Liver Toxicity Observed With Lorlatinib When Combined With Strong CYP3A Inducers: Evaluation of Cynomolgus Monkey as a Nonclinical Model for Assessing the Mechanism of Combinational Toxicity

• DOI: 10.1093/toxsci/kfab056
• Publication Date: 2021-05-19T19:32:16Z
• Authors: Wenyue Hu; Daniel Lettiere; Susanna Tse; Theodore R Johnson; Kathleen E Biddle; Stephane Thibault; Xavier Palazzi; Joseph Chen; Yazdi K Pithavala; Martin Finkelstein
• Keywords: Pregnane X receptor; CYP3A; Constitutive androstane receptor; CYP2B6

Lorlatinib is a potent small-molecule anaplastic lymphoma kinase inhibitor approved for the treatment of patients with nonsmall cell lung cancer. In drug-drug interaction study in healthy human participants, liver enzyme elevations were observed when single 100 mg dose lorlatinib was administered after multiple doses rifampin, strong cytochrome P450 (CYP) 3A inducer and pregnane X receptor (PXR) agonist. A series vitro vivo studies conducted to evaluate potential mechanisms clinical toxicity. To investigate involvement CYP3A and/or PXR toxicity, cynomolgus monkeys alone or coadministration known inducers that are predominantly agonists (rifampin, St. John's wort) constitutive androstane (carbamazepine, phenytoin) net inhibitory agonist (ritonavir). Results from investigative identified as pharmacologically relevant nonclinical model, which recapitulated elevated function test results humans. Furthermore, toxicity only this model coadministered inducers, effects not restricted to, exclusively dependent upon, activation mechanism. These generated mechanistic insights on provided guidance appropriate product safety label lorlatinib.