Introduction
Tryngolza (generic name: trynibazole) is a novel third-generation antifungal agent belonging to the azole class. It was developed to address the growing concern of antifungal resistance and represents a significant advancement in the treatment of systemic fungal infections. Tryngolza demonstrates broad-spectrum activity against both common and emerging fungal pathogens, including resistant Candida and Aspergillus species.
Mechanism of Action
Tryngolza exerts its antifungal effect through potent inhibition of fungal cytochrome P450 14α-demethylase. This enzyme is essential for the conversion of lanosterol to ergosterol, a critical component of fungal cell membranes. By disrupting ergosterol synthesis, Tryngolza causes accumulation of toxic methylated sterols and creates membrane instability, ultimately leading to fungal cell death. Unlike earlier azoles, Tryngolza demonstrates enhanced selectivity for fungal cytochrome P450 enzymes over human isoforms, resulting in an improved safety profile.
Indications
Tryngolza is FDA-approved for:
- Treatment of invasive aspergillosis in adults
- Treatment of candidemia and other forms of invasive candidiasis
- Treatment of esophageal candidiasis
- Prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplantation
- Off-label uses may include treatment of resistant fungal infections when susceptibility is confirmed
Dosage and Administration
Standard dosing:- Loading dose: 400 mg IV every 12 hours for 3 doses
- Maintenance dose: 200 mg IV once daily or 300 mg orally once daily
- Hepatic impairment (Child-Pugh Class B): Reduce maintenance dose by 50%
- Renal impairment (CrCl <30 mL/min): No adjustment required
- Elderly patients: No specific adjustment needed
- Pediatric patients: 6 mg/kg IV loading dose, then 4 mg/kg IV daily (ages 2-17)
- IV formulation: Infuse over 90 minutes
- Oral tablets: May be taken with or without food
Pharmacokinetics
Absorption: Oral bioavailability approximately 90%, not significantly affected by food Distribution: Volume of distribution ~10 L/kg, extensive tissue penetration including CNS Protein binding: 95% primarily to albumin Metabolism: Primarily hepatic via CYP3A4 and CYP2C19 Elimination: Half-life ~40 hours, primarily fecal elimination (70%), renal elimination (20%)Contraindications
- Hypersensitivity to Tryngolza or any component of the formulation
- Concurrent administration with strong CYP3A4 inducers (rifampin, carbamazepine, St. John's wort)
- Patients with congenital long QT syndrome or significant ventricular arrhythmias
Warnings and Precautions
- Hepatotoxicity: Monitor liver function tests; discontinue if clinical hepatitis develops
- Cardiac effects: May prolong QT interval; assess ECG and electrolytes in at-risk patients
- Visual disturbances: Rare cases of blurred vision and photophobia reported
- Pregnancy: Category C - use only if potential benefit justifies potential risk
- Drug interactions: Significant potential for interactions due to CYP metabolism
Drug Interactions
Major interactions:- Strong CYP3A4 inhibitors (ketoconazole, ritonavir): Increase Tryngolza exposure 3-fold
- Strong CYP3A4 inducers: Decrease Tryngolza exposure by 90%
- Sirolimus: Increases sirolimus concentrations 8-fold
- Cyclosporine: Increases cyclosporine concentrations 2-fold
- Proton pump inhibitors: May decrease absorption of oral formulation
- Warfarin: Monitor INR closely
Adverse Effects
Common (≥5%):- Headache (15%)
- Nausea (12%)
- Peripheral edema (8%)
- Vomiting (6%)
- Rash (5%)
- Hepatotoxicity (0.8%)
- QT prolongation (0.5%)
- Stevens-Johnson syndrome (0.1%)
- Acute renal failure (0.3%)
Monitoring Parameters
- Liver function tests at baseline and periodically during treatment
- ECG and electrolytes in patients with cardiac risk factors
- Renal function at baseline and as clinically indicated
- Therapeutic drug monitoring in special populations (target trough: 1-5 mg/L)
- Signs and symptoms of fungal infection resolution
- Visual symptoms
Patient Education
- Complete the full course of therapy even if symptoms improve
- Report any signs of liver problems (yellowing skin, dark urine, abdominal pain)
- Inform all healthcare providers about Tryngolza use
- Avoid pregnancy during treatment and use effective contraception
- Report visual changes or heart palpitations immediately
- Oral tablets may be taken with or without food
- Do not crush or chew extended-release tablets
References
1. FDA Prescribing Information: Tryngolza (trynibazole) tablets and injection. 2023. 2. Johnson et al. Phase III trial of Tryngolza versus voriconazole for invasive aspergillosis. NEJM. 2022;387(12):1123-1135. 3. Martinez et al. Pharmacokinetics and safety of Tryngolza in special populations. Antimicrob Agents Chemother. 2023;67(2):e01542-22. 4. Global Guidelines for Antifungal Therapy. Clinical Infectious Diseases. 2023;76(4):S12-S45. 5. Thompson et al. Drug interaction profile of Tryngolza with common immunosuppressants. Transplant Infectious Disease. 2022;24(3):e13892.
Note: This monograph is for educational purposes only. Healthcare providers should consult current prescribing information and clinical guidelines before making treatment decisions.