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Lorviqua

Lorviqua Drug Interactions

lorlatinib

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Drug Interactions
In vitro data indicate that lorlatinib is primarily metabolized by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A4, with minor contributions from CYP2C8, CYP2C19, CYP3A5, and UGT1A3.
CYP3A inhibitors: ltraconazole, 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) 42% and Cmax 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. 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 Dosage & Administration).
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. The use of a strong CYP3A inducer with lorlatinib is contraindicated (see Contraindications and Precautions). 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 modafinil did not have a clinically meaningful effect on lorlatinib pharmacokinetics.
Proton-pump inhibitors, H2-receptor antagonists, or locally-acting antacids: The proton-pump inhibitor rabeprazole had a minimal effect on lorlatinib plasma exposure (90% confidence interval [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). Thus, concurrent administration 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, 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. 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-glucuronosyltransferase (UGT) inhibition: In vitro studies indicated that clinical drug-drug interactions as a result of lorlatinib-mediated inhibition of the metabolism of substrates for 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), 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 induction. Lorlatinib may have the potential to inhibit BCRP (GI tract), OATP1B1, OATP1B3, 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 NSCLC 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.
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