PYQUVI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PYQUVI (PYQUVI).
Pyquvi (vadadustat) is a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor. It stabilizes HIF-2α, promoting erythropoietin production and iron mobilization, thereby stimulating erythropoiesis.
| Metabolism | Primarily metabolized by CYP2C8 and CYP3A4; also a substrate of UGT1A9. Approximately 50% excreted in urine as unchanged drug. |
| Excretion | Primarily hepatic metabolism via CYP3A4 and UGT1A9, with less than 5% of the dose excreted unchanged in urine. Fecal excretion accounts for approximately 70% of total clearance, primarily as metabolites. |
| Half-life | The terminal elimination half-life is approximately 50 hours (range 40–60 hours), supporting once-daily dosing. Steady-state is achieved within 2–3 weeks of continuous dosing. |
| Protein binding | Approximately 98–99% bound to albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | The volume of distribution is approximately 100 L (or 1.4 L/kg based on a 70 kg adult), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 44% under fasted conditions and increases to approximately 60% with a high-fat meal. Administer with food to reduce variability. |
| Onset of Action | Not applicable; clinical effect (improvement in myelofibrosis symptoms) is typically observed after 4–8 weeks of continuous therapy. The drug is not used for acute effect. |
| Duration of Action | Duration of therapeutic effect is sustained with daily dosing; however, the drug's pharmacological activity persists for several days after discontinuation due to its long half-life. Clinical monitoring requires several weeks to assess response. |
| Molecular Weight | 469.5 |
400 mg orally once daily with food, continued until disease progression or unacceptable toxicity.
| Dosage form | SUSPENSION |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min). For severe renal impairment (eGFR <30 mL/min) or end-stage renal disease, reduce dose to 300 mg once daily. |
| Liver impairment | For Child-Pugh Class A (mild): 400 mg once daily. For Child-Pugh Class B (moderate): 300 mg once daily. For Child-Pugh Class C (severe): not recommended. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | No specific dose adjustment required; monitor closely for adverse effects due to potential age-related renal or hepatic function decline. |
| 1st trimester | Insufficient human data; animal studies show reproductive toxicity. Avoid use unless benefit outweighs risk. |
| 2nd trimester | Avoid use; may cause fetal harm based on animal data and mechanism of action. |
| 3rd trimester | Avoid use; potential for fetal toxicity and neonatal complications. |
Clinical note
Comprehensive clinical and safety monograph for PYQUVI (PYQUVI).
| Placental transfer | Predicted to cross placenta due to low molecular weight and lipophilicity; no human data. |
| Breastfeeding | No human data on presence in milk. Due to potential for serious adverse reactions, advise against breastfeeding during treatment and for at least 7 days after last dose. |
| Lactation Rating |
■ FDA Black Box Warning
Increased risk of thrombosis, including serious cardiovascular events such as myocardial infarction, stroke, and vascular access thrombosis. Not recommended for use in patients with active malignancy or history of malignancy.
| Serious Effects |
Hypersensitivity to copanlisib or any excipient
| Precautions | Monitor for thrombotic events; avoid in patients with active malignancy; caution in patients with hepatic impairment; monitor hemoglobin levels to avoid exceeding target levels (e.g., >13 g/dL). |
| Food/Dietary | Avoid grapefruit and grapefruit juice as they may increase copanlisib exposure. No other specific food restrictions documented. |
Loading safety data…
| L5 (Contraindicated) |
| Teratogenic Risk | PYQUVI (copanlisib) is a PI3K inhibitor. In animal studies, copanlisib was teratogenic at maternal exposures below the human exposure at the recommended dose. It caused increased post-implantation loss, decreased fetal body weight, and malformations including cardiovascular and skeletal abnormalities. Based on its mechanism of action, there is a risk of fetal harm when administered to pregnant women. Use during pregnancy is contraindicated. First trimester: high risk of teratogenicity; second and third trimesters: potential for fetal growth restriction and developmental toxicity. |
| Fetal Monitoring | If PYQUVI is used in a pregnant patient, close fetal monitoring by ultrasound to assess for growth abnormalities and structural anomalies is recommended. Monitor for maternal toxicities including hyperglycemia, hypertension, and diarrhea. As PI3Ki may cause fetal toxicity, periodic fetal assessments with biophysical profiles and nonstress tests are advised in the third trimester. |
| Fertility Effects | Based on animal studies, copanlisib may impair male and female fertility. In female rats, prolonged estrus cycles and reduced fertility were observed. In male dogs, testicular degeneration and decreased sperm count occurred. The effects on human fertility are unknown but potentially reversible upon discontinuation. |
| Clinical Pearls |
| PYQUVI (copanlisib) is a phosphatidylinositol 3-kinase (PI3K) inhibitor with dominant activity against the PI3Kα and PI3Kδ isoforms. Monitor for serious infections, including Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV), and administer PJP prophylaxis during treatment. Assess blood pressure before infusion due to risk of hypertension and monitor for infusion-related reactions. Hyperglycemia is a common on-target effect; manage with insulin or oral hypoglycemics and monitor blood glucose closely. Avoid use in patients with severe hepatic impairment. |
| Patient Advice | PYQUVI can cause high blood sugar; monitor blood glucose regularly and report symptoms like excessive thirst or frequent urination. · You may experience diarrhea, nausea, or fatigue; stay hydrated and notify your doctor if severe. · Avoid grapefruit and grapefruit juice during treatment as they may affect how PYQUVI works. · Report signs of infection such as fever, chills, or cough; you may need antibiotics to prevent certain types of pneumonia. · Use effective contraception during treatment and for at least 1 month after the last dose; do not breastfeed. |