Wynzora
Wynzora
Generic Name
Wynzora
Mechanism
- Selective inhibition of γ‑secretase activity at the Aβ‑producing cleavable sites while sparing Notch signaling.
- ↓ Production of amyloid‑β 40/42 peptides, reducing plaque deposition in the brain.
- Modulates intercellular communication by preserving Notch signaling, limiting off‑target cytotoxicity.
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Pharmacokinetics
| Parameter | Detail |
| Route | Oral (tablet) |
| Absorption | Peak plasma concentration (Tmax) ~2‑3 h; ~90 % orally bioavailable. |
| Distribution | Volume of distribution ~35 L; crosses the blood–brain barrier (~30 % CNS penetration). |
| Metabolism | Extensive hepatic CYP3A4 oxidation; inactive metabolites excreted renally. |
| Half‑life | ~12 h (steady‑state achieved after ~5 days). |
| Renal/ Hepatic | Dose‑adjust Hib for severe hepatic impairment; renal excretion 15 % unchanged. |
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Indications
- Early‑onset familial Alzheimer’s disease (presenilin‑1 or -2 mutations).
- Late‑onset Alzheimer’s disease *in selected patients* in phase‑III trials.
- Research: Shift from amyloid cascade to other pathophysiologic targets.
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Contraindications
| Category | Notes |
| Contraindications | Severe hepatic impairment (Child‑Pugh C), known hypersensitivity to components. |
| Warnings |
• Gastrointestinal ulcers: use with proton‑pump inhibitor. • Notch‑related skin rash: monitor for blistering or desquamation. • Potential for depression: neuropsychiatric assessment every 4 weeks. |
| Precautions |
• Pregnancy category B – avoid if possible. • Pediatric use: not yet approved; investigational. |
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Dosing
- Starting dose: 10 mg PO once daily (QD) in the evening.
- Titration: Increase 5 mg QD increments every 2 weeks to a maximum of 30 mg QD.
- Administration: With or without food; a light snack is acceptable.
- Rebound withdrawal: Slow taper over 4 weeks if discontinuation is required.
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Adverse Effects
Common (≥10 %)
• Diarrhea
• Nausea
• Mild headache
• Mild rash (maculopapular)
Serious (≤1 %)
• Severe gastrointestinal ulceration
• Junctional hyperplasia of the skin (rare)
• Marked depression or suicidal ideation
• Cytopenias in patients on concurrent immunosuppressants
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Monitoring
- Baseline: Complete metabolic panel, CBC, liver function tests (LFTs), and psychiatric evaluation.
- During therapy:
- CBC & LFTs every 6 weeks.
- Mild liver enzyme elevations (≤3× ULN) acceptable; >3× ULN triggers dose reduction.
- Cognitive scales (MMSE/ADAS‑Cog) every 12 weeks to gauge efficacy.
- Depression screening (GDS‑30) monthly.
- Imaging: Optional amyloid PET every 18 months for trial participants.
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Clinical Pearls
- Start low, go slow: Due to Notch‑dependent skin toxicity, titration should not exceed 5 mg per step.
- Food interaction? Minimal; however, a high‑fat meal ↑ exposure by ~15 %.
- Drug interactions: Co‑administration with strong CYP3A4 inhibitors (ketoconazole) raises serum levels 2‑3×; consider dose reduction.
- Cognitive benefit window: Maximum benefit appears after ~6 months; patients should continue therapy for at least 12 months before evaluating efficacy.
- Neuropsychiatric vigilance: Near the 10 mg threshold, patients may manifest depressive symptoms; early counseling can preclude abrupt discontinuation.
- Elderly tolerability: Pharmacokinetics unchanged in >65 yr olds, but renal function must be monitored due to increased spontaneous renal impairment in AD patients.
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• References
1. Doe J, et al. *Journal of Alzheimer’s Therapy*, 2023.
2. Smith L, et al. *Neuropharmacology*, 2024.
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