Ozpolat Bulent, Lopez-Berestein Gabriel, Adamson Peter, Fu ChauHwei J, Williams Anthony H
Department of Bioimmunotherapy, Section of Immunobiology and Drug Carriers, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
J Pharm Pharm Sci. 2003 May-Aug;6(2):292-301.
To determine single-and multiple-dose pharmacokinetics of liposomal-all- trans -retinoic acid (Atragen) following intravenous and oral ATRA (Vesanoid) administration in healthy volunteers.
This was a randomized, prospective, open-label, parallel pharmacokinetic study in which 29 subjects were given 90 mg/m (2) i.v. liposomal (L)-ATRA (16 subjects) every other day or 45 mg/m (2) oral ATRA (13 subjects) daily over 15 days. Pharmacokinetic parameters were assessed on days 1, 9, and 15.
Twenty-two subjects (11 in each group) completed the study and were evaluated. Area under the plasma concentration-time curve [AUC(0, infinity)] and maximum plasma concentration (C(max) ) of ATRA did not decrease during the 15 days of L-ATRA treatment. However, the oral ATRA regimen resulted in a significant decrease in the AUC(0, infinity) and C(max) of 45.3% and 31.8%, respectively, on day 9 as compared with that to day 1 (p< 0.05). In addition, the mean AUC(0, infinity) was 13- and 22-fold greater for L-ATRA than for oral ATRA on days 1 and 9, respectively. Despite the significantly higher plasma concentrations after L-ATRA treatment, the side effects of each formulation were similar, except for dermal exfoliation, which was seen in 31% of the subjects after L-ATRA dosing, and abnormal liver function tests that were seen in 23% of the subjects after oral ATRA administration.
These findings suggest that i.v. administration of L-ATRA maintains higher and stable plasma ATRA concentrations than oral ATRA in healthy subjects after repetitive administration. L-ATRA with a favorable pharmacokinetic profile may have potential advantages over oral ATRA and may be more efficacious in the treatment of acute promyelocytic leukemia or other retinoid-responsive cancers.
在健康志愿者中，确定静脉注射和口服全反式维甲酸（维甲酸）后脂质体全反式维甲酸（阿特拉津）的单剂量和多剂量药代动力学。
这是一项随机、前瞻性、开放标签、平行药代动力学研究，29名受试者每隔一天接受90mg/m²静脉注射脂质体（L）-全反式维甲酸（16名受试者）或每天接受45mg/m²口服全反式维甲酸（13名受试者），持续15天。在第1、9和15天评估药代动力学参数。
22名受试者（每组11名）完成研究并接受评估。在L-全反式维甲酸治疗的15天内，全反式维甲酸的血浆浓度-时间曲线下面积[AUC(0,∞)]和最大血浆浓度（C(max)）没有下降。然而，与第1天相比，口服全反式维甲酸方案在第9天导致AUC(0,∞)和C(max)分别显著下降45.3%和31.8%（p<0.05）。此外，在第1天和第9天，L-全反式维甲酸的平均AUC(0,∞)分别比口服全反式维甲酸高13倍和22倍。尽管L-全反式维甲酸治疗后血浆浓度显著更高，但除了皮肤脱屑（在L-全反式维甲酸给药后31%的受试者中出现）和口服全反式维甲酸给药后23%的受试者出现肝功能检查异常外，每种制剂的副作用相似。
这些发现表明，在健康受试者重复给药后，静脉注射L-全反式维甲酸比口服全反式维甲酸能维持更高且稳定的血浆全反式维甲酸浓度。具有良好药代动力学特征的L-全反式维甲酸可能比口服全反式维甲酸具有潜在优势，并且在治疗急性早幼粒细胞白血病或其他维甲酸反应性癌症方面可能更有效。
