Monif Tausif, Reyar Simrit, Tiwari Hari Krishan, Tippabhotla Sudhakar Koundinya, Khuroo Arshad, Thudi Nageshwar Rao, Ahmed Sarfaraz, Raghuvanshi Rajeev
Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Laboratories Ltd., Plot No. 20, Sector-18, Udyog Vihar Industrial Area, Gurgaon-122 015, Haryana, India.
Arzneimittelforschung. 2009;59(2):104-8. doi: 10.1055/s-0031-1296371.
Lamivudine (CAS 134678-17-4) is a synthetic nucleoside analogue with activity against HIV-1 and HBV. Stavudine (CAS 3056-17-5) is a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV). Lamivudine and stavudine in combination with other antiretroviral (ARV) agents are indicated for the treatment of HIV infection. As there are no suitable pediatric ARVs, adult fixed-dose ARVs are commonly used in children. This practice poses concerns about dose inaccuracy, which may lead to resistance or toxicity. A new fixed-dose combination (FDC) tablet for oral suspension, containing lamivudine 40 mg and stavudine 10 mg has been developed. An open-label, balanced, randomised, two-treatment, two-period, two-sequence, single-dose, crossover bioequivalence study was conducted following administration of a fixed-dose combination of lamivudine and stavudine tablet for oral suspension (test formulation) and innovator products (reference formulations) in healthy, adult, male human subjects under fasting condition. Multiple blood samples were collected up to 36 h post dose. Plasma concentrations of lamivudine and stavudine were assayed using validated high-performance liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters were calculated using non-compartmental analysis and bioequivalence was assessed using a mixed effect ANOVA model. The ratio of the least-square means (FDC to individual products) and 90% confidence intervals (CIs) of AUC(0-t), AUC(0-infinity) and C(max) for lamivudine and stavudine were all within 80.00-125.00%, suggesting a similar rate and extent of ARVs exposure in the bloodstream. The FDC and individual products were equally safe and well tolerated. The current FDC of lamivudine and stavudine is expected to provide a similar efficacy/safety profile as co-administration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV in children.
拉米夫定（CAS 134678-17-4）是一种合成核苷类似物，对HIV-1和HBV具有活性。司他夫定（CAS 3056-17-5）是一种合成胸苷核苷类似物，对人类免疫缺陷病毒（HIV）具有活性。拉米夫定和司他夫定与其他抗逆转录病毒（ARV）药物联合用于治疗HIV感染。由于没有合适的儿科抗逆转录病毒药物，成人固定剂量抗逆转录病毒药物常用于儿童。这种做法引发了对剂量不准确的担忧，这可能导致耐药性或毒性。已开发出一种新的口服混悬液固定剂量组合（FDC）片剂，含有40毫克拉米夫定和10毫克司他夫定。在空腹条件下，对健康成年男性受试者给予拉米夫定和司他夫定口服混悬液固定剂量组合（试验制剂）和创新产品（参比制剂）后，进行了一项开放标签、均衡、随机、双治疗、双周期、双序列、单剂量、交叉生物等效性研究。给药后长达36小时采集多个血样。使用经过验证的高效液相色谱-质谱分析法测定拉米夫定和司他夫定的血浆浓度。使用非房室分析计算药代动力学参数，并使用混合效应方差分析模型评估生物等效性。拉米夫定和司他夫定的AUC(0-t)、AUC(0-无穷大)和C(max)的最小二乘均值之比（FDC与单一产品之比）和90%置信区间（CIs）均在80.00-125.00%范围内，表明抗逆转录病毒药物在血液中的暴露速率和程度相似。FDC和单一产品同样安全且耐受性良好。目前的拉米夫定和司他夫定FDC预计将提供与联合使用单一产品相似的疗效/安全性，更好的治疗依从性，并在儿童HIV治疗中节省大量成本。
