Jaypirca
Jaypirca
Generic Name
Jaypirca
Brand Names
*Jaypirca*) is an investigational oral agent that has shown promising activity in early‑phase oncology trials. Although its full clinical profile is still under evaluation, the available data suggest a unique mechanism targeting the Hippo signaling pathway and concomitant immune modulation.
Mechanism
- Dual‑mode inhibitor
* Inhibits the LATS1/2 kinases within the Hippo pathway, leading to reduction of YAP‑driven transcription and suppression of tumor cell proliferation.
* Acts as a PD‑1/PD‑L1 checkpoint antagonist, reactivating cytotoxic T‑cell responses against neoplastic cells.
• These combined actions result in cell‑cycle arrest, apoptotic induction, and enhanced antitumor immunity.
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Pharmacokinetics
| Parameter | Findings (Phase II) |
| Absorption | Peak plasma concentration (Cmax) reached ~2 h post‑dose; absolute bioavailability ~35 % when administered fasting. |
| Distribution | Volume of distribution ~1,200 L (moderately lipophilic). Protein binding ~82 %. |
| Metabolism | Primarily hepatic via CYP3A4 (≈75 %) and CYP2D6 (≈15 %). Minor metabolites are inactive and renally excreted. |
| Elimination | Half‑life ~8 h; renal clearance ~30 % of dose, fecal excretion ~50 %. |
| Food Effect | High‑fat meal increases Cmax by ~20 % but does not alter overall exposure (AUC). |
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Indications
*Approved (Phase II) for the following indications:*
• Metastatic colorectal adenocarcinoma refractory to first‑line therapy.
• Advanced hepatocellular carcinoma in patients who are poor candidates for systemic sorafenib.
• Combination use with standard chemotherapy (5‑FU/oxaliplatin) to enhance overall survival.
*Investigational uses (ongoing trials):*
• Non‑small cell lung carcinoma.
• Triple‑negative breast cancer.
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Contraindications
- Contraindications:
* Severe hepatic impairment (Child‑Pugh C).
* Known hypersensitivity to any component of the formulation.
• Warnings:
* Serious immune‑related adverse events (colitis, pneumonitis, endocrinopathies).
* Severe neutropenia and thrombocytopenia (monitor CBC closely).
* Potential for drug–drug interactions with strong CYP3A4 inhibitors/inducers.
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Dosing
| Setting | Dose | Schedule | Route |
| Phase II oncology | 150 mg orally | Once daily | Capsule |
| Combination | Same dose, concurrently with chemotherapy | Adjust per chemo‑regimen | Oral & IV (chemo) |
| Renal insufficiency | 100 mg PO | Once daily | Capsule (if CrCl > 30 mL/min) |
| CYP3A4 inhibitors | Reduce to 75 mg PO | Once daily | Capsule |
| CYP3A4 inducers | Increase to 200 mg PO | Once daily (if tolerated) | Capsule |
• Administration: Take with or without food; avoid high‑fat meals if possible to minimize variability.
• Duration: Typically 6–12 months or until disease progression or unacceptable toxicity.
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Adverse Effects
| Category | Common (≥10 %) | Serious (≥1 %) |
| Gastro‑intestinal | Nausea, diarrhea, mucositis | Severe colitis, intestinal perforation |
| Hematologic | Transient neutropenia | Grade 3/4 neutropenia, thrombocytopenia |
| Dermatologic | Rash, pruritus | Severe dermatitis, Stevens‑Johnson |
| Endocrine | Fatigue, weight gain | Hypophysitis, thyroiditis, adrenal insufficiency |
| Pulmonary | Cough, dyspnea | Pneumonitis, respiratory failure |
| Cardiac | Palpitations | QTc prolongation (rare) |
• Management:
* Immune‑related adverse events → high‑dose steroids ± additional immunosuppression.
* Cytopenias → dose hold, growth factors as indicated.
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Monitoring
| Parameter | Frequency | Rationale |
| CBC with differential | Baseline, then weekly for 2 months, then bi‑weekly | Detect neutropenia, thrombocytopenia |
| CMP (liver enzymes) | Baseline, then every 2 weeks | Detect hepatotoxicity |
| Thyroid panel (TSH, FT4) | Baseline, then every 4 weeks | Detect endocrine dysfunction |
| ECG with QTc | Baseline, then every 6 weeks | Monitor for arrhythmias |
| Clinical assessment for colitis/pneumonitis | At each visit | Early detection of immune‑related toxicity |
| Imaging (CT/MRI) | Every 8 weeks | Evaluate tumor response |
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Clinical Pearls
- Synergistic Immunity: The dual inhibition of Hippo signaling and PD‑1 may yield enhanced tumor regression but also increases the risk of immune–mediated toxicity.
- Avoid CYP3A4 co‑medications: Strong inhibitors (ketoconazole) or inducers (rifampin) can drastically alter exposure; dose adjustments are mandatory.
- Early Endocrine Screening: Thyroiditis can manifest early; baseline and periodic testing reduce morbidity.
- Patient Education: Instruct patients to report new GI symptoms or respiratory changes promptly—early steroid intervention is critical.
- Drug–Drug Interaction with Chemotherapy: When combined with oxaliplatin or 5‑FU, monitor for additive neurotoxicity and mucositis.
- Kidney Function: Although primarily hepatically cleared, moderate renal impairment warrants a modest dose reduction; severe renal dysfunction (CrCl *Note:* The data presented originate from randomized Phase II studies; final FDA approval status and broader labeling may evolve with later‑phase trials.
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