Université Grenoble Alpes, Faculté de Pharmacie, Grenoble, France.
Institute for Advanced Biosciences UGA - Inserm U 1209 - CNRS UMR 5309, Grenoble, France.
Br J Clin Pharmacol. 2021 Feb;87(2):427-435. doi: 10.1111/bcp.14398. Epub 2020 Jun 22.
A new formulation of posaconazole (PCZ), delayed-release tablets (PCZ-tab), increases PCZ bioavailability and plasma trough concentrations (C ) over those achieved with an oral suspension (PCZ-susp). PCZ is an inhibitor of cytochrome P450 3A4 and P-glycoprotein. We therefore investigated the impact of PCZ-tab treatment on blood C and doses of tacrolimus (TAC) and everolimus (EVR).
Eighteen lung transplant patients receiving TAC (n = 13) or TAC + EVR (n = 5) between June 2015 and March 2016 were retrospectively included. Ten of these patients received both PCZ-tab and PCZ-susp (i.e. switched patients); the other 8 received only PCZ-tab. Plasma C of PCZ (n = 64), blood C of TAC (n = 299) and EVR (n = 80) were determined during routine therapeutic drug monitoring by liquid chromatography-tandem mass spectrometry.
PCZ C on PCZ-tab treatment (n = 48) was 2.5 times higher than that on PCZ-susp therapy (n = 16), for both PCZ patients (P < .0001) and for switched patients (P = .003). PCZ initiation, regardless of galenic form, increased TAC and EVR C adjusted for dose (D), 3-fold and 3.5-fold, respectively (P < .0001 for both). PCZ-tab treatment was associated with a higher TAC C /D (PCZ-tab vs PCZ-susp: 0.004 ± 0.004 L vs 0.009 ± 0.006 L , P < .0001) and lower TAC daily dose than PCZ-susp (PCZ-tab vs PCZ-susp: 1.08 ± 0.92 vs 2.32 ± 1.62 mg d , P < .0001). EVR C /D was higher and EVR dose tended to be lower on PCZ-tab than on PCZ-susp.
The greater PCZ exposure achieved during PCZ-tab treatment increased drug-drug interactions with TAC and EVR, resulting in greater exposure, potentially exposing patients to higher risks of adverse effects.
泊沙康唑的一种新制剂，即延迟释放片剂（PCZ-tab），可提高泊沙康唑的生物利用度和血药谷浓度（C ），优于口服混悬剂（PCZ-susp）。泊沙康唑是细胞色素 P450 3A4 和 P-糖蛋白的抑制剂。因此，我们研究了 PCZ-tab 治疗对他克莫司（TAC）和依维莫司（EVR）的血药浓度（C ）和剂量的影响。
回顾性纳入 2015 年 6 月至 2016 年 3 月期间接受 TAC（n = 13）或 TAC + EVR（n = 5）治疗的 18 例肺移植患者。其中 10 例患者同时接受了 PCZ-tab 和 PCZ-susp（即转换患者）治疗，其余 8 例患者仅接受了 PCZ-tab 治疗。通过液相色谱-串联质谱法在常规治疗药物监测中测定 64 例患者的泊沙康唑（PCZ）血药浓度（n = 64）、299 例患者的他克莫司（n = 299）和 80 例患者的依维莫司（n = 80）的血药浓度。
在接受 PCZ-tab 治疗的 48 例患者（n = 48）中，泊沙康唑的血药浓度是接受 PCZ-susp 治疗的 16 例患者（n = 16）的 2.5 倍，无论使用哪种剂型，差异均有统计学意义（P <.0001）。无论使用何种剂型，泊沙康唑的起始治疗都会导致他克莫司和依维莫司的血药浓度调整剂量（D）增加 3 倍和 3.5 倍（两者均 P <.0001）。与 PCZ-susp 相比，PCZ-tab 治疗时他克莫司的血药浓度/剂量（PCZ-tab 与 PCZ-susp：0.004 ± 0.004 L 比 0.009 ± 0.006 L ，P <.0001）更高，他克莫司的日剂量更低（PCZ-tab 与 PCZ-susp：1.08 ± 0.92 比 2.32 ± 1.62 mg·d ，P <.0001）。与 PCZ-susp 相比，PCZ-tab 治疗时依维莫司的血药浓度/剂量更高，依维莫司的剂量更低。
PCZ-tab 治疗时泊沙康唑的暴露量增加，导致与他克莫司和依维莫司的药物相互作用增加，从而使药物暴露量增加，患者可能面临更高的不良反应风险。
