Tarlonib Drug Interactions

Erlotinib is metabolized in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2, and the pulmonary isoform CYP1A1. Potential interactions may occur with drugs which are metabolized by, or are inhibitors or inducers of, these enzymes.
Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma concentrations. Inhibition of CYP3A4 metabolism by ketoconazole (200 mg p.o. BID for 5 days) has reported to increase exposure to erlotinib (86% in median erlotinib exposure [AUC]) and a 69% increase in C_max when compared to erlotinib alone. When erlotinib was co-administered with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure [AUC] and maximum concentration (C_max) has reported to increase by 39% and 17%, respectively. Therefore caution should be used when administering erlotinib with potent CYP3A4 or combined CYP3A4/CYP1A2 inhibitors. In these situations, the dose of erlotinib should be reduced if toxicity is observed.
Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib plasma concentrations. Induction of CYP3A4 metabolism by rifampicin (600 mg p.o. QD for 7 days) has reported a 69% decrease in the median erlotinib AUC, following a 150 mg dose of erlotinib, as compared to erlotinib alone.
Pre-treatment and co-administration of rifampicin with a single 450 mg dose of erlotinib has reported in a mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg erlotinib dose in the absence of rifampicin treatment. Alternative treatments lacking potent CYP3A4 inducing activity should be considered when possible. For patients who require concomitant treatment with erlotinib and a potent CYP3A4 inducer such as rifampicin an increase in dose to 300 mg should be considered while their safety (see Precautions) is closely monitored, and if well tolerated for more than 2 weeks, further increase to 450 mg could be considered with close safety monitoring. Higher doses have not been reported in this setting.
Pre-treatment or co-administration of erlotinib did not alter the clearance of the prototypical CYP3A4 substrates midazolam and erythromycin. Significant interactions reported with the clearance of other CYP3A4 substrates are therefore unlikely. Oral availability of midazolam did appear to decrease by up to 24%, which was however not attributed to effects on CYP3A4 activity.
The solubility of erlotinib is pH dependent. Erlotinib solubility decreases as pH increases. Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence its bioavailability. Co-administration of erlotinib with omeprazole, a proton pump inhibitor, has been reported to decrease the erlotinib exposure [AUC] and C_max by 46% and 61%, respectively. No change to T_max or half-life has been reported. Concomitant administration of erlotinib with 300 mg ranitidine, an H₂-receptor antagonist, has been reported to decrease erlotinib exposure [AUC] and C_max by 33% and 54%, respectively. Therefore, co-administration of drugs reducing gastric acid production with erlotinib should be avoided where possible. Increasing the dose of erlotinib when co-administered with such agents is not likely to compensate for this loss of exposure. However, when erlotinib was dosed in a staggered manner 2 hours before or 10 hours after ranitidine 150 mg b.i.d., erlotinib exposure [AUC] and C_max decreased only by 15% and 17%, respectively. If patients need to be treated with such drugs, then an H₂-receptor antagonist such as ranitidine should be considered and used in a staggered manner. Erlotinib must be taken at least 2 hours before or 10 hours after the H₂-receptor antagonist dosing.
Interaction with coumarin-derived anticoagulants, including warfarin, leading to increased International Normalized Ratio (INR) and bleeding events, which in some cases were fatal, have been reported in patients receiving erlotinib. Patients taking coumarin-derived anticoagulants should be monitored regularly for any changes in prothrombin time or INR.
The combination of erlotinib and a statin may increase the potential for statin-induced myopathy, including rhabdomyolysis, which was reported rarely.
Smokers should be advised to stop smoking as cigarette smoking, which is known to induce CYP1A1 and CYP1A2, has been reported to reduce erlotinib exposure by 50-60% (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
In a reported study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.