Difelikefalin
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FDA-approved peripherally restricted kappa-opioid receptor agonist tetrapeptide for CKD-associated pruritus; achieves opioid-mediated benefit without CNS side effects or addiction.
Quick Facts
| Property | Value |
|---|---|
| Also Known As | Korsuva, CR845, MR13A9 |
| Category | Analgesic / Antipruritic (peripheral opioid) |
| Sequence | Synthetic D-amino acid-containing tetrapeptide (D-Phe-D-Phe-D-Leu-D-Lys-[w-PEG₃-COOH]) |
| Molecular Weight | ~579 Da (free base) |
| Molecular Formula | C₃₆H₅₃N₅O₈ |
| PubChem CID | 71587530 |
| Administration | IV (for hemodialysis patients); oral formulation in development |
| Typical Dose Range | 0.5 mcg/kg IV at end of each hemodialysis session (3x/week) |
| Half-Life | ~23-31 hours (terminal) |
| Storage | Room temperature (20-25 C); protect from light |
| FDA Status | FDA Approved (2021) — CKD-associated pruritus in hemodialysis patients (Korsuva, Vifor/CSL Vifor) |
| WADA Status | Not listed |
Mechanism of Action
Difelikefalin is a synthetic tetrapeptide designed as a selective agonist of the kappa-opioid receptor (KOR) that is intentionally restricted to peripheral tissues. Its critical design feature is the incorporation of D-amino acids throughout the peptide backbone, combined with a PEG₃ linker at the C-terminus, creating a molecule that is (1) resistant to peptidase degradation, (2) too hydrophilic and structurally restricted to cross the blood-brain barrier (BBB), and (3) selectively active at peripheral KOR.
Peripheral kappa-opioid receptors are expressed on sensory neurons, immune cells (mast cells, T cells, macrophages), and keratinocytes. In CKD-associated pruritus (CKD-aP), uremic toxins trigger immune dysregulation and neurogenic inflammation that activates itch-transmitting C-fibers. Difelikefalin's activation of peripheral KOR on these cells produces antipruritic and anti-inflammatory effects via several mechanisms:
- Inhibition of pruritogenic signaling — KOR activation on sensory neurons suppresses neuronal excitability and neuropeptide release
- Anti-inflammatory modulation — KOR activation on immune cells reduces pro-inflammatory cytokine release and mast cell degranulation
- Counter-regulation of mu-opioid itch — Peripheral KOR agonism counterbalances the pruritogenic effects of endogenous mu-opioid receptor activation
Because difelikefalin does NOT cross the BBB, it avoids the CNS-mediated side effects of centrally-acting kappa-opioid agonists (dysphoria, sedation, hallucinations) and centrally-acting mu-opioid agonists (euphoria, respiratory depression, addiction). This "peripherally restricted" design represents a paradigm innovation in opioid pharmacology (PMID-31702883).
Key Research Areas
- CKD-associated pruritus — KALM-1 and KALM-2 Phase III trials demonstrated significant itch reduction vs placebo (PMID-31702883, PMID-32405581)
- Peripheral opioid pharmacology — Proof-of-concept for BBB-impermeable opioid agonist design (PMID-36015082)
- Non-addictive opioid therapeutics — No physical dependence, withdrawal, or abuse potential demonstrated
- Oral formulation development — Ongoing trials for non-dialysis CKD-aP and other pruritic conditions
- Peripheral pain modulation — Potential expansion to chronic pain conditions (post-operative, neuropathic)
Evidence Level Summary
| Evidence Type | Count | Notes |
|---|---|---|
| Human RCTs | 4+ | KALM-1, KALM-2, Phase II dose-finding |
| Systematic reviews | 1 | CKD-aP systematic review |
| Human observational | Several | Open-label extension (up to 52 weeks), real-world data |
| Animal in vivo | Several | Preclinical pruritus and pain models |
| In vitro | Several | KOR selectivity and BBB permeability studies |
Clinical Applications
- Chronic kidney disease-associated pruritus — Primary FDA-approved indication
Protocols Using This Peptide
Difelikefalin is administered in hemodialysis centers under medical supervision. It is not used in outpatient peptide protocols.
Ageless Peps Products
Difelikefalin is an FDA-approved prescription medication (Korsuva) and is NOT sold by Ageless Peps. It is included in this vault for educational reference on peripheral opioid receptor pharmacology and peptide design principles.
Dosing Reference
FDA-Approved Dosing
| Route | Dose | Frequency | Duration | Source |
|---|---|---|---|---|
| IV bolus | 0.5 mcg/kg dry body weight | 3x/week at end of hemodialysis | Chronic (ongoing while on HD) | FDA label |
Cycling
Not applicable — administered at each hemodialysis session. Onset of antipruritic effect within 1 week; sustained with continued use. No tolerance observed in clinical trials up to 52 weeks.
Contraindications & Safety
- Contraindications: None listed in FDA label
- Common side effects: Diarrhea (9%), dizziness (6%), nausea (5%), headache, hyperkalemia (from HD patients)
- Serious adverse events: Rare; no CNS opioid effects (no euphoria, sedation, respiratory depression, or dependence)
- Drug interactions: Limited systemic drug interactions; caution with other CNS depressants (theoretical)
- Pregnancy/nursing: Limited data; use only if benefit justifies risk
- Special populations: Dose is weight-based; no adjustment for hepatic impairment; designed for HD patients
Synergistic Combinations
As a prescription medication for hemodialysis patients, difelikefalin is used as monotherapy for pruritus. Its mechanism is complementary to:
- Antihistamines — Different pruritogenic pathways
- Gabapentin/pregabalin — Central vs peripheral anti-itch mechanisms
Related Research
| PMID | Title | Year | Study Type |
|---|---|---|---|
| 31702883 | KALM-1: Phase 3 Trial in HD Pruritus (NEJM) | 2020 | RCT |
| 32405581 | KALM-2: Confirmatory Phase 3 Trial | 2020 | RCT |
| 36015082 | Difelikefalin CKD-aP Systematic Review | 2022 | Systematic Review |
References
- PMID-31702883 — Fishbane et al., KALM-1 Phase 3, NEJM 2020
- PMID-32405581 — Fishbane et al., KALM-2, JASN 2020
- PMID-36015082 — Topf et al., Systematic review, Dermatol Ther 2022
Related
FDA Disclaimer: Difelikefalin (Korsuva) is an FDA-approved prescription medication. This vault entry is for educational and research reference only.
#peptide #fda-approved #not-sold #iv #peripheral-opioid