ZOKINVY
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZOKINVY (ZOKINVY).
ZOKINVY (lonafarnib) is a farnesyltransferase inhibitor (FTI) that inhibits the post-translational farnesylation of proteins, including lamin A and progerin, thereby preventing their abnormal accumulation in the nuclear envelope.
| Metabolism | Metabolized primarily by CYP3A and CYP2D6 enzymes. Excreted in feces (approx. 70%) and urine (approx. 10%). |
| Excretion | Renal (47% as unchanged drug, 22% as metabolites) and biliary/fecal (31% as metabolites and unchanged drug). |
| Half-life | Terminal elimination half-life 39 hours (range 28-51 h) after multiple dosing, supporting once-daily dosing. |
| Protein binding | 99.3% bound to plasma proteins (primarily albumin and alpha-1-acid glycoprotein). |
| Volume of Distribution | Vd 1.1 L/kg, indicating extensive extravascular distribution. |
| Bioavailability | Oral bioavailability 75% (fed state) relative to intravenous administration; absorption increased with fatty meals. |
| Onset of Action | Oral: Onset within 2-4 hours for HIV-1 RNA reduction. |
| Duration of Action | Duration of viral suppression lasts 24 hours with once-daily dosing; trough concentrations remain above IC50. |
Adults: 100 mg orally twice daily (every 12 hours) with or without food.
| Dosage form | CAPSULE |
| Renal impairment | eGFR 30-89 mL/min: No adjustment. eGFR 15-29 mL/min: 100 mg once daily. eGFR <15 mL/min or dialysis: Not recommended. |
| Liver impairment | Child-Pugh A: No adjustment. Child-Pugh B or C: Not recommended due to increased exposure. |
| Pediatric use | Not established; safety and efficacy in pediatric patients (<18 years) have not been studied. |
| Geriatric use | No specific dose adjustment required based on age; monitor renal function and consider age-related decline in eGFR. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ZOKINVY (ZOKINVY).
| Breastfeeding | No data are available on the presence of ZOKINVY in human milk, its effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed during treatment and for 7 months after the last dose. M/P ratio is unknown. |
| Teratogenic Risk | ZOKINVY (lutetium Lu 177 vipivotide tetraxetan) is a radiopharmaceutical. Based on its mechanism of action (delivering ionizing radiation), there is a risk of fetal harm. In animal studies, radiation exposure is teratogenic and can cause fetal death and congenital anomalies. Use during pregnancy is contraindicated. The risk is highest during the first trimester when organogenesis occurs. Second and third trimester exposure may cause growth retardation and CNS effects. |
■ FDA Black Box Warning
No FDA boxed warning.
| Serious Effects |
["Concomitant use with strong CYP3A inducers","Hypersensitivity to lonafarnib or any component of the formulation"]
| Precautions | ["Risk of QT interval prolongation; obtain ECG before and during treatment","Potential for drug-induced liver injury; monitor hepatic function","Gastrointestinal adverse reactions (nausea, vomiting, diarrhea); manage with antiemetics and hydration","Fetal harm based on animal studies; advise effective contraception in females of reproductive potential"] |
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| Fetal Monitoring | Monitor complete blood counts (CBC) with differential, renal function (serum creatinine, eGFR), and liver function tests (ALT, AST, bilirubin) at baseline and periodically during treatment. Assess for signs of radiation exposure. Perform pregnancy testing in females of reproductive potential prior to initiation. |
| Fertility Effects | ZOKINVY may impair fertility in both males and females due to radiation-induced damage to reproductive organs. In male patients, treatment may cause oligospermia or azoospermia. In female patients, it may cause ovarian failure and premature menopause. Advise patients on potential irreversible infertility. |