Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma.
Model-based clinical pharmacology profiling of ipilimumab in patients with advanced melanoma.
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DOI：
10.1111/bcp.12323
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发表时间：
2014-07
影响因子：
3.4
通讯作者：
Roy A
中科院分区：
文献类型：
--
作者：
Feng Y;Masson E;Dai D;Parker SM;Berman D;Roy A
Ipilimumab是一种完全人源的单克隆抗体，可阻断细胞毒性t淋巴细胞抗原-4。本研究的目的是利用群体药代动力学（PPK）方法表征易普利姆单抗的临床药理学特征。PPK模型是利用来自4项II期研究的499例不可切除的III期或IV期黑色素瘤患者的2095个伊匹单抗血清浓度值开发的，伊匹单抗剂量范围为0.3至10 mg kg - 1。通过建立基本的PK模型确定结构PK模型。通过全协变量模型评估协变量对模型参数的影响，该模型将所有预先指定的协变量-参数关系纳入基础模型。最终的模型是通过反向消除来建立的，随后排除了确定与伊匹单抗没有临床相关性的协变量，并针对内部和外部数据集进行了严格的验证。易普利姆单抗PK是线性和时不变的，在可用剂量范围内与剂量成比例暴露，最终半衰期约为15天。伊匹单抗清除率随体重和基线血清乳酸脱氢酶浓度的增加而增加，但不受年龄、性别、布地奈德合用、东部肿瘤合作组表现状态或既往全身抗肿瘤治疗的影响。此外，易匹单抗暴露不受中度肾功能损害或轻度肝功能损害的影响。伊匹单抗浓度-时间数据由线性、双室、零阶静脉输注模型很好地描述。该模型证实，体重标准化给药方案适用于晚期黑色素瘤患者的伊匹单抗治疗。
Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4. The objective of the present study was to characterize the clinical pharmacology profile of ipilimumab using a population pharmacokinetic (PPK) approach. The PPK model was developed using 2095 ipilimumab serum concentration values from 499 patients with unresectable stage III or IV melanoma from four phase II studies, with ipilimumab doses ranging from 0.3 to 10 mg kg−1. The structural PK model was determined by developing a base PPK model. The effect of covariates on model parameters was assessed by a full covariate model, which incorporated all pre-specified covariate-parameter relationships into the base model. The final model was developed by backward elimination, followed by exclusion of covariates determined not to be of clinical relevance to ipilimumab, and was rigorously validated against both internal and external datasets. Ipilimumab PK was linear and time-invariant, with dose-proportional exposures over the available dose range, yielding a terminal half-life of approximately 15 days. Clearance of ipilimumab increased with increasing body weight and baseline serum lactate dehydrogenase concentrations, but was not affected by age, gender, concomitant budesonide, Eastern Cooperative Oncology Group performance status or prior systemic anticancer therapy. Furthermore, ipilimumab exposure was not affected by moderate renal impairment or mild hepatic impairment. Ipilimumab concentration–time data were well described by a linear, two compartment, zero order i.v. infusion model. The model confirms that a body weight-normalized dosing regimen is appropriate for ipilimumab therapy in patients with advanced melanoma.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
7.4
作者：
Hamid O;Schmidt H;Nissan A;Ridolfi L;Aamdal S;Hansson J;Guida M;Hyams DM;Gómez H;Bastholt L;Chasalow SD;Berman D
通讯作者：
Berman D
影响因子：
4.5
作者：
Bai, Shuang;Jorga, Karin;Dresser, Mark J.
通讯作者：
Dresser, Mark J.
影响因子：
2.5
作者：
Mager, DE;Jusko, WJ
通讯作者：
Jusko, WJ
影响因子：
11.5
作者：
Feng, Yan;Roy, Amit;Weber, Jeffrey S.
通讯作者：
Weber, Jeffrey S.