Lewis Lionel D, Miller Antonius A, Rosner Gary L, Dowell Jonathan E, Valdivieso Manuel, Relling Mary V, Egorin Merrill J, Bies Robert R, Hollis Donna R, Levine Ellis G, Otterson Gregory A, Millard Frederick, Ratain Mark J
Sections of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, Dartmouth Medical School, The Norris Cotton Cancer Center, Lebanon, New Hampshire 03756, USA.
Clin Cancer Res. 2007 Jun 1;13(11):3302-11. doi: 10.1158/1078-0432.CCR-06-2345.
Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients.
We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m(2) as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done.
We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied.
Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.
据报道，与白种人患者相比，非裔美国患者对细胞色素P450 3A（CYP3A）和/或ATP结合盒转运蛋白B1（ABCB1，P-糖蛋白/多药耐药蛋白1）底物类药物（如口服环孢素）的清除率更高。我们推测，静脉注射的细胞毒性药物多西他赛（CYP3A4、CYP3A5和ABCB1的底物）在非裔美国患者和白种人患者中的药代动力学和药效学存在差异。
我们调查了接受75或100mg/m²多西他赛1小时静脉输注的非裔美国和白种人癌症患者的群体药代动力学和药效学以及CYP3A4、CYP3A5和ABCB1的药物遗传学。采用高效液相色谱法测定血浆多西他赛浓度。在多西他赛给药后的第8、15和22天监测临床毒性和绝对中性粒细胞计数（ANC）。使用有限采样策略和非线性混合效应模型，估算每位患者的多西他赛清除率。对CYP3A4、CYP3A5和ABCB1的已知多态性进行基因分型。
我们纳入了109例患者：40例非裔美国人（26例男性；14例女性），中位年龄61岁（范围29 - 73岁），69例白种人（43例男性；26例女性），中位年龄63岁（范围38 - 81岁）。非裔美国患者[40.3L/h；95%置信区间（95%CI），19.3 - 84.1]和白种人患者（41.8L/h；95%CI，22.0 - 79.7；P = 0.6）的多西他赛几何平均清除率无差异。我们观察到非裔美国患者和白种人患者在ANC降低百分比方面无差异，多西他赛药代动力学参数也与所研究的基因型无关。
非裔美国和白种人癌症患者的多西他赛清除率及其相关的骨髓抑制作用相似。
