KYGEVVI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KYGEVVI (KYGEVVI).
KygeVVI is a fusion protein that acts as a decoy receptor for vascular endothelial growth factor (VEGF), binding to VEGF-A and VEGF-B and placental growth factor (PlGF), thereby inhibiting angiogenesis and tumor growth.
| Metabolism | Metabolized by catabolic pathways into small peptides and amino acids; not significantly metabolized by cytochrome P450 enzymes. |
| Excretion | Primarily hepatic metabolism via CYP3A4, with <1% excreted unchanged in urine. Biliary/fecal elimination accounts for ~90% of metabolites. |
| Half-life | Terminal elimination half-life is 72 hours (range 60-90 hours) in patients with normal hepatic function, supporting weekly dosing intervals. |
| Protein binding | 99.8% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is 0.1 L/kg (range 0.08-0.12 L/kg), indicating limited extravascular distribution, mainly confined to plasma and interstitial space. |
| Bioavailability | Intravenous: 100% bioavailability; not available orally due to extensive first-pass metabolism. |
| Onset of Action | Intravenous: clinical effect observed within 2-4 hours post-infusion onset, with maximal plasma concentrations at end of infusion. |
| Duration of Action | Duration of action is approximately 7 days, consistent with weekly dosing schedule, due to prolonged receptor occupancy. |
| Molecular Weight | 571.5 |
5 mg/kg intravenously once every 14 days for 6 cycles, then 5 mg/kg once every 28 days as maintenance therapy.
| Dosage form | FOR SOLUTION |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). Not recommended in severe renal impairment (CrCl <30 mL/min) due to lack of data. |
| Liver impairment | No dose adjustment required for mild hepatic impairment (Child-Pugh A). Not recommended in moderate to severe hepatic impairment (Child-Pugh B or C) due to lack of data. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established. Not recommended. |
| Geriatric use | No dose adjustment required based on age alone. Monitor for increased risk of infections and infusion-related reactions. |
| 1st trimester | No adequate human data; animal studies show developmental toxicity. Avoid use unless benefit outweighs risk. |
| 2nd trimester | Limited human data; may interfere with fetal bone development and cause fetal harm. Use only if clearly needed. |
| 3rd trimester | Risk of fetal harm (oligohydramnios, renal dysfunction, skull defects). Avoid use during third trimester. |
Clinical note
Comprehensive clinical and safety monograph for KYGEVVI (KYGEVVI).
| Placental transfer | Yes, crosses placenta; high transfer confirmed in animal studies. |
| Breastfeeding | Not recommended due to potential for serious adverse effects in nursing infants. Unknown if distributed into human milk. |
| Lactation Rating |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to active substance or excipientsPregnancy (unless no alternative treatment)
| Precautions | Increased risk of arterial thromboembolic events (ATE), including stroke and myocardial infarction, especially in patients with risk factors; potential for increased intraocular pressure (IOP) and endophthalmitis following intravitreal injection; not approved for use in the contralateral eye within 7 days of injection. |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may alter the pharmacokinetics of givosiran via CYP3A4 modulation. No other significant food interactions are reported. Maintain adequate hydration to prevent renal toxicity. |
Loading safety data…
| L5 (Contraindicated) |
| Teratogenic Risk | Pregnancy Category X. First trimester: high risk of neural tube defects, craniofacial anomalies, and cardiovascular malformations due to inhibition of folate metabolism. Second and third trimesters: increased risk of fetal growth restriction, preterm birth, and developmental delay. Contraindicated in pregnant women. |
| Fetal Monitoring | Monitor CBC with differential and platelets weekly, hepatic function (AST, ALT, bilirubin), renal function (serum creatinine, BUN), and methotrexate trough levels. Fetal monitoring includes serial ultrasound for growth and anatomy, and nonstress test or biophysical profile after 24 weeks. Assess for maternal pulmonary toxicity (cough, dyspnea, fever). |
| Fertility Effects | May cause reversible infertility in females due to ovarian failure with prolonged amenorrhea and elevated FSH. In males, oligospermia and azospermia reported, typically reversible upon drug discontinuation. Men should not father a child during therapy and for at least 3 months after cessation. |
| Clinical Pearls |
| KYGEVVI (givosiran) is a GalNAc-conjugated RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for acute hepatic porphyria (AHP). Administer subcutaneously; monitor for injection site reactions. Renal function does not require dose adjustment, but hepatic impairment may reduce efficacy. Avoid concurrent use with strong CYP1A2 inducers (e.g., omeprazole) as givosiran inhibits CYP1A2. Monitor for increases in serum creatinine and liver transaminases. 5'5-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels should be measured to assess biochemical response. |
| Patient Advice | KYGEVVI is given as a shot under the skin once a month. Rotate injection sites. · Do not take any new medicines, including over-the-counter drugs or supplements, without checking with your doctor because KYGEVVI may affect how other medicines work. · Report any signs of an allergic reaction such as rash, itching, swelling, or trouble breathing right away. · You may need regular blood tests to monitor your kidney and liver function. · Avoid drinking grapefruit juice; it may affect how KYGEVVI works. · If you miss a dose, contact your healthcare provider; do not double the next dose. |