School of Medicine, Discipline of Pharmacology, University of Adelaide, Adelaide, Australia.
Pharmacy Department, Royal Adelaide Hospital, Port Road, Adelaide, Australia.
J Antimicrob Chemother. 2024 Mar 1;79(3):567-577. doi: 10.1093/jac/dkae006.
Invasive fungal disease (IFD) in the early post-allogeneic HSCT (alloHCT) period is associated with increased likelihood of catastrophic outcomes. The utility of oral modified release (MR) posaconazole tablets is limited by reduced drug absorption from gastrointestinal toxicity induced by cytotoxic chemotherapy, necessitating a switch to the IV posaconazole formulation.
To describe the population pharmacokinetics of posaconazole for oral MR and IV formulations in alloHCT patients and determine dosing regimens likely to achieve therapeutic exposures.
We performed a prospective observational pharmacokinetic study in adult patients in the early post-alloHCT period requiring a change in posaconazole formulation (oral to IV). Samples were analysed using a validated LC-MS/MS method. Population pharmacokinetic analysis and Monte Carlo simulations (n = 1000) were performed using Pmetrics for R.
Twenty patients aged between 21 and 70 years were included in the study. A two-compartment model, incorporating mucositis/diarrhoea to modify the bioavailability for oral administration best described the data. To achieve ≥90% PTA, simulations showed that higher than currently recommended doses of oral MR posaconazole were required for prophylaxis Cmin targets (≥0.5 and ≥0.7 mg/L), while increased doses of both formulations were required for IFD treatment PK/PD targets, with patients experiencing oral mucositis/diarrhoea unlikely to achieve these.
Increased doses of posaconazole should be considered for both prophylaxis and treatment of IFD to increase the proportion of alloHCT patients achieving therapeutic exposures, particularly the oral formulation in patients with mucositis and/or diarrhoea. Posaconazole therapeutic drug monitoring should be considered for all formulations in this setting.
异基因造血干细胞移植（alloHCT）后早期侵袭性真菌病（IFD）与灾难性结局的可能性增加有关。由于细胞毒性化疗引起的胃肠道毒性导致口服改良释放（MR）泊沙康唑片剂的药物吸收减少，其应用受到限制，需要转换为 IV 泊沙康唑制剂。
描述 alloHCT 患者口服 MR 和 IV 泊沙康唑制剂的群体药代动力学特征，并确定可能实现治疗暴露的给药方案。
我们对 alloHCT 后早期需要改变泊沙康唑制剂（口服改为 IV）的成年患者进行了一项前瞻性观察性药代动力学研究。使用经过验证的 LC-MS/MS 方法对样本进行分析。使用 Pmetrics for R 进行群体药代动力学分析和蒙特卡罗模拟（n=1000）。
本研究纳入了 21 至 70 岁之间的 20 名患者。一个两室模型，纳入了黏膜炎/腹泻来改变口服给药的生物利用度，能最好地描述数据。为了实现≥90%的 PTA，模拟显示对于预防 Cmin 目标（≥0.5 和≥0.7mg/L），需要更高的口服 MR 泊沙康唑剂量，而对于 IFD 治疗 PK/PD 目标，两种制剂都需要增加剂量，而经历口腔黏膜炎/腹泻的患者不太可能达到这些目标。
应考虑增加泊沙康唑的剂量，以提高 alloHCT 患者实现治疗暴露的比例，特别是在有黏膜炎和/或腹泻的患者中使用口服制剂，用于预防和治疗 IFD。在这种情况下，应考虑对所有制剂进行泊沙康唑治疗药物监测。
