Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics.
Evaluation of rodent-only toxicology for early clinical trials with novel cancer therapeutics.
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DOI：
10.1038/sj.bjc.6690761
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发表时间：
1999-11
影响因子：
8.8
通讯作者：
Connors TA
中科院分区：
文献类型：
--
作者：
Newell DR;Burtles SS;Fox BW;Jodrell DI;Connors TA
临床前毒理学研究在新型癌症疗法的I期试验之前进行，以确定安全的临床起始剂量和潜在的人体毒性。本研究的主要目的是评估仅对啮齿动物进行毒理学研究以确定安全的I期试验起始剂量的能力。此外，还研究了小鼠研究定量和定性预测癌症治疗药物的人类毒理学的能力。对25种癌症药物的数据进行了整理，这些药物的临床前和临床给药途径和时间表要么相同（22/25），要么密切匹配。确定了24种药物的最大耐受剂量/ 10%小鼠致死剂量（MTD/LD10），在20种化合物的初始临床试验中，患者的最大给药剂量（MAD）与剂量限制性毒性（DLT）相关。此外，对于13种药物，在重复给药（20次剂量）后，在大鼠中也研究了药物在小鼠MTD/LD10的十分之一时的毒性。I期试验起始剂量为小鼠MTD/LD10 （mg - m-2）的十分之一，对所有25种化合物来说都是安全的。除了在啮齿类动物中无法评估的恶心和呕吐，其他常见的dlt都可以通过小鼠研究准确预测（即7/7的血液学dlt和3/3的神经学dlt）。在对大鼠进行研究的13种药物中，有两种药物重复给药剂量为小鼠MTD/LD10的十分之一是有毒的，导致I期试验起始剂量减少；然而，十分之一的小鼠MTD/LD10随后在患者中耐受。在达到临床DLT的20种药物中，人类MAD与小鼠MTD/LD10之比的中位数为2.6（范围为0.2-16），临床起始剂量与MAD之比的中位数为35（范围为2.3-160）。相比之下，在随后的13项I期试验中，最初25种药物中的11种，临床起始剂量与MAD的中位数比值为2.8（范围1.6-56），强调了早期临床数据在快速确定治疗性研究剂量范围方面的价值。对于所研究的所有25种药物，仅啮齿动物毒理学提供了一种安全快速的方法来确定I期试验的起始剂量并预测常见的dlt。这项研究表明，在癌症治疗的初步临床试验之前，在临床前毒理学研究中常规使用非啮齿动物是没有必要的。©1999癌症研究运动
Preclinical toxicology studies are performed prior to phase I trials with novel cancer therapeutics to identify a safe clinical starting dose and potential human toxicities. The primary aim of this study was to evaluate the ability of rodent-only toxicology studies to identify a safe phase I trial starting dose. In addition, the ability of murine studies to predict the quantitative and qualitative human toxicology of cancer therapeutics was studied. Data for 25 cancer drugs were collated for which the preclinical and clinical routes and schedules of administration were either the same (22/25), or closely matched. The maximum tolerated dose/dose lethal to 10% of mice (MTD/LD10) was identified for 24 drugs, and in patients the maximum administered dose (MAD) was associated with dose-limiting toxicity (DLT) in initial clinical trials with 20 compounds. In addition, for 13 agents, the toxicity of the drug at one-tenth the mouse MTD/LD10 was also investigated in rats, following repeated administration (20 doses). A phase I trial starting dose of one-tenth the mouse MTD/LD10 (mg m–2) was, or would have been, safe for all 25 compounds. With the exception of nausea and vomiting, which cannot be assessed in rodents, other common DLTs were accurately predicted by the murine studies (i.e. 7/7 haematological and 3/3 neurological DLTs). For two of the 13 drugs studied in rats, repeated administration of one-tenth the mouse MTD/LD10 was toxic, leading to a reduction in the phase I trial starting dose; however, one-tenth the mouse MTD/LD10 was subsequently tolerated in patients. For the 20 drugs where clinical DLT was reached, the median ratio of the human MAD to the mouse MTD/LD10 was 2.6 (range 0.2–16) and the median ratio of the clinical starting dose to the MAD was 35 (range 2.3–160). In contrast, in 13 subsequent phase I trials with 11 of the initial 25 drugs, the median ratio of the clinical starting dose to the MAD was 2.8 (range 1.6–56), emphasizing the value of early clinical data in rapidly defining the dose range for therapeutic studies. For all 25 drugs studied, rodent-only toxicology provided a safe and rapid means of identifying the phase I trial starting dose and predicting commonly encountered DLTs. This study has shown that the routine use of a non-rodent species in preclinical toxicology studies prior to initial clinical trials with cancer therapeutics is not necessary. © 1999 Cancer Research Campaign
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影响因子：
8.8
作者：
Newlands, ES;Rustin, GJS;Brampton, MH
通讯作者：
Brampton, MH
影响因子：
8.8
作者：
FOSTER, BJ;NEWELL, DR;CALVERT, AH
通讯作者：
CALVERT, AH
影响因子：
8.8
作者：
Carmichael J;Cantwell BM;Mannix KA;Veale D;Elford HL;Blackie R;Kerr DJ;Kaye SB;Harris AL
通讯作者：
Harris AL
影响因子：
45.3
作者：
McKeage, MJ;Raynaud, F;Judson, IR
通讯作者：
Judson, IR
DOI：
10.1093/jnci/85.3.217
发表时间：
1993-02-03
期刊：
JOURNAL OF THE NATIONAL CANCER INSTITUTE
影响因子：
--
作者：
MICK, R;RATAIN, MJ
通讯作者：
RATAIN, MJ