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Concomitant use of Lorlatinib with a strong CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of Lorlatinib.
Severe hepatotoxicity occurred in healthy subjects receiving Lorlatinib with rifampin, a strong CYP3A inducer. In 12 healthy subjects receiving a single 100 mg dose of Lorlatinib with multiple daily doses of rifampin, Grade 3 or 4 increases in ALT or AST occurred in 83% of subjects and Grade 2 increases in ALT or AST occurred in 8%. A possible mechanism for hepatotoxicity is through activation of the pregnane X receptor (PXR) by Lorlatinib and rifampin, which are both PXR agonists.
Lorlatinib is contraindicated in patients taking strong CYP3A inducers. Discontinue strong CYP3A inducers for 3 plasma half-lives of the strong CYP3A inducer prior to initiating Lorlatinib.
Concomitant use of Lorlatinib with a moderate CYP3A inducer decreased lorlatinib plasma concentrations, which may decrease the efficacy of Lorlatinib. Avoid concomitant use of moderate CYP3A inducers with Lorlatinib. If concomitant use is unavoidable, increase the Lorlatinib dose.
Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of Lorlatinib. Avoid concomitant use of Lorlatinib with a strong CYP3A inhibitor. If concomitant use cannot be avoided, reduce the Lorlatinib dosage.
Concomitant use of Lorlatinib with fluconazole may increase lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of Lorlatinib. Avoid concomitant use of Lorlatinib with fluconazole. If concomitant use cannot be avoided, reduce the Lorlatinib dosage.
Lorlatinib is a moderate CYP3A inducer. Concomitant use of Lorlatinib decreases the concentration of CYP3A substrates, which may reduce the efficacy of these substrates. Avoid concomitant use of Lorlatinib with certain CYP3A substrates, for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the CYP3A substrate dosage in accordance with approved product labeling.
Lorlatinib is a moderate P-gp inducer. Concomitant use of Lorlatinib decreases the concentration of P-gp substrates, which may reduce the efficacy of these substrates. Avoid concomitant use of Lorlatinib with certain P-gp substrates for which minimal concentration changes may lead to serious therapeutic failures. If concomitant use is unavoidable, increase the P-gp substrate dosage in accordance with approved product labeling.
FDA,2021.03
