O'Bryant C L, Lieu C H, Leong S, Boinpally R, Basche M, Gore L, Leonardi K, Schultz M K, Hariharan S, Chow L, Diab S, Gibbs A, Eckhardt S G
University of Colorado Cancer Center, Aurora 80045, USA.
Cancer Chemother Pharmacol. 2009 Feb;63(3):477-89. doi: 10.1007/s00280-008-0761-3. Epub 2008 May 29.
To evaluate the safety, pharmacokinetics and determine the recommended dose of the selective apoptotic antineoplastic drug, OSI-461 administered on a twice-daily regimen to patients with advanced solid malignancies.
In this phase I trial, 33 patients were treated with OSI-461 doses ranging from 400 to 1,200 mg given twice daily in 4-week cycles. Pharmacokinetic studies were performed to characterize the plasma disposition of OSI-461 and the effect of food intake on OSI-461 absorption. Secondary biomarker studies were performed to assess the biologic activity of OSI-461 including the measurement of pGSK-3beta, a PKG substrate, and pharmacogenetic studies to identify polymorphisms of CYP3A that influence drug metabolism and of ABCG2, involved in drug resistance.
Thirty-three patients were treated with 86 courses of OSI-461. The dose-limiting toxicities were grade 3 abdominal pain, found in one patient at the 1,000 mg BID fed dose level and all patients at the 1,200 mg BID fed dose level. There was also one episode each of grade 3 fatigue and grade 3 constipation at the 1,000 and 1,200 mg BID fed dose levels, respectively. Other common toxicities included mild to moderate fatigue, nausea, anorexia and mild elevation in bilirubin. Pharmacokinetic studies of OSI-461 revealed approximately a twofold increase in AUC(0-24) when OSI-461 was administered with food. An increase in pGSK-3beta post-dose was seen in the majority of patients and was greater at higher dose levels. No patients exhibited CYP3A4 polymorphisms, while 100% of patients were found to have the CYP3A53/CYP3A53 polymorphism. Two known polymorphisms of the ABCG2 gene, G34 --> A34 and C421 --> A421, occurred at frequencies of 11.76 and 29%, respectively.
Toxicity and pharmacodynamic data show that the recommended oral dose of OSI-461 is 800 mg twice daily administered with food. The drug appears to be well-tolerated, and overall bioavailability appears to be markedly increased when the drug is administered with food. These results support further disease-directed evaluations of OSI-461 at a dose of 800 mg BID in combination with other chemotherapeutic agents.
评估选择性凋亡抗肿瘤药物OSI-461每日两次给药方案用于晚期实体恶性肿瘤患者的安全性、药代动力学并确定推荐剂量。
在该I期试验中，33例患者接受OSI-461治疗，剂量范围为400至1200mg，每日两次，每4周为一个周期。进行药代动力学研究以表征OSI-461的血浆处置情况以及食物摄入对OSI-461吸收的影响。进行次要生物标志物研究以评估OSI-461的生物活性，包括测量PKG底物pGSK-3β，以及进行药物遗传学研究以鉴定影响药物代谢的CYP3A多态性和参与耐药性的ABCG2多态性。
33例患者接受了86个疗程的OSI-461治疗。剂量限制性毒性为3级腹痛，在1000mg每日两次进食时剂量水平的1例患者以及1200mg每日两次进食时剂量水平的所有患者中出现。在1000mg和1200mg每日两次进食时剂量水平分别还各有1例3级疲劳和3级便秘。其他常见毒性包括轻度至中度疲劳、恶心、厌食以及胆红素轻度升高。OSI-461的药代动力学研究显示，与食物一起给药时AUC(0 - 24)增加约两倍。大多数患者给药后pGSK-3β升高，且在较高剂量水平时升高更明显。没有患者表现出CYP3A4多态性，而发现100%的患者具有CYP3A53/CYP3A53多态性。ABCG2基因的两种已知多态性G34→A34和C421→A421的发生频率分别为11.76%和29%。
毒性和药效学数据表明，OSI-461的推荐口服剂量为每日两次800mg，与食物一起服用。该药物似乎耐受性良好，并且与食物一起给药时总体生物利用度似乎明显增加。这些结果支持进一步以800mg每日两次的剂量对OSI-461与其他化疗药物联合进行针对疾病的评估。
