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Drug Interactions between Noxafil and seladelpar

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

posaconazole seladelpar

Applies to: Noxafil (posaconazole) and seladelpar

MONITOR: Concomitant use with a moderate to potent CYP450 3A4 inhibitor may significantly increase seladelpar's exposure in patients who are CYP450 2C9 poor metabolizers. The proposed mechanism is reduced clearance of seladelpar, which is primarily metabolized via CYP450 2C9 and to a lesser extent via CYP450 3A4 and 2C8. The activity of CYP450 2C9 is decreased in individuals with genetic variants of the isoenzyme. After a single dose of seladelpar (1 mg to 15 mg), dose-normalized systemic exposure (AUC) was 48% higher in CYP450 2C9 poor metabolizers (n=2) and 24% higher in CYP450 2C9 intermediate metabolizers (n=28) compared to normal metabolizers (n=84). However, the maximum plasma concentration (Cmax) was similar regardless of metabolizer status. These increases in AUC are not considered clinically relevant alone. Similarly, physiologically based pharmacokinetic model simulations predicted that coadministration with the potent CYP450 3A4 inhibitor itraconazole (300 mg daily) and the moderate CYP450 3A4 inhibitor erythromycin (500 mg 4 times daily) increased seladelpar's AUC by 34% and 24% and its Cmax by 18% and 14%, respectively. These changes were also not considered clinically relevant alone. However, use of a concomitant moderate to potent CYP450 3A4 inhibitor in a patient classified as a CYP450 2C9 poor metabolizer may result in clinically significant changes. While in vivo data specific to this scenario are lacking, coadministration with the moderate CYP450 2C9 and 3A4 inhibitor fluconazole (400 mg) increased the AUC of seladelpar (10 mg) by 2.4-fold, which was considered clinically significant.

MANAGEMENT: If concomitant use of a moderate to potent CYP450 3A4 inhibitor is clinically necessary during treatment with seladelpar, caution and determining the patient's CYP450 2C9 genotype may be advisable. Patients who are classified as poor CYP450 2C9 metabolizers should be monitored more closely for adverse reactions (e.g., abnormal liver function tests) during coadministration. Should adverse reactions occur, treatment with seladelpar may need to be held or permanently discontinued as indicated by the manufacturer. The labeling of the inhibitor should also be consulted as some inhibitors may continue to have effects on CYP450 3A4 even after the agent has been discontinued.

References (2)
  1. (2024) "Product Information. Livdelzi (seladelpar)." Gilead Sciences
  2. Cymabay Therapeutics Inc (2024) Center for drug evaluation and research. Application Number: 217899Orig1s000 integrated review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2024/217899Orig1s000IntegratedR.pdf

Drug and food interactions

Moderate

posaconazole food

Applies to: Noxafil (posaconazole)

ADJUST DOSING INTERVAL: Food significantly increases the absorption of posaconazole from the oral suspension but only modestly from the delayed-release tablet. Following single-dose administration, posaconazole mean peak plasma concentration (Cmax) and systemic exposure (AUC) are approximately 2.5 to 3 times higher when the oral suspension is given with a nonfat meal or a nutritional supplement (14 grams of fat) than when given under fasting conditions, and approximately 3.5 to 4 times higher when given during or 20 minutes after a high-fat meal (50 grams of fat) than under fasting conditions. Acidic beverages may also increase posaconazole absorption. In 12 healthy volunteers, administration of a single 400 mg dose of posaconazole suspension with 12 ounces of ginger ale increased posaconazole Cmax by 92% and AUC by 70% compared to administration after fasting. In contrast, the Cmax and AUC of posaconazole increased by just 16% and 51%, respectively, when posaconazole tablets were given as a single 300 mg dose to healthy volunteers after a high-fat meal relative to a fasted state.

GENERALLY AVOID Concomitant use of alcohol and posaconazole administered in the form of delayed-release oral suspension may lead to a faster release of posaconazole. An in vitro dissolution study determined a potential for alcohol-induced dose-dumping with the delayed-release oral suspension of posaconazole.

MONITOR: In 5 study subjects, posaconazole Cmax decreased by 27% to 53% and AUC decreased by 33% to 51% when the oral suspension was administered via a nasogastric tube as opposed to orally.

MANAGEMENT: Posaconazole tablets should be taken with food, whereas posaconazole oral suspension should be administered during or immediately (i.e., within 20 minutes) following a full meal to enhance bioavailability. Patients who cannot eat a full meal should take the suspension with a liquid nutritional supplement or an acidic carbonated beverage such as ginger ale. In patients who cannot eat a full meal or tolerate an oral nutritional supplement or an acidic carbonated beverage and who do not have the option of taking another formulation of posaconazole, alternative antifungal therapy should be considered; otherwise, monitor patients closely for breakthrough fungal infections. Patients receiving posaconazole via a nasogastric tube should also be closely monitored due to increased risk of treatment failure associated with lower plasma exposure. Administration of alcohol with posaconazole from the delayed-release oral suspension formulation is not recommended.

References (4)
  1. (2006) "Product Information. Noxafil (posaconazole)." Schering-Plough Corporation
  2. Sansone-Parsons A, Krishna G, Calzetta A, et al. (2006) "Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers." Antimicrob Agents Chemother, 50, p. 1881-3
  3. Krishna G, Moton A, Ma L, Malavade D, Medlock M, McLeod J (2008) "Effect of gastric pH, dosing regimen and prandial state, food and meal timing relative to dose, and gastro-intestinal motility on absorption and pharmacokinetics of the antifungal posaconazole." 18th European Congress of Clinical Microbiology and Infectious Diseases, April, p. 20
  4. Walravens J, Brouwers J, Spriet I, Tack J, Annaert P, Augustijns P (2011) "Effect of pH and Comedication on Gastrointestinal Absorption of Posaconazole: Monitoring of Intraluminal and Plasma Drug Concentrations." Clin Pharmacokinet, 50, p. 725-34

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

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