Metabolism, Excretion, and Pharmacokinetics of Lorlatinib (PF-06463922) and Evaluation of the Impact of Radiolabel Position and Other Factors on Comparability of Data Across 2 ADME Studies
Metabolism, Excretion, and Pharmacokinetics of Lorlatinib (PF-06463922) and Evaluation of the Impact of Radiolabel Position and Other Factors on Comparability of Data Across 2 ADME Studies
复制标题
DOI：
10.1002/jcph.1621
复制
发表时间：
2020-05-22
影响因子：
2.9
通讯作者：
Pithavala, Yazdi K.
中科院分区：
文献类型：
--
作者：
Stypinski, Daria;Fostvedt, Luke;Pithavala, Yazdi K.
虽然一项初步的临床吸收、分布、代谢和排泄(ADME)研究(研究1；N=6)证实了劳拉替尼的主要代谢途径是氧化(N-去甲基化，N-氧化)和N-葡萄糖醛酸化，产生了主要的循环苯甲酸代谢物(M8)和未标记的吡啶-吡唑亚结构。对与这种分子内切割途径相关的未知代谢物的命运的担忧导致进行了第二项ADME研究(研究2；N=6)，设计相同，但放射性标记位于吡唑环上。在两项研究中，在总体质量平衡、劳拉替尼血浆暴露和保留放射性标记的代谢物的排泄物代谢情况方面，结果是相似的。两组受试者的血浆总放射性暴露量(从0到无穷大的血浆浓度-时间曲线下面积的2倍)和尿液与粪便中恢复剂量百分比的相对比率(研究1为48%比41%；研究2为28%比%)均有差异。此外，从代谢特征数据得出的数值与从特定生物分析方法得出的数值相比，M8与劳拉替尼的平均摩尔暴露比大约相差3倍(研究1和研究2分别为0.5和1.4)。这些研究间差异归因于多种因素的组合，包括放射标记位置的改变、正交分析方法和受试者之间的变异性，说明临床ADME研究的结果并不是明确的，应该在具体研究设计考虑的背景下进行解释。
While an initial clinical absorption, distribution, metabolism, and excretion (ADME) study (Study 1; N = 6) with 100 mg/100 mu Ci [C-14]lorlatinib, radiolabeled on the carbonyl carbon, confirmed that the primary metabolic pathways for lorlatinib are oxidation (N-demethylation, N-oxidation) and N-glucuronidation, it also revealed an unanticipated, intramolecular cleavage metabolic pathway of lorlatinib, yielding a major circulating benzoic acid metabolite (M8), and an unlabeled pyrido-pyrazole substructure. Concerns regarding the fate of unknown metabolites associated with this intramolecular cleavage pathway led to conduct of a second ADME study (Study 2; N = 6) of identical design but with the radiolabel positioned on the pyrazole ring. Results were similar with respect to the overall mass balance, lorlatinib plasma exposures, and metabolic profiles in excreta for the metabolites that retained the radiolabel in both studies. Differences were observed in plasma total radioactivity exposures (2-fold area under the plasma concentration-time curve from time 0 to infinity difference) and relative ratios of the percentage of dose recovered in urine vs feces (48% vs 41% in Study 1; 28% vs 64% in Study 2). In addition, an approximately 3-fold difference in the mean molar exposure ratio of M8 to lorlatinib was observed for values derived from metabolic profiling data relative to those derived from specific bioanalytical methods (0.5 vs 1.4 for Studies 1 and 2, respectively). These interstudy differences were attributed to a combination of factors, including alteration of radiolabel position, orthogonal analytical methodologies, and intersubject variability, and illustrate that results from clinical ADME studies are not unambiguous and should be interpreted within the context of the specific study design considerations.