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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PYQUVI (PYQUVI).
| Breastfeeding | It is unknown whether copanlisib is excreted in human milk. However, due to the potential for serious adverse reactions in breastfed infants, women should not breastfeed during treatment with PYQUVI and for at least 1 month after the last dose. M/P ratio not available. |
| 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. |
■ 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 |
Uncontrolled hypertension, active malignancy, history of malignancy (relative), hypersensitivity to vadadustat, and patients with chronic kidney disease not on dialysis (due to safety concerns).
| 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). |
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| 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. |