Burade Vinod, Bhowmick Subhas, Maiti Kuntal, Zalawadia Rishit, Ruan Harry, Thennati Rajamannar
Sun Pharma Advanced Research Company Ltd., 17 B Mahal Industrial Estate, Mahakali Caves Road, Andheri (East), Mumbai, Maharashtra, 400 093, India.
Sun Pharma Advanced Research Centre (SPARC), Tandalja, Vadodara, Gujarat, 390 020, India.
BMC Cancer. 2017 Jun 6;17(1):405. doi: 10.1186/s12885-017-3377-3.
Doxorubicin (DXR) hydrochloride (HCl) liposome injection is an important part of the treatment armamentarium for a number of cancers. With growing needs for affordable and effective anticancer treatments, the development of generics is becoming increasingly important to facilitate patient access to vital medications. We conducted studies in relevant mouse models of cancer to compare the preclinical antitumour efficacy and plasma pharmacokinetic profile of a proposed generic DXR HCl liposome injection developed by Sun Pharmaceutical Industries Ltd. (SPIL DXR HCl liposome injection) with Caelyx® (reference DXR HCl liposome injection).
Syngeneic fibrosarcoma (WEHI 164)-bearing BALB/c mice and athymic nude mice transplanted with MX-1 human mammary carcinoma xenografts were treated with SPIL DXR HCl liposome injection, reference DXR HCl liposome injection or placebo, to compare tumour volume, antitumour activity (percentage test/control [%T/C] ratio, tumour regression, and specific tumour growth delay) and toxicity (survival and weight changes) in response to treatment. The pharmacokinetic profile of the SPIL and reference product was also studied in syngeneic fibrosarcoma-bearing mice.
Treatment with either SPIL or reference DXR HCl liposome injection resulted in significant reduction in tumour volume from baseline in both models at all doses tested. High antitumour activity (%T/C ≤ 10) was seen from Day 21 and Day 14 onwards in SPIL and reference DXR HCl liposome injection-treated syngeneic fibrosarcoma-bearing mice, respectively, at 9 mg/kg. Moderate antitumour activity (%T/C ≤ 20) was seen from Day 17 and Day 24 onwards in SPIL and reference DXR HCl liposome injection-treated MX-1-bearing mice, respectively, at 6 mg/kg. No significant differences in tumour volume and %T/C were observed between SPIL and reference DXR HCl liposome injection-treated groups at any dose (p ≥ 0.05). Toxicity profiles were considered to be generally comparable. Evaluation of test/reference (A/B) ratios and 90% confidence intervals (CIs) for peak serum concentration (C) and area under the curve (AUC, and AUC) demonstrated bioequivalence of SPIL and reference DXR HCl liposome injections.
Establishing similarity is of critical importance during the development of generic treatments. SPIL and reference DXR HCl liposome injections were shown to be comparable with regards to antitumour activity, toxicity and pharmacokinetics.
盐酸多柔比星（DXR）脂质体注射液是多种癌症治疗药物库的重要组成部分。随着对经济有效抗癌治疗需求的不断增长，仿制药的开发对于促进患者获得重要药物变得越来越重要。我们在相关的癌症小鼠模型中进行了研究，以比较太阳制药工业有限公司开发的一种拟仿制药盐酸多柔比星脂质体注射液（SPIL盐酸多柔比星脂质体注射液）与楷莱®（参比盐酸多柔比星脂质体注射液）的临床前抗肿瘤疗效和血浆药代动力学特征。
用SPIL盐酸多柔比星脂质体注射液、参比盐酸多柔比星脂质体注射液或安慰剂治疗荷同基因纤维肉瘤（WEHI 164）的BALB/c小鼠和移植了MX-1人乳腺癌异种移植物的无胸腺裸鼠，以比较治疗后的肿瘤体积、抗肿瘤活性（试验组/对照组百分比[T/C]比值、肿瘤消退和特定肿瘤生长延迟）和毒性（生存率和体重变化）。还在荷同基因纤维肉瘤的小鼠中研究了SPIL和参比产品的药代动力学特征。
在所有测试剂量下，SPIL或参比盐酸多柔比星脂质体注射液治疗均导致两种模型的肿瘤体积较基线显著减小。在9mg/kg剂量下，SPIL和参比盐酸多柔比星脂质体注射液治疗的荷同基因纤维肉瘤小鼠分别从第21天和第14天起出现高抗肿瘤活性（%T/C≤10）。在6mg/kg剂量下，SPIL和参比盐酸多柔比星脂质体注射液治疗的荷MX-1小鼠分别从第17天和第24天起出现中度抗肿瘤活性（%T/C≤20）。在任何剂量下，SPIL和参比盐酸多柔比星脂质体注射液治疗组之间的肿瘤体积和%T/C均未观察到显著差异（p≥0.05）。毒性特征被认为总体相当。对峰血清浓度（C）和曲线下面积（AUC）的试验/参比（A/B）比值和90%置信区间（CI）的评估表明，SPIL和参比盐酸多柔比星脂质体注射液具有生物等效性。
在仿制药开发过程中确定相似性至关重要。SPIL和参比盐酸多柔比星脂质体注射液在抗肿瘤活性、毒性和药代动力学方面具有可比性。
