Drug Interactions between efavirenz / lamivudine / tenofovir disoproxil and glasdegib

GENERALLY AVOID: Efavirenz can cause significant QT interval prolongation in patients with the CYP450 2B6 *6/*6 genotype due to reduced metabolic clearance of the drug stemming from decreased levels of functional CYP450 2B6 isoenzyme. Glasdegib may cause dose-related prolongation of the QT interval. In a QT study conducted in 58 healthy subjects enriched for CYP450 2B6 polymorphisms, mean efavirenz peak plasma concentration (Cmax) in subjects with the CYP450 2B6 *6/*6 genotype was 2.25-fold that observed in subjects with the CYP450 2B6 *1/*1 genotype following administration of efavirenz 600 mg daily for 14 days. A positive relationship between efavirenz concentration and QTc prolongation was observed, with mean QTc prolongation and its upper bound 90% confidence interval at 8.7 ms and 11.3 ms in subjects with the CYP450 2B6 *6/*6 genotype. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of glasdegib with efavirenz should generally be avoided. Consider alternatives to efavirenz. Caution and clinical monitoring are recommended if concomitant use is required. Patients should have electrocardiograms (ECGs) performed prior to initiation of treatment with glasdegib, approximately one week after initiation, and then once monthly for the next two months, although patients with risk factors may require more frequent and ongoing ECG monitoring. If QTc interval is greater than 500 msec at any time during treatment, interrupt and reduce glasdegib dosing in accordance with product labeling recommendations. Glasdegib should be permanently discontinued in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia. Because hypokalemia and hypomagnesemia are risk factors for ventricular arrhythmias, electrolyte levels should also be obtained prior to and during treatment, and any abnormalities corrected as necessary. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

ADJUST DOSE: Coadministration with moderate inducers of CYP450 3A4 may decrease the plasma concentrations of glasdegib, which is primarily metabolized by the isoenzyme. When glasdegib was coadministered with rifampin, a potent CYP450 3A4 inducer, glasdegib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 35% and 70%, respectively, compared to administration of glasdegib alone. Coadministration with efavirenz, a moderate CYP450 3A4 inducer, is predicted to decrease glasdegib Cmax and AUC by 25% and 55%, respectively. Reduced efficacy of glasdegib may occur.

MANAGEMENT: Concomitant use of glasdegib with moderate CYP450 3A4 inducers such as efavirenz should generally be avoided. If concomitant use cannot be avoided, the glasdegib dose should be increased as tolerated from 100 mg once a day to 200 mg once a day or from 50 mg once a day to 100 mg once a day. If efavirenz is discontinued, the glasdegib dose should return to the recommended dose after 7 days.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; other HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

MONITOR: Coadministration of efavirenz with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Efavirenz has been associated with hepatotoxicity during postmarketing use. Among reported cases of hepatic failure, a few occurred in patients with no preexisting hepatic disease or other identifiable risk factors.

MANAGEMENT: The risk of hepatic injury should be considered when efavirenz is used in combination with other agents that are potentially hepatotoxic (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; other HIV reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Monitoring of liver function tests should occur before and during treatment, especially in patients with underlying hepatic disease (including hepatitis B or C coinfection) or marked transaminase elevations. The benefit of continued therapy with efavirenz should be considered against the unknown risks of significant liver toxicity in patients who develop persistent elevations of serum transaminases greater than five times the upper limit of normal.

MONITOR: Coadministration with glasdegib may increase the plasma concentrations of drugs that are substrates of the P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) efflux transporters. In vitro data suggest that glasdegib may have the potential to inhibit P-gp (in the gastrointestinal (GI) tract) and BCRP (systemically and in the GI tract) at clinically relevant concentrations, which may result in decreased clearance of concomitantly administered P-gp and BCRP substrates. The clinical relevance is unknown.

MANAGEMENT: Caution is advised if glasdegib is coadministered with drugs that are substrates of P-gp and/or BCRP, particularly those with a narrow therapeutic range. Clinical and laboratory monitoring should be considered whenever glasdegib is added to or withdrawn from therapy with these drugs, and dosages adjusted as necessary. Patients should be monitored for the development of adverse effects.