Drug Interactions between IsonaRif and lenvatinib

MONITOR CLOSELY: The risk of hepatotoxicity is greater when rifampin and isoniazid (INH) are given concomitantly, than when either drug is given alone. The proposed mechanism is rifampin's induction of isoniazid hydrolase, an enzyme involved in the conversion of INH to isonicotinic acid and hydrazine. Hydrazine is the proposed toxic metabolite of INH, which has been shown in animal studies to cause steatosis, hepatocyte vacuolation and glutathione depletion. Some studies have also shown that slow acetylators have a two-fold increased risk of developing antituberculosis drug-induced hepatotoxicity (ATDH) as compared with fast acetylators due to more available INH for direct hydrolysis to hydrazine. Theoretically, a similar reaction may occur with rifabutin and isoniazid. Additional risk factors for developing hepatotoxicity include patients with advanced age, malnutrition, existing hepatic impairment, daily alcohol consumption, female gender, HIV infection, extra-pulmonary tuberculosis and/or patients who are taking other potent CYP450-inducing agents.

MANAGEMENT: Caution and close monitoring should be considered if isoniazid (INH) is coadministered with rifampin or rifabutin. In cases where coadministration is required, careful monitoring of liver function, especially ALT and AST, should be done at baseline and then every 2 to 4 weeks during therapy, or in accordance with individual product labeling. Some manufacturers of INH recommend strongly considering its discontinuation if serum aminotransferase concentrations (AST or SGOT, ALT or SGPT) exceed 3 to 5 times the upper limit of normal. Product labeling for rifampin also recommends the immediate discontinuation of therapy if hepatic damage is suspected. INH product labeling suggests alternate drugs be used if hepatitis is attributed to INH in patients with tuberculosis. However, if INH must be used, it should only be resumed after the patient's symptoms and laboratory abnormalities have cleared. It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement. Patients should be counseled to immediately report signs or symptoms consistent with liver damage and notified that prodromal symptoms usually consist of fatigue, weakness, malaise, anorexia, nausea, and/or vomiting.

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MONITOR: Coadministration of isoniazid (INH) with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. INH-associated hepatotoxicity is believed to be due to an accumulation of toxic metabolites and may also be partly immune mediated, though the exact mechanisms are not universally agreed upon. INH is metabolized by N-acetyltransferase and CYP450 2E1. The rate of INH's acetylation is genetically determined and generally classified as slow or rapid, with slow acetylators characterized by a relative lack of N-acetyltransferase. While the rate of acetylation does not significantly alter INH's effectiveness, it can lead to higher blood levels of INH and an increase of adverse reactions. In addition, INH is an in vitro inhibitor of several CYP450 isoenzymes (2C9, 2C19, 2E1, and 3A4). Coadministration of hepatotoxic drugs eliminated by one or more of these pathways may lead to elevated concentrations of the concomitant drug and increase the risk of hepatotoxicity. Most of the INH-associated hepatitis cases occur during the first 3 months of treatment, but may occur at any time and have been reported to be severe or even fatal. INH is reported in medical literature to cause clinically apparent acute liver injury with jaundice in 0.5% to 1% and fatality in 0.05% to 0.1% of recipients. A United States Public Health Service Surveillance Study of 13,838 people taking INH reported 8 deaths among 174 cases of hepatitis. Risk factors for INH related liver injury may include: age > 35 years, female gender, postpartum period, daily consumption of alcohol, injection drug user, slow acetylator phenotype, malnutrition, HIV infection, pre-existing liver disease, extra-pulmonary tuberculosis, and concomitant use of hepatotoxic medications. Clinical data have been reported with concurrent use of acetaminophen, alcohol, carbamazepine, phenobarbital, phenytoin, and rifampin.

MANAGEMENT: Coadministration of isoniazid (INH) with other hepatotoxic medications should be done with caution and close clinical monitoring. Some authorities recommend avoiding concurrent use when possible. If coadministration is needed, baseline and monthly liver function testing as well as monthly interviewing of the patient to check for signs and symptoms of adverse effects is recommended. More frequent testing may be advisable in patients at increased risk of INH-associated liver injury. Some manufacturers of INH recommend strongly considering its discontinuation if serum aminotransferase concentrations (AST or SGOT, ALT or SGPT) exceed 3 to 5 times the upper limit of normal. Patients should be counseled to immediately report signs or symptoms consistent with liver damage and notified that prodromal symptoms usually consist of fatigue, weakness, malaise, anorexia, nausea, and/or vomiting. If hepatic damage is suspected, INH should be immediately discontinued as continuation may lead to more severe damage. If hepatitis is attributed to INH in patients with tuberculosis, alternative drugs should be used. However, if INH must be used, it should only be resumed after the patient's symptoms and laboratory abnormalities have cleared. It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement. Consultation with product labeling and relevant guidelines is advisable.

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The pharmacokinetics of lenvatinib are not significantly altered by rifampin, which acts as an inhibitor of P-glycoprotein (P-gp) during acute administration and an inducer of both P-gp and CYP450 3A4 during chronic administration. Following single-dose coadministration of lenvatinib 24 mg and rifampin 600 mg, lenvatinib peak plasma concentration (Cmax) increased by 33% and systemic exposure (AUC) increased by 31% compared to administration of lenvatinib alone. When a single 24 mg dose of lenvatinib was administered on day 15 of chronic rifampin dosing (600 mg/day for 21 days), lenvatinib AUC decreased by just 18% while Cmax did not change.

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