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General Description:

Lonafarnib, identified by CAS number 193275-84-2, is a notable compound with significant therapeutic applications. Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant disorder estimated to affect approximately one in 20 million individuals resulting in adverse symptoms associated with premature ageing: skeletal dysplasia, joint contractures, atherosclerosis, myocardial fibrosis/dysfunction, scleroderma-like cutaneous effects, lipoatrophy, alopecia, and a severe failure to thrive; HGPS is uniformly fatal. Mechanistically, HGPS is underpinned by a single heterozygous C-to-T mutation at position 1824 of the _LMNA_ gene, which results in the accumulation of an aberrant farnesylated form of lamin A called progerin in the inner nuclear membrane. Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), which reduces the farnesylation of numerous cellular proteins, including progerin; as progerin farnesylation is important for localization to the nuclear membrane, lonafarnib inhibits progerin accumulation and improves symptoms in HGPS patients. Merck originally developed Lonafarnib and subsequently licensed it to Eiger Biopharmaceuticals Inc, which currently markets it under the trademark ZOKINVY™. Lonafarnib was granted FDA approval on November 20, 2020, and is the first FDA-approved treatment for HGPS and other related progeroid laminopathies.

Indications:

This drug is primarily indicated for: Lonafarnib is a farnesyltransferase inhibitor indicated in patients aged 12 months and older with a body surface area of at least 0.39 m² to reduce the risk of mortality associated with Hutchinson-Gilford progeria syndrome (HGPS). It is also indicated in this same population for the treatment of processing-deficient progeroid laminopathies that either involve a heterozygous _LMNA_ mutation resulting in the accumulation of a progerin-like protein or homozygous/compound heterozygous mutations in _ZMPSTE24_. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Lonafarnib undergoes metabolic processing primarily in: Lonafarnib is metabolized _in vitro_ primarily by CYP3A4/5 and partially by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1. Formation of the primary metabolites involves oxidation and subsequent dehydration in the pendant piperidine ring. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Lonafarnib are crucial for its therapeutic efficacy: The absolute oral bioavailability of lonafarnib is unknown; in healthy subjects administration of either 75 or 100 mg of lonafarnib twice daily resulted in mean peak plasma concentrations (%CV) of 834 (32%) and 964 (32%) ng/mL, respectively. Twice daily administration of 115 mg/m² lonafarnib in HGPS patients resulted in a median t_max of 2 hours (range 0-6), mean C_max of 1777 ± 1083 ng/mL, mean AUC_0-8hr of 9869 ± 6327 ng\*hr/mL, and a mean AUC_tau of 12365 ± 9135 ng\*hr/mL. The corresponding values for a dose of 150 mg/m² are: 4 hours (range 0-12), 2695 ± 1090 ng/mL, 16020 ± 4978 ng\*hr/mL, and 19539 ± 6434 ng\*hr/mL, respectively. Following a single oral dose of 75 mg in healthy subjects, the C_max of lonafarnib decreased by 55% and 25%, and the AUC decreased by 29% and 21% for a high/low-fat meal compared to fasted conditions. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Lonafarnib is an important consideration for its dosing schedule: Lonafarnib has a mean half-life of approximately 4-6 hours following oral administration of 100 mg twice daily in healthy subjects. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Lonafarnib exhibits a strong affinity for binding with plasma proteins: Lonafarnib exhibits _in vitro_ plasma protein binding of ≥99% over a concentration range of 0.5-40.0 μg/mL. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Lonafarnib from the body primarily occurs through: Up to 240 hours following oral administration of 104 mg -lonafarnib in fasted healthy subjects, approximately 62% and <1% of the initial radiolabeled dose was recovered in feces and urine, respectively. The two most prevalent metabolites were the active HM21 and HM17, which account for 14% and 15% of plasma radioactivity. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Lonafarnib is distributed throughout the body with a volume of distribution of: In healthy patients administered either 75 or 100 mg lonafarnib twice daily, the steady-state apparent volumes of distribution were 97.4 L and 87.8 L, respectively. This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Lonafarnib exerts its therapeutic effects through: Lonafarnib is a direct farnesyl transferase inhibitor that reduces the farnesylation of numerous cellular proteins, including progerin, the aberrantly truncated form of lamin A that accumulates in progeroid laminopathies such as Hutchinson-Gilford progeria syndrome. Treatment with lonafarnib has been associated with electrolyte abnormalities, myelosuppression, and increased liver enzyme levels (AST/ALT), although causation remains unclear. Also, lonafarnib is known to cause nephrotoxicity in rats and rod-dependent low-light vision decline in monkeys at plasma levels similar to those achieved under recommended dosing guidelines in humans; patients taking lonafarnib should undergo regular monitoring for both renal and ophthalmological function. In addition, based on observations from animal studies with rats, monkeys, and rabbits with plasma drug concentrations approximately equal to those attained in humans, lonafarnib may cause both male and female fertility impairment and embryo-fetal toxicity. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Lonafarnib functions by: Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant disorder estimated to affect approximately one in 20 million individuals resulting in premature ageing, associated cardiovascular, cerebrovascular, and musculoskeletal effects and early death around 14 years of age. The _LMNA_ gene encodes lamin A and lamin C, two proteins involved in nuclear integrity and function at the inner nuclear membrane. Under normal conditions, the 12-exon _LMNA_ gene produces full-length prelamin A, which undergoes farnesylation of the C-terminal _CaaX_ motif, followed by proteolytic cleavage of the terminal three amino acids (_aaX_) by the metalloproteinase ZMPSTE24, subsequent carboxymethylation, and finally removal of the last 15 amino acids to yield mature, unfarnesylated, lamin A protein. In HGPS, a single heterozygous C-to-T mutation at position 1824 results in a cryptic splice site that removes the last 150 nucleotides of exon 11 and a concomitant 50-amino acid deletion in the C-terminus of the prelamin A protein. This aberrant prelamin A protein, often called progerin, is permanently farnesylated but unable to complete maturation due to the removal of the second endoproteolytic cleavage site. Although the exact mechanism is unclear, progerin accumulation results in a host of adverse symptoms associated with ageing such as skeletal dysplasia, joint contractures, atherosclerosis, myocardial fibrosis/dysfunction, scleroderma-like cutaneous effects, lipoatrophy, alopecia, and a severe failure to thrive. An additional notable effect of HGPS is increased vascular and peripheral calcification. Children affected by HGPS typically die due to myocardial infarction or stroke. Mechanistic understanding of HGPS remains unclear, although a recent study correlated progerin accumulation, telomere dysfunction, DNA damage-mediated inflammatory cytokine release, and HGPS symptoms, suggesting that the nuclear effects of progerin accumulation may result in pleiotropic downstream effects. Lonafarnib is a farnesyl transferase (FTase) inhibitor (FTI), with a reported IC₅₀ value of 1.9 nM; lonafarnib is specific for FTase, as it does not appreciably inhibit the related GGPT-1 enzyme at concentrations up to 50 μM. Inhibition of progerin farnesylation reduces progerin accumulation in the inner nuclear membrane, which subsequently slows the progression of HGPS and other progeroid laminopathies. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Lonafarnib belongs to the class of organic compounds known as benzocycloheptapyridines. These are aromatic compounds containing a benzene ring and a pyridine ring fused to a seven membered carbocycle, classified under the direct parent group Benzocycloheptapyridines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Benzocycloheptapyridines class, specifically within the None subclass.

Categories:

Lonafarnib is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, BCRP/ABCG2 Inhibitors, Cytochrome P-450 CYP1A2 Substrates, Cytochrome P-450 CYP2A6 Substrates, Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 inhibitors (strength unknown), Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (strength unknown), Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP2E1 Substrates, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (strong), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A5 Inhibitors, Cytochrome P-450 CYP3A5 Inhibitors (strong), Cytochrome P-450 CYP3A5 Substrates, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Enzyme Inhibitors, Farnesyltransferase Inhibitor, Farnesyltransferase Inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, Organic Anion Transporting Polypeptide 1B1 Inhibitors, Organic Anion Transporting Polypeptide 1B3 Inhibitors, P-glycoprotein inhibitors, P-glycoprotein substrates, Various Alimentary Tract and Metabolism Products. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Lonafarnib include:

• Water Solubility: ~3mg/ml