Pfizer (Clinical Pharmacology Oncology), La Jolla, 10555 Science Center Drive, CB10-2727, San Diego, CA, 92121, USA.
Pfizer (Pharmacometrics Oncology), Groton, CT, USA.
Cancer Chemother Pharmacol. 2022 Jan;89(1):71-81. doi: 10.1007/s00280-021-04368-1. Epub 2021 Oct 26.
Lorlatinib is a third-generation tyrosine kinase inhibitor currently approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. This open-label, phase 1, randomized two-sequence, two-treatment, two-period, crossover study investigated the absolute oral bioavailability of lorlatinib in healthy participants.
Eligible participants were randomized to receive two treatments in one of two sequences: lorlatinib 100 mg single oral dose followed by lorlatinib 50 mg intravenous (IV) dose, or lorlatinib IV dose followed by lorlatinib oral dose, each with at least a 10-day washout between successive lorlatinib doses. Blood samples for pharmacokinetics were collected for up to 144 hours (h) after dosing. Validated liquid chromatographic-tandem mass spectrometry was used to determine plasma concentrations of lorlatinib and its benzoic acid metabolite PF-06895751.
In total, 11 participants were enrolled (mean age 37.6 years, all male). The adjusted geometric mean (90% confidence interval) for the absolute oral bioavailability was 80.78% (75.73-86.16%). Using non-compartmental analysis, the estimated arithmetic mean elimination plasma half-life of lorlatinib was 25.5 and 27.0 h after the oral and IV doses, respectively. No deaths, serious adverse events (AEs), or severe AEs were reported, and most treatment-emergent AEs were mild in severity, with two events of transaminase increase of moderate severity. All treatment-emergent AEs were resolved by the end of the study.
Both oral and IV lorlatinib were well-tolerated in healthy participants and oral lorlatinib is highly bioavailable after oral administration.
洛拉替尼是一种第三代酪氨酸激酶抑制剂，目前被批准用于治疗间变性淋巴瘤激酶（ALK）阳性转移性非小细胞肺癌。这项开放标签、I 期、随机、两序列、两治疗、两周期、交叉研究旨在调查健康参与者中洛拉替尼的绝对口服生物利用度。
符合条件的参与者被随机分配接受两种治疗中的一种，两种序列之一：洛拉替尼 100mg 单口服剂量后给予洛拉替尼 50mg 静脉（IV）剂量，或洛拉替尼 IV 剂量后给予洛拉替尼口服剂量，每个剂量之间至少有 10 天的洗脱期。给药后最多采集 144 小时（h）的药代动力学血样。使用经验证的液相色谱-串联质谱法测定洛拉替尼及其苯甲酸代谢物 PF-06895751 的血浆浓度。
共纳入 11 名参与者（平均年龄 37.6 岁，均为男性）。绝对口服生物利用度的调整后几何均数（90%置信区间）为 80.78%（75.73-86.16%）。非房室分析估计洛拉替尼口服和 IV 剂量后消除血浆半衰期的算术平均值分别为 25.5 和 27.0h。未报告死亡、严重不良事件（AE）或严重 AE，大多数治疗后出现的 AE 为轻度，有 2 例转氨酶升高为中度严重。所有治疗后出现的 AE 在研究结束时均已解决。
洛拉替尼口服和静脉制剂在健康参与者中均耐受良好，口服洛拉替尼口服后具有较高的生物利用度。
