Pharmacokinetics and pharmacodynamics of anti-BR3 monoclonal antibody in mice.
Pharmacokinetics and pharmacodynamics of anti-BR3 monoclonal antibody in mice.
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DOI：
10.1007/s11095-012-0813-6
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发表时间：
2012-11
影响因子：
3.7
通讯作者：
Mager, Donald E.
中科院分区：
文献类型：
--
作者：
Marathe, Anshu;Iyer, Suhasini;Qiu, Zhihua Julia;Visich, Jennifer;Mager, Donald E.
关键词：
表征小鼠静脉（IV）和皮下（SC）给药后针对B细胞活化因子（BAFF）受体3（BR 3）的单克隆抗体的药代动力学（PK）和药效学（PD）特性。向小鼠单次IV给予0.2、2.0和20 mg/kg剂量和单次SC注射20 mg/kg抗BR 3抗体。在不同时间点测量血清药物和BAFF浓度以及脾B细胞浓度。通过具有时间依赖性非线性消除的双房室模型描述汇总PK特征，通过间接应答模型定义BAFF特征。分数受体占有率作为竞争性可逆拮抗模型的驱动函数，以表征B细胞动力学。非房室分析显示，随着IV剂量的增加，药物清除率降低（31.3 - 7.93 mL/天/kg）。SC剂量表现出缓慢吸收（Tmax=2天）和完全生物利用度。所有剂量均导致BAFF浓度呈剂量依赖性增加，B细胞计数降低。所提出的模型合理地捕获了IV和SC给药后抗BR 3抗体的复杂PK/PD特征。开发了一种机制模型，描述了抗BR 3抗体和BAFF之间对BR 3受体的可逆竞争及其对B细胞药效学的影响。
To characterize the pharmacokinetic (PK) and pharmacodynamic (PD) properties of a monoclonal antibody directed against the B-cell activating factor (BAFF) receptor 3 (BR3), following intravenous (IV) and subcutaneous (SC) administration in mice. Single IV doses of 0.2, 2.0 and 20 mg/kg and a single SC injection of 20 mg/kg of anti-BR3 antibody was administered to mice. Serum drug and BAFF concentrations and splenic B-cell concentrations were measured at various time points. Pooled PK profiles were described by a two-compartmental model with time-dependent nonlinear elimination, and BAFF profiles were defined by an indirect response model. Fractional receptor occupancy served as the driving function for a competitive reversible antagonism model to characterize B-cell dynamics. Noncompartmental analysis revealed a decrease in drug clearance (31.3 to 7.93 mL/day/kg) with increasing IV doses. The SC dose exhibited slow absorption (Tmax=2 days) and complete bioavailability. All doses resulted in a dose-dependent increase in BAFF concentrations and decrease in B-cell counts. The proposed model reasonably captured complex PK/PD profiles of anti-BR3 antibody after IV and SC administration. A mechanistic model was developed that describes the reversible competition between anti-BR3 antibody and BAFF for BR3 receptors and its influence on B-cell pharmacodynamics.
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影响因子：
27.4
作者：
Lavie, Frederic;Miceli-Richard, Corinne;Mariette, Xavier
通讯作者：
Mariette, Xavier
影响因子：
3.7
作者：
Tribouley, C;Wallroth, M;Williams, LT
通讯作者：
Williams, LT
影响因子：
4.4
作者：
Shulga-Morskaya, S;Dobles, M;Scott, ML
通讯作者：
Scott, ML
影响因子：
6
作者：
Vugmeyster, Y;Seshasayee, D;Danilenko, DM
通讯作者：
Danilenko, DM
DOI：
10.1007/bf01061691
发表时间：
1993-08-01
期刊：
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS
影响因子：
--
作者：
DAYNEKA, NL;GARG, V;JUSKO, WJ
通讯作者：
JUSKO, WJ