9.2 Drug Interactions Overview
In vitro data indicate that LORBRENA (lorlatinib) is primarily metabolized by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
9.4 Drug-Drug Interactions
CYP3A inhibitors
Itraconazole, a strong inhibitor of CYP3A, administered at a dose of 200 mg once daily for 5 days, increased the mean area under the curve (AUC) by 42% and Cmax by 24% of a single 100 mg oral dose of lorlatinib in healthy volunteers. Concomitant administration of lorlatinib with strong CYP3A inhibitors (e.g., boceprevir, cobicistat, conivaptan, itraconazole, ketoconazole, posaconazole, telaprevir, troleandomycin, voriconazole, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either danoprevir, elvitegravir, indinavir, lopinavir, saquinavir, or tipranavir) may increase lorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib plasma concentrations. Concomitant use with a strong CYP3A inhibitor increased lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of LORBRENA. An alternative concomitant medicinal product with less potential to inhibit CYP3A should be considered. If a strong CYP3A inhibitor must be concomitantly administered, a dose reduction of lorlatinib is recommended (see 4 DOSAGE AND ADMINISTRATION). Based on PBPK simulations, concomitant use of LORBRENA with fluconazole may increase lorlatinib plasma concentrations, which may increase the incidence and severity of adverse reactions of LORBRENA. Avoid concomitant use of LORBRENA with fluconazole. If concomitant use cannot be avoided, reduce the LORBRENA starting dose to 75 mg once daily.
CYP3A inducers
Rifampin, a strong inducer of CYP3A, administered at a dose of 600 mg once daily for 9 days, reduced the mean lorlatinib AUC by 85% and Cmax by 76% of a single 100-mg dose of lorlatinib in healthy volunteers; increases in liver function tests (AST and ALT) were also observed. Concomitant administration of lorlatinib with strong CYP3A inducers (e.g., rifampin, carbamazepine, enzalutamide, mitotane, phenytoin and St. John’s wort) may decrease lorlatinib plasma concentrations. Severe hepatotoxicity occurred in healthy subjects receiving LORBRENA with rifampin, a strong CYP3A inducer. The use of a strong CYP3A inducer with lorlatinib is contraindicated (see 2 CONTRAINDICATIONS and 4 DOSAGE AND ADMINISTRATION). Any strong CYP3A inducers have to be discontinued for at least 3 plasma half-lives of the strong CYP3A inducer before lorlatinib treatment is started. No clinically meaningful changes in liver function test results were seen after administration of the combination of a single 100 mg oral dose of lorlatinib with the moderate CYP3A inducer, modafinil (400 mg once daily for 19 days) in healthy volunteers. Concomitant use of lorlatinib with a moderate CYP3A inducer decreased lorlatinib plasma AUC by 23% and decreased Cmax by 22%. (see 10 CLINICAL PHARMACOLOGY). If concomitant use cannot be avoided, increase LORBRENA starting dose to 125 mg once daily.
Proton Pump inhibitors, H2-receptor antagonists, or locally acting antacids
The proton-pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (90% CI for the AUCinf ratio, expressed as a percentage: 97.6%, 104.3%).
No dose adjustment is required when lorlatinib is taken with proton-pump inhibitors, H2-receptor antagonists, or locally acting antacids.
Drugs whose plasma concentrations may be altered by lorlatinib:
CYP3A substrates
Lorlatinib has a net induction effect on CYP3A both in vitro and in vivo. Lorlatinib 150 mg orally once daily for 15 days decreased AUCinf by 64% and Cmax by 50% of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate). Concurrent administration of lorlatinib in patients resulted in decreased mean oral midazolam AUC and Cmax than that observed when midazolam was administered alone, suggesting that lorlatinib is an inducer of CYP3A. Thus, coadministration of lorlatinib with CYP3A substrates with narrow therapeutic indices, including but not limited to hormonal contraceptives, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided since the concentration of these drugs may be reduced by lorlatinib.
In vitro studies of other CYP inhibition and induction
In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib mediated inhibition of the metabolism of substrates for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 are unlikely to occur.
In vitro, studies indicated that lorlatinib is an inhibitor of CYP2C9 and that it activates the human pregnane X receptor (PXR), with the net effect in vivo being weak CYP2C9 induction. In vitro studies also indicated that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A, with the net effect in vivo being induction. In vitro studies also indicated that lorlatinib is an inducer of CYP2B6 and activates the human constitutive androstane receptor (CAR), and in vivo lorlatinib is a weak inducer of CYP2B6. Therefore, concomitant use of lorlatinib with CYP2B6 substrates (e.g., bupropion, efavirenz) may result in reduced plasma concentrations of the CYP2B6 substrate. In vitro, lorlatinib has a low potential to cause drug-drug interactions by induction of CYP1A2.
In vitro, the major circulating metabolite for lorlatinib showed a low potential to cause drug‑drug interaction by inhibiting CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A, or by inducing CYP1A2, CYP2B6, and CYP3A.
In vitro studies of UDP-glucuronysyltransferase (UGT) inhibition
In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib mediated inhibition of the metabolism of substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 are unlikely to occur. In vitro studies indicated that lorlatinib is an inhibitor of UGT1A1 and that it activates PXR, with the net effect in vivo being weak UGT induction.
In vitro studies indicated that clinical drug‑drug interactions as a result of inhibition by the major lorlatinib circulating metabolite of substrates for UGT1A1, UGT1A4, UGT1A6, UGT1A9, UGT2B7, and UGT2B15 are unlikely to occur.
In vitro studies with drug transporters
In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib mediated inhibition of breast cancer resistance protein (BCRP, systemically), organic anion transporting polypeptide (OATP)1B1, OATP1B3, multidrug and toxin extrusion protein (MATE)2K, organic anion transporter (OAT)1, and organic cation transporter (OCT)2 are unlikely. In vitro studies indicated that lorlatinib is an inhibitor of P-glycoprotein (P-gp) and that it activates PXR, with the net effect in vivo being moderate P‑gp induction. Lorlatinib may have the potential to inhibit P glycoprotein (P-gp, systemically and at the gastrointestinal [GI] tract), BCRP (GI tract), OCT1, MATE1, and OAT3 at clinically relevant concentrations.
In vitro studies indicated that clinical drug-drug interactions as a result of inhibition by the major lorlatinib circulating metabolite of substrates for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2K are unlikely to occur.
In vivo studies with drug transporters
A drug interaction study conducted in non-small cell lung cancer patients indicated that lorlatinib is a moderate inducer of P gp. P-gp substrates with narrow therapeutic index (e.g., digoxin) should be used with caution in combination with lorlatinib due to the likelihood of reduced plasma concentrations of these substrates.
9.5 Drug-Food Interactions
Lorlatinib can be taken with or without food. Administration of lorlatinib with a high fat, high calorie meal resulted in 5% higher AUCinf and 9% lower Cmax (AUCinf ratio of 104.7%; 90% CI for the ratio: 101.3%, 108.3%; Cmax ratio of 90.89%; 90% CI for the ratio: 84.82%, 97.40%), compared to overnight fasting. However, taking lorlatinib with foods that are strong CYP3A inhibitors (e.g. Grapefruit products) may increase lorlatinib plasma concentrations and should be avoided.
9.6 Drug-Herb Interactions
Co-administration of lorlatinib with herbal products that are strong CYP3A inducers (e.g. St. John’s wort) may decrease lorlatinib plasma concentrations. The use of a strong CYP3A inducer with lorlatinib is contraindicated (see 2 CONTRAINDICATIONS and 4 DOSAGE AND ADMINISTRATION). Avoid concomitant use with herbal products that are moderate CYP3A inducers, if possible, as they may also reduce lorlatinib plasma concentrations.