Zokinvy

Uses

Zokinvy is a potent farnesyl transferase inhibitor used to reduce mortality associated with Hutchinson-Gilford progeria syndrome (HGPS) and other progeroid laminopathies.

Zokinvy 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.

Zokinvy is also used to associated treatment for these conditions: Death, Processing-deficient Progeroid Laminopathies

How Zokinvy works

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.

Zokinvy 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.

Toxicity

Toxicity information regarding lonafarnib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as altered electrolyte, blood cell, and liver enzyme levels, retinal toxicity, nephrotoxicity, fertility impairment, and embryo-fetal toxicity. Symptomatic and supportive measures are recommended.

Food Interaction

• Avoid grapefruit products. Co-administration with strong or moderate CYP3A inhibitors is contraindicated; avoid consuming grapefruit or Seville oranges.
• Take with food. Administration with food is recommended to reduce gastrointestinal adverse reactions. However, co-administration with food does affect lonafarnib absorption.

[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of lonafarnib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Inhibition of hepatic CYP450 3A4 may also contribute.

The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors.

When a single 50 mg oral dose of lonafarnib was administered following pretreatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily for 5 days) in healthy study subjects, lonafarnib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 270% and 425%, respectively, compared to lonafarnib administered alone.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased exposure to lonafarnib may increase the risk and
ADJUST DOSING INTERVAL: Food does not have clinically relevant effects on the oral bioavailability of lonafarnib.

When a single 75 mg oral dose of lonafarnib was administered with a high-fat meal (952 calories; approximately 43% from fat) in healthy subjects, lonafarnib Cmax and AUC decreased by 55% and 29%, respectively, compared to administration under fasted conditions.

When administered with a low-fat meal (421 calories; approximately 12% from fat), lonafarnib Cmax decreased by 25% and AUC decreased by 21% relative to fasting.

However, administration with food may help improve gastrointestinal tolerance to lonafarnib, which may commonly cause nausea, vomiting, diarrhea, and abdominal pain.

MANAGEMENT: Zokinvy should be administered with the morning and evening meals and an adequate amount of water.

Patients should avoid consumption of grapefruit or grapefruit juice and Seville oranges (also known as bitter or sour oranges).during treatment with lonafarnib.

Zokinvy Disease Interaction

Moderate: hepatic dysfunction, nephrotoxicity

Volume of Distribution

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.

Elimination Route

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.

Half Life

Zokinvy has a mean half-life of approximately 4-6 hours following oral administration of 100 mg twice daily in healthy subjects.

Elimination Route

Up to 240 hours following oral administration of 104 mg [14C]-lonafarnib in fasted healthy subjects, approximately 62% and 13

Innovators Monograph

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