Drug Interactions between efavirenz / lamivudine / tenofovir disoproxil and pralsetinib

GENERALLY AVOID: Coadministration with moderate inducers of CYP450 3A4 may significantly decrease the plasma concentrations of pralsetinib, which is primarily metabolized by the isoenzyme. Concurrent use with the moderate CYP450 3A4 inducer efavirenz (600 mg once daily) is predicted to decrease the peak plasma concentration (Cmax) and systemic exposure (AUC) of pralsetinib by 18% and 45%, respectively. Reduced therapeutic efficacy may occur. In addition, when two or more medications with similar side effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can lead to elevations in liver transaminases may result in additive effects and an increased risk of hepatotoxicity.

MANAGEMENT: Concomitant use of pralsetinib with moderate CYP450 3A4 inducers should generally be avoided. If coadministration is considered clinically necessary, the current dose of pralsetinib should be increased starting on Day 7 of coadministration with the moderate CYP450 3A4 inducer. The manufacturer recommends increasing the dose of pralsetinib as follows: 600 mg once daily for patients receiving 400 mg once daily, 500 mg once daily for patients receiving 300 mg once daily, and 300 mg once daily for patients receiving 200 mg once daily. Once the moderate CYP450 3A4 inducer has been discontinued for at least 14 days, the pralsetinib dose taken prior to initiating the inducer may be resumed. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate serious adverse effects including but not limited to hepatotoxicity. Consult the individual product labeling for further guidance; for example, in instances when the potency of the CYP450 3A4 inducer may be affected by dose or dosage form.

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 pralsetinib may increase the plasma concentrations of drugs that are P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, organic anion transporter 1 (OAT1), multidrug and toxin extrusion 1 (MATE1), and/or MATE2-K substrates. Based on in vitro studies, pralsetinib may decrease clearance via inhibition of these transporters, resulting in increased plasma concentrations of agents that are carried by one or more of these transporters. Clinical and pharmacokinetic data are currently lacking.

MANAGEMENT: Caution is advised if pralsetinib is used concomitantly with drugs that are substrates of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, MATE1, and/or MATE2-K, particularly sensitive substrates or those with a narrow therapeutic range. Some authorities recommend avoiding coadministration of pralsetinib with substrates of these transporters for which minimal concentration changes may lead to therapeutic failure or serious toxicities. If coadministration is required, dosage adjustments as well as clinical and laboratory monitoring may be appropriate whenever pralsetinib is added to or withdrawn from therapy. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration and for any dosage adjustments that may be required.