Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects
Safety, tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 cytolytic antibody TAK-079 in healthy subjects
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DOI：
10.1111/bcp.14241
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发表时间：
2020-02-22
影响因子：
3.4
通讯作者：
Mclean, Lachy
中科院分区：
文献类型：
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作者：
Fedyk, Eric R.;Zhao, Lin;Mclean, Lachy
目的研究抗CD38抗体TAK-079的耐受性、药代动力学和药效学。输液或皮下注射(S.C.)74名健康受试者以递增剂量注射TAK-079，并于暴露后92d进行随访。所有不良反应均为轻度或中度。在测试的静脉注射过程中，没有出现撤药、输液或注射部位反应。和S.C.剂量分别为0.06和0.6 mg kg(-1)。在较高剂量下，瞬时细胞因子水平在静脉注射后增加。给药时CD38表达细胞减少；临床症状包括轻度发热、头痛和体位性低血压。在静脉注射之后。静脉滴注0.06mgkg-1TAK079，最大观察血药浓度(C-max)为100.4(%CV：52)ng mL(-1)，达到C-max的时间为输注结束，自然杀伤细胞(NK细胞)较基线水平下降93.8(+/-8.5)%。在S.C.之后。注射0.6 mg kg(-1)TAK-079后，C-max为23.0(%CV：67)ng mL(-1)，达到C-max的时间为24(7.98-96.02)小时，浆母细胞较给药前减少了93.4(+/-8.8)%。血清免疫球蛋白(Ig)M、Ig A和Ig G水平下降15-60%，在皮下注射后78天内仍未恢复到基础水平。皮下注射0.6 mg kg(-1)对NK细胞的影响。结论TAK-079耐受性良好，皮下注射TAK-079耐受性良好。给药后，浆母细胞和NK细胞的减少更为持久。这种血浆溶血谱可用于治疗由血浆或NK细胞、恶性对应物和/或致病抗体引起的疾病。
Aims This investigation characterised tolerability, pharmacokinetics and pharmacodynamics of the anti-CD38 antibody TAK-079.Methods A randomised, double-blind, placebo-controlled trial of a single intravenous (i.v.) infusion or subcutaneous (s.c.) injection of TAK-079 at escalating doses in healthy subjects (n = 74), who were followed for 92 days postexposure.Results TAK-079 was well tolerated. All adverse events were mild or moderate. There were no withdrawals, infusion, or injection site reactions over the tested i.v. and s.c. doses up to 0.06 and 0.6 mg kg(-1), respectively. At higher doses, transient cytokine level increases, following i.v. administration, coincided with reduction in CD38-expressing cells; clinical symptoms included mild pyrexia, headache, and postural hypotension. Following an i.v. infusion of 0.06 mg kg(-1) TAK-079, maximum observed serum concentration (C-max) was 100.4 (%CV: 52) ng mL(-1), time to C-max was the end of infusion and natural killer (NK_ cells were reduced 93.8 (+/- 8.5) % from baseline levels. Following a s.c. injection of 0.6 mg kg(-1) TAK-079, C-max was 23.0 (%CV: 67) ng mL(-1) with time to C-max of 24 (range 7.98-96.02) hours, and plasmablasts were subsequently reduced 93.4 (+/- 8.8) % from predose levels. Serum immunoglobulin (Ig)M, IgA and IgG levels were reduced by 15-60% and had not returned to baseline levels within 78 days after administration at >= 0.3 mg kg(-1) s.c. Reductions in NK cells at 0.6 mg kg(-1) s.c. were approximately 2-3 times more durable than at 0.06 mg kg(-1) i.v.Conclusions TAK-079 was well tolerated and s.c. administration elicited more durable reductions in plasmablasts and NK cells. This plasmacytolytic profile could be useful for treating disorders caused by plasma or NK cells, malignant counterparts, and/or pathogenic antibodies.