Antibody-directed enzyme prodrug therapy: Pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial
Antibody-directed enzyme prodrug therapy: Pharmacokinetics and plasma levels of prodrug and drug in a phase I clinical trial
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DOI：
10.1007/s002800050646
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发表时间：
1997-07-01
影响因子：
3
通讯作者：
Springer, CJ
中科院分区：
文献类型：
--
作者：
Martin, J;Stribbling, SM;Springer, CJ
在一项I期临床试验中，对10名患者进行了抗体导向酶前药物治疗（ADEPT）。目的是测量血浆前药4-[（2-氯乙基）（2-甲氧基乙基）氨基]苯甲酰-l -谷氨酸（CMDA）和由肿瘤定位的羧肽酶G2 （CPG2）酶释放的双功能烷基化药物（CJS 11）的水平。采用固相吸附和洗脱法提取血浆前药和药物，并测定血浆和组织中CPG2的活性。采用高效液相色谱法（HPLC）和液相色谱-质谱法（LC-MS）对提取物进行分析。在转移性肿瘤活检中发现CPG2活性，但在正常组织中未发现，表明定位成功。以46.5 mg/m(2)给药的清除剂SB43-gal达到了清除循环中非肿瘤局部化酶的目的，这表明前药到药物的转化只能发生在局部偶联物的位置。在给药后120分钟的“治疗窗口”内，血浆前药并不总是保持在所需的3 μ M以上，但每天第一次给药后残余前药的存在表明，在接下来的8小时内剩余的4次给药期间，这一阈值可以实现。尽管患者间前药血浆浓度存在相当大的差异，但前药的消除半衰期在18 +/- 8分钟可显著重现。药物在血浆中的快速出现表明前药的成功转化已经发生，但也不希望从定位部位泄漏到血液中。然而，药物血浆水平在10 - 60分钟内迅速下降至少50%，半衰期为36 +/- 14分钟。对血浆提取物的LC/MS分析表明，该技术可用于定性确认前药、药物及其代谢物的存在。
Antibody-directed enzyme prodrug therapy (ADEPT) was administered to ten patients in a phase I clinical trial. The aim was to measure plasma levels of the prodrug 4-[(2-chloroethyl)(2-mesyloxyethyl) amino] benzoyl-L-glutamic acid (CMDA) and the bifunctional alkylating drug (CJS 11) released from it by the action of tumour-localised carboxypeptidase G2 (CPG2) enzyme. New techniques were developed to extract the prodrug and drug from plasma by solid-phase adsorbtion and elution and to measure CPG2 activity in plasma and tissue. All extracts were analysed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). CPG2 activity was found in metastatic tumour biopsies but not in normal tissue, indicating that localisation had been successful. The clearing agent SB43-gal, given at 46.5 mg/m(2), achieved the aim of clearing non-tumour-localised enzyme in the circulation, indicating that conversion of prodrug to drug could take place only at the site of localised conjugate. Plasma prodrug did not always remain above its required threshold of 3 mu M for the ''therapeutic window'' of 120 min after dosing, but the presence of residual prodrug after the first administration of each day indicated that this could be achieved during the remaining four doses over the following 8 h. Despite considerable inter-patient prodrug plasma concentration variability, the elimination half-life of the prodrug was remarkably reproducible at 18 +/- 8 min. Rapid appearance of the drug in plasma indicated that successful conversion from the prodrug had taken place, but also undesirable leakback from the site of localisation into the bloodstream. However, drug plasma levels fell rapidly by at least 50% at between 10 and 60 min with a half-life of 36 +/- 14 min. Analysis of the plasma extracts by LC/MS indicated that this technique might be used to confirm qualitatively the presence of prodrug, drug and their metabolites.