Drug interactions of Lorlatinib

This product is primarily metabolized by CYP3A4 and UGT1A4, with minor contributions from the CYP2C8, CYP2C19, CYP3A5 isozymes and UGT1A3.

In vitro studies demonstrate that this product exerts time-dependent inhibition and induction of CYP3A, while activating the pregnane X receptor (PXR); its net in vivo effect is induction. Additionally, this product induces CYP2B6 and activates the human constitutive androstane receptor (CAR).

This product inhibits P-glycoprotein (P-gp), organic cation transporter 1 (OCT1), organic anion transporter 3 (OAT3), multidrug and toxin extrusion protein 1 (MATE1) and intestinal breast cancer resistance protein (BCRP).

Neither lorlatinib nor its major metabolite M8 inhibits the CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 isozymes, nor the UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, UGT2B15 isozymes. Notably, M8 does not inhibit CYP3A, nor does it induce CYP1A2, CYP2B6 or CYP3A.

Lorlatinib does not inhibit organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OAT1, OCT2, MATE2K or systemic BCRP. M8 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1 or MATE2K.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A Inducers

Co-administration carries a risk of severe hepatotoxicity and is contraindicated. Furthermore, it may decrease the peak plasma concentration and exposure of lorlatinib. Prior to initiating lorlatinib therapy, discontinue potent CYP3A inducers and wait for a period equivalent to 3 plasma half-lives of the inducer before administering lorlatinib.

Moderate CYP3A Inducers

The risk of hepatotoxicity with co-administration has not been established; avoid co-administration if possible. If co-administration is unavoidable, adjust the lorlatinib dosage to 125 mg once daily.

Potent CYP3A Inhibitors

Co-administration may increase lorlatinib plasma concentrations, thereby elevating the incidence and severity of adverse reactions; avoid co-administration if possible. If co-administration is unavoidable, reduce the lorlatinib dosage: from 100 mg once daily to 75 mg once daily, or from 75 mg once daily to 50 mg once daily. After discontinuing the potent CYP3A inhibitor, wait for a period equivalent to 3 plasma half-lives of the inhibitor before resuming the tolerated pre-co-administration lorlatinib dosage.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A Substrates

Co-administration may decrease the plasma concentrations of such drugs and impair their efficacy.

For CYP3A substrates where minor changes in plasma concentrations may lead to severe treatment failure, avoid co-administration with lorlatinib. If co-administration is unavoidable, adjust the dosage of the CYP3A substrate in accordance with the product labeling of the respective drug.

Drugs Affected by Transport Systems

P-gp or UGT1A Substrates

Co-administration may decrease the plasma concentrations of such drugs and impair their efficacy.

For P-gp substrates with a narrow therapeutic window, avoid co-administration with lorlatinib. If co-administration is unavoidable, refer to the manufacturer’s prescribing information of the P-gp substrate for dosage adjustment recommendations.

FDA,2021.03