Yorvipath
Yorvipath
Generic Name
Yorvipath
Mechanism
- Selective CXCR4 antagonist: Binds the extracellular domain of CXCR4, preventing ligand (CXCL12) activation.
- Down‑regulation of downstream signaling: Blocks PI3K/AKT and MAPK pathways, leading to decreased tumor cell survival and metastasis.
- Immune modulation: Rearranges the tumor microenvironment by displacing myeloid‑derived suppressor cells (MDSCs) and enhancing cytotoxic T‑cell infiltration.
Pharmacokinetics
| Parameter | Value | Notes |
| Absorption | Rapid; peak plasma concentration (Tmax) ≈ 2 h post‑oral dose | Notably reduced in patients on proton‑pump inhibitors (↓ AUC ≈ 15 %) |
| Bioavailability | 60‑70 % | Food increases exposure by ~20 % |
| Distribution | Extensive; Vd ≈ 4.5 L/kg; ~85 % protein‑bound (primarily to albumin) | CNS penetration limited |
| Metabolism | Primarily via CYP3A4 (≈ 65 %) and CYP2D6 (≈ 20 %) | Minor glucuronidation via UGT1A1 |
| Elimination | Renal (55 %) and fecal (30 %) | Half‑life 10–12 h in normal subjects |
| Drug interactions | Strong CYP3A4 inhibitors ↑Yorvipath levels; CYP3A4 inducers ↓levels | Avoid concomitant use of potent inhibitors/inducers |
Indications
- Metastatic pancreatic adenocarcinoma (in combination with gemcitabine‑based chemotherapy).
- Refractory Hodgkin lymphoma (as add‑on to brentuximab vedotin).
- Phase II indications: Chronic graft‑versus‑host disease (GVHD) and systemic sclerosis (experimental).
Contraindications
| Category | Details |
| Contraindications | |
| *Known hypersensitivity* to Yorvipath or any excipients. | |
| Severe hepatic impairment (Child‑Pugh C). | |
| Warnings | |
| *Pregnancy/Lactation*: Animal studies show teratogenicity; category B (use only if benefits outweigh risks). | |
| *QT prolongation*: Rare, monitor ECG in patients with existing QT prolongation or concomitant QT‑prolonging drugs. | |
| *Renal dysfunction*: Dose adjustment required for CrCl < 30 mL/min. |
Dosing
- Metastatic pancreatic cancer – 250 mg PO twice daily (BID).
- Refractory Hodgkin lymphoma – 200 mg PO once daily.
- Dose adjustments:
- CrCl < 30 mL/min: 150 mg BID.
- Hepatic impairment (Child‑Pugh B): 200 mg PO once daily.
- Administration: Take with food to enhance absorption unless contraindicated.
Adverse Effects
- Common (≥ 10 %):
- Nausea, diarrhea, fatigue, mild QT prolongation.
- Serious (≤ 1 %):
- Severe hepatotoxicity (ALT/AST > 5× ULN), fulminant hepatic failure, severe QTc prolongation (> 500 ms).
- Rare (< 0.1 %):
- Hypersensitivity reactions (rash, eosinophilia, anaphylaxis).
Monitoring
- Baseline: CBC, CMP, liver enzymes, electrolytes, ECG.
- Every 4 weeks: CBC (for neutropenia), LFTs, electrolytes.
- QTc: Baseline, 2 h and 6 h post‑dose during titration; repeat if any QTc > 460 ms in females or > 450 ms in males.
- Renal function: At least every 3 months; adjust dose if CrCl declines.
Clinical Pearls
1. Drug–Drug Interaction Check: Because Yorvipath is a CYP3A4 substrate, review for concurrent medications that may inhibit or induce the enzyme—especially macrolides, azoles, and carbamazepine.
2. Food Modulation: A high‑fat meal increases bioavailability by ~20 %; patients on a low‑fat diet can achieve therapeutic levels without dose escalation.
3. Peri‑operative Management: If surgery is planned within 2 weeks of stopping Yorvipath, hold the drug 72 h pre‑op to reduce hepatic strain and monitor CK and liver function post‑operatively.
4. Pediatric Use: Limited data; dosing extrapolated from adult mg/m² body surface area; strict monitoring of liver enzymes.
5. Patient Education: Advise patients to report any signs of liver dysfunction (jaundice, dark urine) and cardiac symptoms (palpitations, syncope) promptly.
---