Agamree
Agamree
Generic Name
Agamree
Mechanism
Agamree is a potent, orally‑available selective antagonist of the serotonin 5‑HT7 receptor.
• By competitively inhibiting 5‑HT7 at the postsynaptic site, it reduces cyclic‑AMP accumulation and downstream protein kinase A signaling.
• The blockade diminishes the serotonergic hyper‑activation that underlies visceral hypersensitivity in irritable bowel syndrome (IBS) and reduces colonic smooth‑muscle tone.
• In preclinical models, Agamree also exhibits weak affinity for the 5‑HT3 receptor, contributing to decreased nausea and vomiting.
> *Clinical implication:* Selectivity for 5‑HT7 allows mitigation of IBS‑related pain without the motor side effects seen with non‑selective serotonergic agents.
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Pharmacokinetics
| Parameter | Details |
| Absorption | Rapid, >80 % bioavailability after a standard 200 mg dose; onset ≈30 min. |
| Distribution | Extensive tissue distribution (Vss ≈ 4 L/kg). Protein binding ~92 % (primarily to albumin). |
| Metabolism | Predominantly CYP3A4‑mediated N‑dealkylation → active metabolite M1 (≈15 % of exposure). Minor CYP2D6 oxidation. |
| Elimination | Renal excretion (~20 % unchanged) and hepatic biliary excretion (~70 %). Mean terminal half‑life 6–8 h. |
| Drug‑Drug Interactions | Co‑administration with strong CYP3A4 inhibitors (ketoconazole) increases Cmax by ~2‑fold; no clinically significant interactions with CYP2D6 inhibitors. |
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Indications
- Irritable Bowel Syndrome – Diarrhea‑predominant (IBS‑D)
*Primary indication* for relief of abdominal pain and stool urgency.
• Irritable Bowel Syndrome – Mixed (IBS‑M)
Added benefit for patients with predominant pain but occasional constipation.
• Functional Dyspepsia (off‑label)
Small‑dose trial use to manage epigastric burning and bloating.
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Contraindications
- Contraindications
- Known hypersensitivity to any component of Agamree.
- Severe hepatic impairment (Child‑Pugh C).
- Warnings
- QT Prolongation: Mild QTc prolongation in high‑dose, but no arrhythmias reported in phase 3 trials. Routine ECG only if concomitant QT‑interfering drugs.
- Pregnancy & Lactation: Category C; animal studies show no teratogenicity, but human data limited. Prefer discontinuation if pregnancy is confirmed.
- Renal Dysfunction: Dose adjustment (dose = 200 mg PO BID) for eGFR <30 mL/min/1.73 m².
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Dosing
| Formulation | Dose | Frequency | Notes |
| 200 mg oral capsule | 200 mg | BID (morning & evening) | Once daily dose increases tolerated but BID remains optimal for steady plasma levels. |
| 400 mg (study) | 400 mg | QD | Not approved; used in clinical trials for short duration (≤4 weeks). |
• Take with or without food; absorption marginally increased (~10 %) when taken with a light meal.
• If a dose is missed, skip and resume routine schedule; do not double‑dose.
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Adverse Effects
Common (≥5 %)
• Nausea
• Diarrhea
• Headache
• Dry mouth
Less Common (1–5 %)
• Dizziness
• Fatigue
• Palpitations (mostly transient)
Serious (≤1 %)
• Severe constipation → paralytic ileus (rare).
• QTc interval >500 ms (monitor only if risk factors).
• Hepatotoxicity (elevated ALT/AST >3× ULN) – discontinued immediately.
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Monitoring
| Parameter | Frequency | Rationale |
| Baseline CBC & LFTs | Pre‑therapy | Detect existing hepatic or hematologic conditions. |
| ECG | Baseline + 4 weeks if on QT‑risk drugs | Screen for QT prolongation. |
| Renal Function (eGFR) | Every 3 months (or sooner if symptomatic) | Adjust dose in CKD. |
| Symptom Diary | Daily | Track abdominal pain, stool pattern, adverse events. |
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Clinical Pearls
- Efficient Pain Control via 5‑HT7 Modulation: Unlike 5‑HT3 antagonists, Agamree does not alter gastrointestinal motility, making it ideal for pain‑dominant IBS patients who can’t tolerate motility drugs.
- Dual Activity: The weak 5‑HT3 antagonism explains the low incidence of nausea, a common objection with pure 5‑HT7 agents.
- Fast Onset: Oral dosing yields pain relief within 30 min—critical for patients requiring rapid symptom control before meals.
- Safe Renal Screening: Because only 20 % is renally cleared unchanged, patients can continue therapy even with mild CKD; however, the active metabolite circulates longer in severe CKD, necessitating caution.
- Avoid Overlap with Tricyclics: Both agents engage serotonergic pathways; concurrent use may amplify serotonergic side‑effects.
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