Lonafarnib
Mechanism :
Lonafarnib is an inhibitor of farnesyltransferase enzyme. Mutation in the LMNA gene results in excess production of progerin protein which then is acted upon by farnesylesterase following which it accumulates in the nuclear membrane. This accumulation makes the nucleus unstable which is a key step in the premature aging process in children with progeria syndromes.
Indication :
- Hutchinson Gilford Progeria Syndrome: For patients with age >12 months and body surface area >0.39m2
- Progeroid Laminopathies: For processing-deficient progeoird laminopathies in patients >12 months with body surface area >0.39m2.
Contraindications :
• Midazolam
• Lovastatin, Simvastatin, Atorvastatin
• Strong or moderate CYP3A4 inhibitors or inducers
Dosing :
Available as capsules of 50 mg, 75 mg.
Starting dose of 115mg/m2 PO twice a day with meals in the morning and evening.
This is increased after 4 months to 150 mg/m2 PO twice a day.
Adverse Effect :
• Decrease in appetite
• URTI
• Rise in liver enzymes
• Electrolyte abnormalities
• Musculoskeletal pain
• Abdominal pain
• Decrease in blood bicarbonate
• Rise in blood pressure
• Cough
• Nausea, vomiting, diarrhea
• Myelosuppression
• Epistaxis
• Rhinitis
• Ocular changes
• Rash
• Cerebral ischaemia
• Pruiritus
• Dehydration
• Depressed mood
• Ftigue
• Infection
Interaction :
• CYP3A4: Lonafarnib is a sensitive substrate of CYP3A4 as well as a strong inhibitor of CYP3A4.
• CYP3A4 inducers and inhibitors: Contraindicated
• CYP3A4 substrates:
o HMG CoA Reductase Inhibitors: contraindicated
o Midazolam: Discontinue Lonafarnib for 10-14days prior to administration of Midazolam and 2 days after administration of Midazolam.
o Loperamide: When co-administered, dose of Loperamide should not exceed 1mg per day initially.
o Other substrates: If unavoidable, monitor for adverse reactions
• CYP2C9 Inhibitors: Lonafarnib is a CYP2C9 substrate
o Coadministration may increase Lonafarnib peak concentration thus avoid.
o If unavoidable, monitor for arrhythmias, syncope, palpitations.
• CYP2C19 substrates: Lonafarnib may increase the peak concentration of these drugs, thus avoid coadministration.
• P-gp substrates: Lonafanib is a weak inhibitor of P-gp
o If coadministered with P-gp substrates such as Digoxin, Dabigatran, monitor for adverse reactions.
Hepatic Dose :
No specific guidelines available yet