Piotrovsky V K, Huang M L, Van Peer A, Langenaecken C
Janssen Research Foundation, Clinical Pharmacokinetics, Beerse, Belgium.
Cancer Chemother Pharmacol. 1998;42(3):221-8. doi: 10.1007/s002800050808.
Vorozole (VOR) is a selective nonsteroidal inhibitor of the cytochrome P450-dependent aromatase that catalyzes the conversion of androgens to estrogens. It is currently being developed as a therapeutic agent in the endocrine treatment of postmenopausal women with breast cancer. This work was aimed to explore the effects of demographic and other variables on VOR pharmacokinetics.
VOR plasma concentration-time data were obtained in healthy volunteers and in breast cancer patients after the oral administration of 2.5 mg of VOR as a single dose or once daily. The data obtained in 6 formal pharmacokinetics (PK) studies with frequent plasma sampling were included in the data base (84 healthy male and female volunteers and 13 breast cancer patients). Also included were data from 2 clinical efficacy trials involving 286 breast cancer patients who were treated for several months (1 sample per visit, up to 14 samples/patient). The nonlinear mixed-effect modeling (NONMEM) approach was applied. The two-compartment linear PK model with first-order absorption parameterized in terms of apparent clearance (CL), apparent central and peripheral volumes of distribution (Vc and Vp, respectively), apparent distributional flow (Q), and absorption constant (ka) was used. A population model was developed using data from formal PK studies. The final estimates of fixed and random effect parameters were obtained using both formal study data and clinical-efficacy trial data.
The typical CL value obtained after a single dose was lower in patients (4.8 l/h) as compared with healthy volunteers (8.6 l/h) and did not depend on gender. The multiple- to single-dose ratio was 0.76. CL was constant over ages of up to 50 years and then decreased slightly (0.047 l/h per year). The typical CL value did not depend on any demographic variable related to body size (total body weight, WT; body surface area; lean body mass). Q and Vc were proportional to WT (0.17 l h(-1) kg(-1) and 0.43 l/kg, respectively). Vp was also proportional to WT and was higher in women as compared with men (0.64 and 0.40 l/kg, respectively). The same was true for the apparent steady-state volume of distribution. No effect of race or the duration of therapy (0.5-28 months) was seen. The unexplained variability in CL and the residual variability in VOR plasma concentrations were 39% and 28% (coefficient of variation), respectively.
Healthy volunteer/patient, single/multiple dosing differences, and age were identified as the fixed effects influencing the CL of VOR. WT was the main determinant of distributional PK parameters. The peripheral and steady-state volumes of distribution were gender-dependent. In view of the relatively high degree of residual interpatient variability in CL, the slight effect of age on it is unlikely to be clinically significant.
伏洛唑（VOR）是一种细胞色素P450依赖性芳香化酶的选择性非甾体抑制剂，该酶催化雄激素转化为雌激素。目前它正作为一种治疗药物用于绝经后乳腺癌女性的内分泌治疗。这项研究旨在探讨人口统计学及其他变量对伏洛唑药代动力学的影响。
在健康志愿者和乳腺癌患者口服2.5mg伏洛唑单剂量或每日一次后，获取伏洛唑血浆浓度-时间数据。6项进行频繁血浆采样的正式药代动力学（PK）研究中获得的数据被纳入数据库（84名健康男性和女性志愿者以及13名乳腺癌患者）。还包括来自2项临床疗效试验的数据，这2项试验涉及286名接受数月治疗的乳腺癌患者（每次访视1个样本，每位患者最多14个样本）。应用非线性混合效应建模（NONMEM）方法。使用以表观清除率（CL）、表观中央和外周分布容积（分别为Vc和Vp）、表观分布血流量（Q）和吸收常数（ka）参数化的二室线性PK模型。利用正式PK研究的数据建立群体模型。使用正式研究数据和临床疗效试验数据获得固定效应和随机效应参数的最终估计值。
单剂量给药后，患者的典型CL值（4.8l/h）低于健康志愿者（8.6l/h），且不依赖于性别。多剂量与单剂量之比为0.76。CL在50岁及以下年龄段保持恒定，之后略有下降（每年0.047l/h）。典型CL值不依赖于任何与体型相关的人口统计学变量（总体重、WT；体表面积；瘦体重）。Q和Vc与WT成正比（分别为0.17lh⁻¹kg⁻¹和0.43l/kg）。Vp也与WT成正比，女性高于男性（分别为0.64和0.40l/kg）。表观稳态分布容积情况相同。未观察到种族或治疗持续时间（0.5 - 28个月）的影响。CL中无法解释的变异性和伏洛唑血浆浓度的残余变异性分别为39%和28%（变异系数）。
健康志愿者/患者、单/多剂量差异以及年龄被确定为影响伏洛唑CL的固定效应。WT是分布性PK参数的主要决定因素。外周和稳态分布容积与性别有关。鉴于CL中患者间残余变异性程度相对较高，年龄对其的轻微影响在临床上不太可能具有显著意义。
