), and AUC 24 h <120 mg·h/L (53%) for dosing 1 h before dialysis.
Postdialysis dosing resulted in a low TA of C max >8 mg/L; however, predialysis dosing ensured a high TA of C max >8 mg/L and acceptable TA of C max <20 mg/L, AUC 24 h >70 mg·h/L, and AUC 24 h <120 mg·h/L, which could increase the efficacy of gentamicin. Therefore, clinicians should consider predialysis dosing of gentamicin in patients undergoing intermittent hemodialysis.
庆大霉素用于治疗严重感染，治疗窗较小。本研究旨在通过模拟透析前和透析后给药期间的浓度-时间曲线，基于已发表的药代动力学模型，优化间歇性血液透析患者的庆大霉素给药方案。
对包括脓毒症患者在内的虚拟患者进行药代动力学模拟，这些患者接受庆大霉素治疗，并每周进行 48 h-48 h-72 h 的血液透析。模拟了以下给药方案：对于非脓毒症患者，在透析前 1 小时或 2 小时给予 5mg/kg 庆大霉素，或在透析后立即给予 2.5mg/kg 的起始剂量和 1.5mg/kg 的维持剂量；对于脓毒症患者，在透析前 1 小时或 2 小时给予 6mg/kg 庆大霉素，或在透析后立即给予 3mg/kg 的起始剂量和 1.8mg/kg 的维持剂量。计算并比较了药效学目标的平均最大浓度（C max ）、24 小时 AUC 和目标达成率（TA）。以下目标取自文献：C max >8mg/L 和 <20mg/L，AUC 24 h >70mg·h/L 和 <120mg·h/L。
在非脓毒症患者中，透析后给药的 C max >8mg/L 的 TA 为 35%，<20mg/L 的 TA 为 100%，AUC 24 h >70mg·h/L 的 TA 为 100%，<120mg·h/L 的 TA 为 45%。透析前 2 小时给药的 C max >8mg/L 的 TA 为 100%，<20mg/L 的 TA 为 40%，AUC 24 h >70mg·h/L 的 TA 为 65%，<120mg·h/L 的 TA 为 77%。脓毒症患者的模拟结果相似，透析前 1 小时给药时 C max <20mg/L 的 TA 更高（96%），AUC 24 h >70mg·h/L 的 TA 为 90%，AUC 24 h <120mg·h/L 的 TA 为 53%。
透析后给药 C max >8mg/L 的 TA 较低；然而，透析前给药可确保 C max >8mg/L 的高 TA 和可接受的 C max <20mg/L、AUC 24 h >70mg·h/L 和 AUC 24 h <120mg·h/L 的 TA，从而提高庆大霉素的疗效。因此，临床医生应考虑在接受间歇性血液透析的患者中进行透析前庆大霉素给药。
