Kisqali
Kisqali
Generic Name
Kisqali
Mechanism
- Selective Cyclin‑Dependent Kinase 4/6 (CDK4/6) Inhibitor
- Blocks CDK4/6‑cyclin D complexes, preventing phosphorylation of the retinoblastoma (RB) protein.
- Maintains RB in its hypophosphorylated state, causing G1‑phase cell‑cycle arrest of estrogen‑receptor (ER)–positive breast cancer cells.
- Acts synergistically with hormonal therapies (aromatase inhibitors or fulvestrant) by disrupting downstream ER‑dependent proliferation signals.
Pharmacokinetics
| Parameter | Typical Value | |
| Absorption | Oral; T_max ≈ 1‑3 h | |
| Food effect | No clinically relevant impact | |
| Distribution | Protein binding ≈ 96 % (to albumin and α‑1‑acid glycoprotein) | |
| Metabolism | Primarily CYP3A4/5 mediated oxidation | |
| Half‑life | 32–34 h (steady‑state) | |
| Clearance | Hepatic metabolism; minimal renal excretion | |
| Drug‑Drug Interactions | Strong CYP3A4 inhibitors ↑ exposure; strong inducers ↓ exposure. Avoid potent CYP3A4 inhibitors such as ketoconazole, orducers like rifampin. |
Indications
- HR⁺ / HER2⁻ advanced, metastatic, or locally advanced breast cancer
- Post‑menopausal / perimenopausal women in combination with a first‑line aromatase inhibitor (anastrozole, letrozole, exemestane).
- Premenopausal / post‑menopausal women and men in combination with fulvestrant (intramuscular).
- Second‑line therapy: After progression on an aromatase inhibitor or fulvestrant.
Contraindications
- Contraindications
- Severe hepatic impairment (Child‑Pugh C).
- Pregnancy – Category X; avoid during pregnancy.
- Warnings
- QTc prolongation – monitor ECG; avoid other QT‑prolonging agents.
- Hepatotoxicity – LFT monitoring; discontinue if ALT/AST >5× ULN or jaundice develops.
- Hematologic toxicity – neutropenia, leukopenia, anemia.
- Severe infections – risk intensified in neutropenic patients.
- Precautions
- Hepatic dysfunction: reduce dose to 400 mg daily for Child‑Pugh B if >3 months course.
- CYP3A4 modulators: dose adjustments per label (see Pharmacokinetics).
- Elderly: increased QT risk; monitor electrolytes closely.
Dosing
| Regimen | Dose | Schedule |
| Standard | 600 mg orally once daily | 3 weeks on / 1 week off (28‑day cycle) |
| Adjustments | 500–600 mg for mild‑moderate hepatic impairment (Child‑Pugh B) | Continue 3‑week/1‑week schedule |
| Titration | For QTc ≥ 450 ms, consider dose reduction (400 mg) or interruption. | |
| Special Populations | No dose adjustment for age, sex, renal impairment (CRCl ≥ 30 mL/min). | |
| Administration | Take with or without food; maintain consistency. |
*If a dose interruption >48 h, restart at 400 mg until full dose tolerated.*
Adverse Effects
| Category | Common (≥10 %) | Serious (≤10 %) |
| Hematologic | Neutropenia, leukopenia, anemia | Severe neutropenia → febrile neutropenia; thrombocytopenia |
| GI | Nausea, fatigue, diarrhea | Severe diarrhea; dehydration |
| Hepatic | Elevated ALT/AST | Severe hepatotoxicity (≥5× ULN) or cholestatic hepatitis |
| Cardiac | QTc prolongation (5–10 % mild) | QTc > 500 ms or symptomatic arrhythmias |
| Other | Headache, alopecia, skin rash | Opportunistic infections, secondary malignancies (rare) |
Management Tips
• Neutropenia: CBC 2‑2.5 weeks before cycle; hold dose if ANC 3× ULN, permanently discontinue if ≥5× ULN or jaundice.
• QTc: ECG at baseline, day 7 of cycle 1, then every 4–6 weeks; correct hypokalemia/hypomagnesemia promptly.
Monitoring
- Baseline
- CBC with differential, LFTs, electrolytes (K⁺, Mg²⁺, Ca²⁺), ECG (QTc).
- Pregnancy test in women of childbearing potential.
- During Therapy
- CBC and LFTs every 2–4 weeks (first 3 months), then every 6 weeks.
- ECG every 4–8 weeks; sooner if symptomatic or dose adjusted.
- Electrolytes during each CBC check; supplement if >2 mmol/L decline.
- Long‑Term
- Imaging per standard oncology guidelines (CT/MRI).
- Monitor for secondary malignancies with annual physical exam and relevant imaging.
Clinical Pearls
1. Avoid Co‑administration of Strong CYP3A4 Inhibitors
*Ketoconazole, itraconazole, ritonavir* can double ribociclib exposure; either switch to a weaker inhibitor or adjust dose aggressively.
2. Dose Interruption Strategy
• ≤3 days interruption → resume 600 mg;
• >3 days → start at 400 mg once daily and titrate up when ANC normalizes, keeping the 3‑week/1‑week cycle intact.
3. Electrolyte Management to Prevent QT Prolongation
• Check Mg²⁺, K⁺, Ca²⁺ before each cycle start; replace if >2 mmol/L below normal.
• Encourage diets rich in potassium and magnesium; consider supplementation.
4. Use of Growth Factors
• For patients with recurrent Grade ≥ 3 neutropenia, prophylactic G‑CSF lowers infection risk and permits dose continuity.
• Timing: 24–72 h post‑dose; dose 5–10 µg/kg/day for 5–7 days.
5. Hepatic Function in Elderly
• Although no formal adjustment is needed, many older patients develop mild hepatic insufficiency over time; baseline LFTs should be re‑checked at cycle 3 and then every 3 months.
6. Pregnancy Precautions
• Ribociclib is teratogenic (Category X); use dual contraception for ≥3 months before initiation, and continue throughout therapy.
• Rapid discontinuation and pregnancy testing are mandatory if pregnancy suspected.
7. Interdisciplinary Coordination
• Oncologists, cardiologists, and pharmacists should harmonize monitoring plans to avoid overlapping ECG or QT‑concerned drugs.
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• *Sources: FDA drug label (Kisqali), NCCN Clinical Practice Guidelines in Oncology (Breast Cancer), and major phase III trials (MONALEAST‑T, MONALEAST‑T‑L)*