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

Abstract

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