Anil Kumar Mysore S, Papp Kim, Tainaka Ryo, Valluri Udaya, Wang Xuegong, Zhu Tong, Schwabe Christian
Astellas Pharma, Inc., Northbrook, Illinois, USA.
K Papp Clinical Research and Probity Medical Research, Waterloo, Canada.
Biopharm Drug Dispos. 2018 May;39(5):245-255. doi: 10.1002/bdd.2130.
This study evaluated the pharmacokinetics (PK), efficacy, safety, and tolerability of bleselumab - a fully-human anti-CD40 monoclonal recombinant IgG4. Patients with moderate-to-severe psoriasis were randomized on day 1 to receive bleselumab or placebo on days 1, 15 and 29 in a dose-escalation of bleselumab at 0.1, 0.3, 1.0 or 3.0 mg/kg. The safety-analysis set (SAF) and full-analysis set (FAS) included all patients who received bleselumab or placebo, and the PK-analysis set (PKAS) included patients in the SAF with ≥1 quantifiable serum bleselumab concentration. Serial blood samples were collected after each dose, and the bleselumab serum concentration was measured. After each dose, the area-under-the-concentration-time curve over 336 hours (AUC ) and the maximum serum concentration (C ), and dose proportionality of AUC and C were determined. The psoriasis area and severity index (PASI) score, the physician static global assessment (PSGA) score, the percentage body surface area (%BSA) affected with psoriasis, adverse events and laboratory parameters were assessed. Sixty patients were randomized and included in the SAF/FAS (bleselumab, n = 49; placebo, n = 11); 48 formed the PKAS. Bleselumab C and AUC were more than dose proportional in the range 0.1-3.0 mg/kg, suggesting nonlinear PK after single/multiple doses. No clinically significant infusion reactions, cytokine-release syndrome, or thromboembolic events were reported. Bleselumab did not improve the PASI scores, PSGA scores, or %BSA versus placebo. Transient elevation of alanine aminotransferase and aspartate aminotransferase levels by >3 × upper limit of normal were observed in four (8.2%) and two (4.1%) patients, respectively, in the 1.0 or 3.0 mg/kg groups. Patients with liver function test increases had no concurrent changes in bilirubin. Bleselumab demonstrated nonlinear PK after single and multiple doses, with few adverse reactions.
本研究评估了全人源抗CD40单克隆重组IgG4药物bleaselumab的药代动力学（PK）、疗效、安全性和耐受性。中度至重度银屑病患者在第1天随机分组，在第1、15和29天接受bleaselumab或安慰剂，bleaselumab剂量按0.1、0.3、1.0或3.0mg/kg逐步递增。安全性分析集（SAF）和全分析集（FAS）包括所有接受bleaselumab或安慰剂的患者，PK分析集（PKAS）包括SAF中血清bleaselumab浓度≥1个可量化值的患者。每次给药后采集系列血样，并测定bleaselumab血清浓度。每次给药后，测定336小时的浓度-时间曲线下面积（AUC）和最大血清浓度（C），以及AUC和C的剂量比例关系。评估银屑病面积和严重程度指数（PASI）评分、医师静态整体评估（PSGA）评分、银屑病累及的体表面积百分比（%BSA）、不良事件和实验室参数。60例患者被随机分组并纳入SAF/FAS（bleaselumab组，n = 49；安慰剂组，n = 11）；48例组成PKAS。在0.1 - 3.0mg/kg范围内，bleaselumab的C和AUC与剂量的比例关系大于剂量比例，提示单剂量/多剂量给药后药代动力学呈非线性。未报告有临床意义的输注反应、细胞因子释放综合征或血栓栓塞事件。与安慰剂相比，bleaselumab未改善PASI评分、PSGA评分或%BSA。在1.0或3.0mg/kg组中，分别有4例（8.2%）和2例（4.1%）患者的丙氨酸转氨酶和天冬氨酸转氨酶水平短暂升高超过正常上限的3倍。肝功能检查结果升高的患者胆红素无同时变化。Bleselumab单剂量和多剂量给药后药代动力学呈非线性，不良反应较少。
