Krishna Gopal, AbuTarif Malaz, Xuan Fengjuan, Martinho Monika, Angulo David, Cornely Oliver A
1 Schering-Plough Research Institute, Kenilworth, New Jersey.
Pharmacotherapy. 2008 Oct;28(10):1223-32. doi: 10.1592/phco.28.10.1223.
To analyze the pharmacokinetics of posaconazole administered as prophylaxis for invasive fungal infection (IFI) in neutropenic patients receiving chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS).
Pharmacokinetic subanalysis of a phase III, prospective, randomized, multicenter, evaluator-blinded trial comparing posaconazole with standard azoles (fluconazole and itraconazole).
One hundred ninety-four patients with AML or MDS who received posaconazole oral suspension 200 mg 3 times/day with meals or a nutritional supplement for a minimum of 7 days to achieve steady state and for a maximum of 12 weeks.
For the first 20 patients, blood samples were collected before the first dose on day 8 and at 2, 4, 6, and 24 hours after that first dose; for all other patients, blood samples were collected at 1 and 3 hours after the first dose on day 8 and during the first episode of evaluation for a possible IFI.
The effects of the following covariates on average (Cav) and maximum (Cmax) posaconazole plasma concentrations at steady state were explored: age, sex, and race-ethnicity; proven or probable IFI; baseline body weight and body surface area; and baseline (on or before day 7) increases in liver enzyme levels, mucositis, neutropenia, diarrhea, vomiting, or use of an H2-receptor antagonist or proton pump inhibitor. Diarrhea, proton pump inhibitor use, gamma-glutamyl transferase level of 2 or more times the upper limit of normal, and race-ethnicity reduced Cav. Although statistically significant, these results were not considered clinically significant and did not necessitate posaconazole dosage adjustments. Mean Cav and Cmax values did not appear different in the six patients with IFIs (three with proven IFIs, three with probable IFIs) compared with the entire sample of 194 patients; however, a definitive conclusion cannot be made due to the small sample size of patients with IFI. No factor found to affect posaconazole concentrations predominated in patients with IFIs.
Oral posaconazole 200 mg 3 times/day provided plasma concentrations adequate for preventing IFIs. No dosage adjustments are recommended based on any covariate tested.
分析泊沙康唑用于预防接受急性髓性白血病（AML）或骨髓增生异常综合征（MDS）化疗的中性粒细胞减少患者侵袭性真菌感染（IFI）时的药代动力学。
一项III期、前瞻性、随机、多中心、评估者盲法试验的药代动力学亚分析，比较泊沙康唑与标准唑类（氟康唑和伊曲康唑）。
194例AML或MDS患者，接受200mg泊沙康唑口服混悬液，每日3次，与餐同服或与营养补充剂同服，至少7天以达到稳态，最长12周。
对于前20例患者，在第8天首次给药前以及首次给药后2、4、6和24小时采集血样；对于所有其他患者，在第8天首次给药后1和3小时以及首次评估可能的IFI期间采集血样。
探讨了以下协变量对稳态时泊沙康唑平均血浆浓度（Cav）和最大血浆浓度（Cmax）的影响：年龄、性别、种族；确诊或疑似IFI；基线体重和体表面积；以及基线（第7天或之前）肝酶水平升高、粘膜炎、中性粒细胞减少、腹泻、呕吐或使用H2受体拮抗剂或质子泵抑制剂。腹泻、质子泵抑制剂的使用、γ-谷氨酰转移酶水平高于正常上限2倍及以上以及种族会降低Cav。尽管这些结果具有统计学意义，但未被认为具有临床意义，也无需调整泊沙康唑剂量。与194例患者的整个样本相比，6例IFI患者（3例确诊IFI，3例疑似IFI）的平均Cav和Cmax值似乎没有差异；然而，由于IFI患者样本量小，无法得出明确结论。在IFI患者中，未发现影响泊沙康唑浓度的主要因素。
每日3次口服200mg泊沙康唑可提供足以预防IFI的血浆浓度。不建议根据所测试的任何协变量调整剂量。
