Generic Name

Votrient (MK‑8776)

Mechanism

• Selective ATP‑competitive inhibitor of *AKT1, AKT2, and AKT3* isoforms.
• Blocks phosphorylation of downstream substrates such as mTOR, FOXO, and BAD, interrupting cell‑survival, proliferation, and metabolism pathways.
• Different from PI3K inhibitors: Votrient targets the serine/threonine kinase domain downstream of PI3K, offering a distinct therapeutic profile.

Pharmacokinetics

• Routes: Oral.
• Absorption: Rapid, peak plasma concentrations within 2–4 h post‑dose.
• Metabolism: Primarily by CYP3A4 and CYP2C19; minor contribution from *UGT1A1*.
• Elimination: Predominantly biliary; fecal excretion >80 %.
• Half‑life: ~10–12 h (steady‑state achieved after 4–5 days).
• Drug interactions: Strong CYP3A4 inhibitors/inducers alter exposure; caution with concurrent agents metabolized by CYP3A4.

Indications

• Phase I/II: Selected adult patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or other refractory hematologic malignancies where AKT pathway aberrations are documented.
• Solid tumors: Investigational in NSCLC, breast, and pancreatic cancers with evidence of AKT activation.

> Note: Votrient is not yet FDA‑approved; use is restricted to clinical trials or compassionate use.

Contraindications

• Contraindications
• Known hypersensitivity to Votrient or its excipients.
• Warnings
• Hepatotoxicity: Elevated ALT/AST may occur (≥3× ULN). Monitor LFTs every 2–4 weeks.
• Hyperglycemia/Diabetes: AKT inhibition can impair insulin signaling; screen fasting glucose.
• QT prolongation: Minimal data; monitor ECG if on QT‑extending drugs.
• Pregnancy: Potential teratogenicity; contraindicated.
• Renal impairment: Limited data; consider dose adjustment.

Dosing

• Typical regimen:
• Adults: 200 mg PO once daily on a 21‑day cycle (days 1‑21).
• Pediatric: 1 mg/kg PO (infants/children).
• Adjustments
• Hepatic impairment: Reduce dose by 50 % if Child‑Pugh B or C.
• Renal impairment: No routine adjustment; monitor for toxicity.
• Special instructions
• Take on an empty stomach or with food; absorption is minimally affected.
• Avoid concomitant strong CYP3A4 inhibitors (e.g., ketoconazole) unless dose is reduced.

Adverse Effects

• Common (>20 %)
• Nausea, vomiting, diarrhea.
• Fatigue, anorexia.
• Elevated liver enzymes (ALT, AST).
• Less common (5–20 %)
• Hypomagnesemia, electrolyte shifts.
• Hyperglycemia.
• Skin rash.
• Serious (≤5 %)
• Hepatic failure, severe hyperglycemia requiring insulin, QT prolongation.
• Severe allergic reactions (anaphylaxis).
• Laboratory abnormalities
• Transient neutropenia or thrombocytopenia in a minority of patients.

Monitoring

• Baseline: CBC, CMP (including ALT/AST, bilirubin), fasting glucose, electrolytes, and ECG if indicated.
• During therapy
• LFTs every 2–4 weeks; discontinue if ≥3× ULN.
• Fasting glucose twice monthly.
• CBC biweekly in first 2 cycles, then monthly.
• ECG every 3 cycles if on QT‑extending agents.

Clinical Pearls

• AKT signaling is central to metabolic regulation – expect hyperglycemia and consider pre‑existing diabetes as a risk factor.
• Liver function monitoring is critical; a sudden rise in ALT/AST can precede clinical hepatitis.
• Drug interactions via CYP3A4: Even weak CYP3A4 inducers (e.g., rifampin) may lower Votrient exposure; consider monitoring therapeutic levels in high‑risk situations.
• Patient selection: Prioritize patients with documented AKT pathway activation (e.g., PIK3CA or PTEN mutations) to maximize benefit.
• Combination strategy: Early data hint Votrient may synergize with BCL‑2 inhibitors (venetoclax) in AML; watch for additive neutropenia.
• Metabolism in children: Children metabolize via more robust CYP3A4; dose adjustments may differ from adults; parametric scaling is warranted in pediatric protocols.

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• *For the most current evidence and dosing guidelines, always refer to the latest *Phase* clinical trial reports and drug labeling updates.*