Zokinvy (lonafarnib)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Lonafarnib is a farnesyltransferase inhibitor.
Lonafarnib is a farnesyltransferase inhibitor that prevents post-translational farnesylation, which is a necessary step in processing many cellular proteins. Accumulation of abnormal farnesylated proteins (progerin) in Hutchinson-Gilford Progeria Syndrome (HGPS) results in damage to cells, including changes to nuclear structure and cellular function; these pathogenic changes cause severe disease manifestations, including failure to thrive, scleroderma-like skin, lipoatrophy, alopecia, joint contractures, skeletal dysplasia, and atherosclerosis. Lonafarnib binds to the farnesyltransferase inhibitor binding site on post-translational processing pathways and blocks accumulation of abnormal progerin and progerin-like proteins in the inner nuclear membrane.
In vitro, lonafarnib improves nuclear morphology and normalizes the structure and function of progerin-containing cells.
Following oral administration of lonafarnib 115 mg/m2 and 150 mg/m2 twice daily, peak plasma concentrations of lonafarnib were attained at a median time of 2 and 4 hours, respectively. Steady-state concentrations of lonafarnib are achieved by approximately 3 days. The absolute bioavailability of lonafarnib has not been determined.
Administration of lonafarnib with a high-fat meal decreased the peak plasma concentration and AUC of lonafarnib by 55 and 29%, respectively, compared with administration in the fasted state; administration with a low-fat meal decreased the peak plasma concentration and AUC of lonafarnib by 25 and 21%, respectively. Lonafarnib is approximately 99% bound to plasma proteins. Lonafarnib is metabolized primarily by cytochrome P-450 (CYP) isoenzyme 3A and to a lesser extent by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 to inactive (i.e., HM17) and active (i.e., HM21) metabolites.
The half-life of lonafarnib is approximately 4-6 hours. Lonafarnib is excreted in the urine and feces; fecal excretion is the principal route of elimination. About 62% of the dose is excreted in the feces and less than 1% of the dose is excreted in urine.
USES: This medication is used to lower the risk of death in people with a certain rare condition (Hutchinson-Gilford Progeria Syndrome - HGPS). It is also used to treat people with certain other rare conditions (Progeroid Laminopathies). Lonafarnib works by decreasing the amount of a harmful substance (progerin) caused by these conditions.
Generic name: lonafarnib
Pronunciation: (LOE-na-FAR-nib)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Zokinvy
Indications
The following indications are listed for Zokinvy:
- Hutchinson-Gilford Progeria Syndrome
- Processing-Deficient Progeroid Laminopathy With Heterozygous Lmna Mutation
- Processing-Deficient Progeroid Laminopathy With Zmpste24 Mutation
Also known as: Hutchinson-Gilford Syndrome, Premature Senility Syndrome, Progeria.
Dosing
If the QTc interval is >=500 msec, lonafarnib should be withheld until the QTc interval is <470 msec, then therapy should be resumed at the same dosage.
If vomiting and/or diarrhea resulting in dehydration or weight loss occurs in patients receiving a maintenance lonafarnib dosage of 150 mg/m2, reduce the daily dosage of lonafarnib to 115 mg/m2 twice daily. (see Table 1.)
Lonafarnib is administered orally twice daily with morning and evening meals.
Lonafarnib capsules should be swallowed whole with a sufficient amount of water and should not be chewed.
Alternatively, for patients who are unable to swallow whole capsules, each capsule may be opened and the contents emptied into a container containing 5-10 mL of Ora Blend SF(R), Ora-Plus(R) orange juice, or 1-2 teaspoonfuls of applesauce, and mixed thoroughly with a spoon. The entire mixture should be consumed immediately or within 10 minutes of mixing. Do not mix with juices containing grapefruit or Seville oranges.
If a dose of lonafarnib is missed by 8 hours or less, the prescribed dose should be taken as soon as it is remembered. If a dose is missed by more than 8 hours, the missed dose should be skipped, and the regular dosing schedule resumed at the next scheduled time.
Store lonafarnib capsules at 20-25degreesC; excursions permitted between 15-30degreesC.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Lonafarnib is metabolized principally by cytochrome P-450 (CYP) 3A4 and, to a lesser extent, by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1.
In vitro studies suggest that lonafarnib is a sensitive substrate for CYP3A and a potent time-dependent and mechanism-based inhibitor of CYP3A. Lonafarnib also inhibits CYP2C8 and CYP2C19. In vitro, lonafarnib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, or CYP2D6, and is unlikely to induce CYP1A2, CYP2B6, and CYP3A.
In vitro, lonafarnib is not a substrate for organic anion transporting polypeptide (OATP) 1B1, OATP1B3, or breast cancer resistance protein (BCRP). In vitro, lonafarnib inhibits P-glycoprotein (P-gp), OATP1B1, OATP1B3, and BCRP.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*Concomitant use with strong CYP3A inhibitors.
*Concomitant use with moderate or strong CYP3A inducers.
*Concomitant use with midazolam, lovastatin, simvastatin, or atorvastatin.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in >=25% of patients receiving lonafarnib in clinical studies include vomiting, diarrhea, infection, nausea, decreased appetite, fatigue, upper respiratory tract infection, abdominal pain, musculoskeletal pain, electrolyte abnormalities, decreased weight, headache, myelosuppression, increased aspartate aminotransferase, decreased blood bicarbonate, cough, hypertension, and increased alanine aminotransferase.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
Safety and efficacy of lonafarnib have not been established in children <12 months of age. Safety and efficacy have been established in children >=12 months of age with Hutchinson-Gilford Progeria syndrome (HGPS) and processing-deficient Progeroid Laminopathies (PL) and use is supported by adequate and well controlled studies in children >=2 years of age.
There are no adequate and well-controlled studies of lonafarnib in pregnant women; however, animal studies suggest that lonafarnib may cause fetal harm.
Lonafarnib is distributed into milk in rats. It is not known whether lonafarnib is distributed into human milk or if the drug has any effect on milk production or the nursing infant. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for lonafarnib and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.
Patients with HGPS and processing-deficient PL do not reach geriatric age. Clinical trials for treatment of HGPS and processing-deficient PL did not include patients >=65 years of age.
Following administration of a single 100-mg dose of lonafarnib in patients >=65 years of age, peak plasma and systemic exposure were increased by 27 and 59%, respectively.
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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