Buchner Anton, Lammerich Andreas, Abdolzade-Bavil Afsaneh, Müller Udo, Bias Peter
Merckle GmbH/Teva Pharmaceuticals Inc. , Ulm , Germany.
Curr Med Res Opin. 2014 Dec;30(12):2523-33. doi: 10.1185/03007995.2014.962131. Epub 2014 Sep 25.
Two phase I, single-blind (subject blinded to treatment), randomized studies were conducted to assess the pharmacodynamics, pharmacokinetics, safety, and tolerability of lipegfilgrastim compared with pegfilgrastim in healthy adult volunteers.
Study 1 consisted of a pilot safety phase (N = 8) during which subjects received a single body-weight-adjusted subcutaneous dose of lipegfilgrastim 25 µg/kg and a dose escalation phase (N = 45) wherein subjects received lipegfilgrastim 50 or 100 μg/kg or pegfilgrastim 100 μg/kg. Study 2 was a single-blind, fixed-dose study (N = 36) comparing subcutaneous lipegfilgrastim 6 mg and pegfilgrastim 6 mg.
Cumulative exposure (AUC0-t last and AUC 0-∞) and peak exposure (Cmax) were higher for lipegfilgrastim than pegfilgrastim after both weight-adjusted and fixed dosing. In both studies, the terminal elimination half-life of lipegfilgrastim was 5-10 hours longer than the terminal elimination half-life for pegfilgrastim at the maximum dose, and the time to maximum serum concentration (tmax) was observed later for lipegfilgrastim than for pegfilgrastim. The area over the baseline effect curve (AOBEC) for absolute neutrophil count (ANC) was approximately 30% greater after lipegfilgrastim dosing compared with the same dose of pegfilgrastim at the maximum dose. Both drugs were well tolerated, with a similar occurrence of adverse events between treatment groups. Key limitations of these studies include the small numbers of subjects and differences in dosage regimens between the two studies.
In these studies, lipegfilgrastim provided a longer-lasting increase in ANC compared with pegfilgrastim at an equivalent dose, without increasing the peak ANC values. This may reflect the higher cumulative exposure and slower clearance (therefore longer body residence) of lipegfilgrastim. These data support the use of single-dose lipegfilgrastim 6 mg in subsequent phase III trials as prophylactic treatment for patients receiving myelosuppressive chemotherapy.
开展两项I期单盲（受试者对治疗不知情）随机研究，在健康成年志愿者中评估培非格司亭与来格司亭相比的药效学、药代动力学、安全性和耐受性。
研究1包括一个初步安全性阶段（N = 8），在此阶段受试者接受一次根据体重调整的皮下注射剂量为25 μg/kg的来格司亭，以及一个剂量递增阶段（N = 45），在此阶段受试者接受50或100 μg/kg的来格司亭或100 μg/kg的培非格司亭。研究2是一项单盲固定剂量研究（N = 36），比较皮下注射6 mg来格司亭和6 mg培非格司亭。
在根据体重调整剂量和固定剂量给药后，来格司亭的累积暴露量（AUC0 - t末次和AUC0 - ∞）和峰值暴露量（Cmax）均高于培非格司亭。在两项研究中，来格司亭在最大剂量时的终末消除半衰期比培非格司亭长5 - 10小时，且来格司亭达到最大血清浓度的时间（tmax）比培非格司亭晚。与最大剂量时相同剂量的培非格司亭相比，来格司亭给药后绝对中性粒细胞计数（ANC）的基线效应曲线下面积（AOBEC）大约高30%。两种药物耐受性均良好，治疗组之间不良事件发生率相似。这些研究的主要局限性包括受试者数量少以及两项研究之间给药方案存在差异。
在这些研究中，与等效剂量的培非格司亭相比，来格司亭使ANC升高的持续时间更长，且未增加ANC峰值。这可能反映出来格司亭具有更高的累积暴露量和更慢的清除率（因此在体内停留时间更长）。这些数据支持在后续III期试验中使用单剂量6 mg来格司亭作为接受骨髓抑制性化疗患者的预防性治疗。
