Tolbert Jaszianne A, Bai Shasha, Abdel-Rahman Susan M, August Keith J, Weir Scott J, Kearns Gregory L, Neville Kathleen A
Divisions of Hematology/Oncology, Children's Mercy Hospitals and Clinics, Kansas City, Missouri.
Divisions of Clinical Pharmacology, Medical Toxicology, and Therapeutic Innovation, Children's Mercy Hospitals and Clinics, Kansas City, Missouri.
Pediatr Blood Cancer. 2017 Aug;64(8). doi: 10.1002/pbc.26465. Epub 2017 Mar 10.
A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation.
Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m ) was given after an 8-hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6-MP concentrations were determined using a good laboratory practice (GLP)-validated liquid chromatography-tandem mass spectrometry method. PK parameters were calculated using noncompartmental analysis and compared within and between cohorts, and thiopurine methyltransferase (TPMT) genotype was analyzed.
No patient had a TPMT genotype reflective of a poor metabolizer phenotype. Comparison of PK parameters between 5 and 50 mg/ml treatments revealed significant differences (P <0.05) in AUC (where AUC is area under the curve), C , and T . Comparisons within each group revealed significant differences in AUC and T in the 5 mg/ml group.
Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered.
基于健康成人的生物利用度（BA）数据，6-巯基嘌呤（6-MP）的液体制剂最近获得了美国食品药品监督管理局的批准（商品名Purixan®）。我们比较了市售片剂、两种临时配制的液体制剂以及已批准液体制剂的数据，研究了6-MP在急性淋巴细胞白血病（ALL）儿童中的药代动力学（PK）和生物利用度。
22名儿童（6至17岁）参与了一项针对两个队列的随机双向交叉研究。第1组（n = 11；5名男性）在不同时间分别接受5 mg/ml液体制剂和市售50 mg 6-MP片剂，第2组（n = 11；5名男性）接受50 mg/ml液体制剂和市售片剂。在禁食8小时后给予常规规定的6-MP剂量（25 - 115 mg/m²）。给药后8小时内采集系列血样。使用经过良好实验室规范（GLP）验证的液相色谱 - 串联质谱法测定血浆6-MP浓度。使用非房室分析计算PK参数，并在队列内和队列间进行比较，同时分析硫嘌呤甲基转移酶（TPMT）基因型。
没有患者的TPMT基因型显示为代谢不良者表型。5 mg/ml和50 mg/ml治疗之间的PK参数比较显示，曲线下面积（AUC）、Cmax（最大浓度）和Tmax（达峰时间）存在显著差异（P <0.05）。每组内的比较显示，5 mg/ml组的AUC和Tmax存在显著差异。
已批准液体制剂在健康成人中确定的6-MP药代动力学特征可能无法反映ALL儿童的PK特征。PK方面的制剂特异性差异可能会显著影响这些儿童的剂量 - 暴露情况，必须予以考虑。
