Parra-Guillen Zinnia P, Cendrós Carreras Josep María, Peraire Concepción, Obach Rosendo, Prunynosa Joan, Chetaille Eric, Trocóniz Iñaki F
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, 31080, Spain.
Pharm Res. 2015 Apr;32(4):1493-504. doi: 10.1007/s11095-014-1555-4. Epub 2014 Oct 30.
Irosustat is the 'first-in-class' irreversible potent steroid sulphatase inhibitor with lack of oestrogenic activity. The objective of this work was to develop a population model characterizing simultaneously the pharmacokinetic profiles of irosustat in plasma and whole blood.
This clinical study was an open label, multicentre, phase I multiple cohort dose escalation trial conducted in 35 postmenopausal women with oestrogen-receptor positive breast cancer. Patients received 1, 5, 20, 40, or 80 mg oral doses. Irosustat was administered as a single oral dose to each patient followed by an observation period of 7 days. On day 8 each patient received once daily oral administration until day 34. Concentrations of irosustat in both blood and plasma were obtained and pharmacokinetic analyses were performed with NONMEM 7.2.
Irosustat showed non-linear disposition characteristics modelled as maximum binding capacity into the red blood cells. Plasma concentration corresponding to half of the maximum capacity was 32.79 ng/mL. The value of the blood to plasma concentration ratio in linear conditions was 419, indicating very high affinity for the red blood cells. Apparent plasma and blood clearances were estimated in 1199.52 and 3.90 L/day, respectively. Pharmacokinetics of irosustat showed low-moderate inter-subject variability, and neither the demographics (e.g., age, or weight) nor the phenotypes for CYP2C9, CYP2C19, and CYP3A5 enzymes showed statistically significant effects. Relative bioavailability was decreased as the administered dose was augmented. The model predicted a 47% decrease in relative bioavailability in the 40 mg with respect to the 1 mg dose.
伊罗司他是首个具有不可逆性且强效的甾体硫酸酯酶抑制剂，无雌激素活性。本研究的目的是建立一个群体模型，同时表征伊罗司他在血浆和全血中的药代动力学特征。
本临床研究为开放标签、多中心、I期多队列剂量递增试验，在35名雌激素受体阳性的绝经后乳腺癌女性患者中进行。患者接受1、5、20、40或80mg的口服剂量。每位患者口服单次剂量的伊罗司他，随后观察7天。在第8天，每位患者每天口服给药一次，直至第34天。测定血液和血浆中伊罗司他的浓度，并使用NONMEM 7.2进行药代动力学分析。
伊罗司他表现出非线性处置特征，模型显示其在红细胞中的最大结合能力。对应最大容量一半的血浆浓度为32.79ng/mL。线性条件下血药浓度与血浆浓度之比为419，表明其对红细胞具有非常高的亲和力。表观血浆清除率和血液清除率分别估计为1199.52和3.90L/天。伊罗司他的药代动力学显示受试者间变异性为低到中度，人口统计学特征（如年龄或体重）以及CYP2C9、CYP2C19和CYP3A5酶的表型均未显示出统计学上的显著影响。随着给药剂量的增加，相对生物利用度降低。该模型预测，40mg剂量相对于1mg剂量，相对生物利用度降低47%。
