Lorviqua Drug Interactions

Pharmacokinetic interactions: In vitro data indicate that lorlatinib is primarily metabolised by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5 and UGT1A3.
Effect of medicinal products on lorlatinib: CYP3A4/5 inducers: Rifampin, a strong inducer of CYP3A4/5, administered at oral doses of 600 mg once daily for 12 days, reduced the mean lorlatinib area under curve (AUC_inf) by 85% and C_max by 76% of a single 100 mg oral dose of lorlatinib in healthy volunteers; increases in AST and ALT were also observed. Concomitant administration of lorlatinib with strong CYP3A4/5 inducers (e.g., rifampicin, carbamazepine, enzalutamide, mitotane, phenytoin, and St. John's wort) may decrease lorlatinib plasma concentrations. The use of a strong CYP3A4/5 inducer with lorlatinib is contraindicated (see Contraindications and Precautions). 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 CYP3A4/5 inducer, modafinil (400 mg once daily for 19 days) in healthy volunteers. Concomitant use of modafinil did not have a clinically meaningful effect on lorlatinib pharmacokinetics.
CYP3A4/5 inhibitors: Itraconazole, a strong inhibitor of CYP3A4/5, administered at oral doses of 200 mg once daily for 5 days, increased the mean lorlatinib AUC_inf by 42% and C_max by 24% of a single 100 mg oral dose of lorlatinib in healthy volunteers. Concomitant administration of lorlatinib with strong CYP3A4/5 inhibitors (e.g., boceprevir, cobicistat, itraconazole, ketoconazole, posaconazole, troleandomycin, voriconazole, ritonavir, paritaprevir in combination with ritonavir and ombitasvir and/or dasabuvir, and ritonavir in combination with either elvitegravir, indinavir, lopinavir or tipranavir) may increase lorlatinib plasma concentrations. Grapefruit products may also increase lorlatinib plasma concentrations and should be avoided. An alternative concomitant medicinal product with less potential to inhibit CYP3A4/5 should be considered. If a strong CYP3A4/5 inhibitor must be concomitantly administered, a dose reduction of lorlatinib is recommended (see Dosage & Administration).
Effect of lorlatinib on other medicinal products: CYP3A4/5 substrates: In vitro studies indicated that lorlatinib is a time-dependent inhibitor as well as an inducer of CYP3A4/5. Lorlatinib 150 mg orally once daily for 15 days decreased AUC_inf and C_max of a single oral 2 mg dose of midazolam (a sensitive CYP3A substrate) by 61% by 50%, respectively; hence, lorlatinib is a moderate CYP3A inducer. Thus, concurrent administration of lorlatinib with CYP3A4/5 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus, and tacrolimus, should be avoided since the concentration of these medicinal products may be reduced by lorlatinib (see Precautions).
CYP2B6 substrates: Lorlatinib 100 mg once daily for 15 days decreased AUC_inf and C_max of a single oral 100 mg dose of bupropion (a combined CYP2B6 and CYP3A4 substrate) by 49.5% and 53%, respectively. Thus, lorlatinib is a weak inducer of CYP2B6, and no dose adjustment is necessary when lorlatinib is used in combination with medicinal products that are mainly metabolised by CYP2B6.
CYP2C9 substrates: Lorlatinib 100 mg once daily for 15 days decreased AUC_inf and C_max of a single oral 500 mg dose of tolbutamide (a sensitive CYP2C9 substrate) by 43% and 15%, respectively. Thus, lorlatinib is a weak inducer of CYP2C9, and no dose adjustment is required for medicinal products that are mainly metabolised by CYP2C9. However, patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by CYP2C9 (e.g., coumarin anticoagulants).
UGT substrates: Lorlatinib 100 mg once daily for 15 days decreased AUC_inf and C_max of a single oral 500 mg dose of acetaminophen (a UGT, SULT and CYP1A2, 2A6, 2D6, and 3A4 substrate) by 45% and 28%, respectively. Thus, lorlatinib is a weak inducer of UGT, and no dose adjustment is required for medicinal products that are mainly metabolised by UGT. However, patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by UGT.
P-glycoprotein substrates: Lorlatinib 100 mg once daily for 15 days decreased AUC_inf and C_max of a single oral dose of 60 mg fexofenadine [a sensitive P-glycoprotein (P-gp) substrate] by 67% and 63%, respectively. Thus, lorlatinib is a moderate inducer of P-gp. Medicinal products that are P-gp substrates with narrow therapeutic indices (e.g., digoxin, dabigatran etexilate) should be used with caution in combination with lorlatinib due to the likelihood of reduced plasma concentrations of these substrates.
In vitro inhibition and induction studies of other CYP enzymes: In vitro, lorlatinib has a low potential to cause drug-drug interactions by induction of CYP1A2.
In vitro studies with drug transporters other than P-gp: In vitro studies indicated that lorlatinib may have the potential to inhibit BCRP (gastrointestinal tract), OATP1B1, OATP1B3, OCT1, MATE1, and OAT3 at clinically relevant concentrations. Lorlatinib should be used with caution in combination with substrates of BCRP, OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 as clinically relevant changes in the plasma exposure of these substrates cannot be ruled out.