How Do Farnesyltransferase Inhibitors Work?

Farnesyltransferase inhibitors (FTIs) are a class of drugs used in patients aged one year or older with a body surface area of 0.39 m2 and above to reduce the risk of mortality in Hutchinson-Gilford progeria syndrome (HGPS-a rare, fatal, genetic condition of childhood with striking features resembling premature aging) and for treatment of processing-deficient progeroid laminopathies (characterized by the premature appearance of certain signs of physiological aging in a subset of tissues caused by mutations in genes coding for A-type lamins or lamin-binding proteins) with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations.

HGPS is estimated to affect approximately one in 20 million individuals, resulting in adverse symptoms associated with premature aging. Affected children typically look normal at birth and in early infancy, but then grow more slowly than other children and do not gain weight at the expected rate (failure to thrive). They develop a characteristic facial appearance with symptoms such as:

• Facial appearance-prominent eyes, a thin nose with a beaked tip, thin lips, a small chin, and protruding ears
• Alopecia (hair loss)
• Aged-looking skin
• Joint abnormalities
• Loss of fat under the skin (subcutaneous fat)
• Arteriosclerosis (severe hardening of the arteries that increases the chances of having a heart attack or stroke at a young age)

FTIs are administered orally, typically twice a day.

FTIs work in the following ways:

• HGPS is a result of heterozygous C-to-T mutation of the LMNA gene that results in the accumulation of an aberrant farnesylated form of lamin A called "progerin" (a protein) in the inner nuclear cell membrane.
• FTIs work by reducing the farnesylation of numerous cellular proteins including progerin which inhibits progerin production and accumulation, thus improving the symptoms in patients with HGPS.

FTIs are used in conditions such as:

• HGPS, a rare, fatal, genetic condition of childhood with striking features resembling premature aging)
• Progeroid laminopathies (characterized by the premature appearance of certain signs of physiological aging in a subset of tissues caused by mutations in genes coding for A-type lamins or lamin-binding proteins)

Some of the common side effects include:

• Diarrhea
• Nausea
• Vomiting
• Anorexia (lack or loss of appetite)
• Headache
• Abdominal pain
• Fatigue (overall feeling of tiredness or lack of energy)
• Flatulence (gas)
• Constipation

Other rare side effects include:

• Muscle/joint pain
• Hypertension (high blood pressure)
• Unusual weight loss
• Dizziness (feeling faint, weak, or unsteady)
• Depressed mood
• Pruritis (itching)
• Epistaxis (bleeding from the nose)
• Increased aspartate aminotransferase
• Cough
• Upper respiratory tract infection
• Decreased blood bicarbonate
• Electrolyte abnormalities

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of FTIs include:

• Lonafarnib
• Zokinvy