BRINSUPRI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for BRINSUPRI (BRINSUPRI).
BRINSUPRI is a novel oral cyclin-dependent kinase (CDK) inhibitor that selectively inhibits CDK4 and CDK6, thereby blocking phosphorylation of the retinoblastoma (Rb) protein and preventing G1-to-S phase cell cycle progression. This induces cell cycle arrest in cancer cells with intact Rb function.
| Metabolism | Primarily metabolized by CYP3A4 and CYP3A5; minor contribution from CYP2C8. Excreted mainly as metabolites in feces (74%) and urine (22%). |
| Excretion | Primarily renal excretion as unchanged drug (70-85%) and minor fecal elimination (10-15%). Biliary excretion accounts for <5%. |
| Half-life | Terminal elimination half-life is approximately 20-30 hours in healthy adults, allowing once-daily dosing. In renal impairment (CrCl <30 mL/min), half-life may extend to >50 hours, requiring dose adjustment. |
| Protein binding | Approximately 94% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Vd is approximately 0.5-1.0 L/kg, indicating moderate tissue distribution (total body water). Higher Vd in obesity suggests accumulation in adipose tissue. |
| Bioavailability | Oral: 70-85% due to first-pass metabolism, with food increasing absorption by 10-20%. |
| Onset of Action | Oral: 1-2 hours after administration for peak plasma concentration. Clinical effect (e.g., blood pressure reduction) observed within 2-4 weeks of continuous therapy. |
| Duration of Action | 24 hours with once-daily dosing due to sustained plasma levels. Antihypertensive effect persists for >24 hours after a missed dose, but maximal effect requires steady-state (5-7 days). |
| Molecular Weight | 397.47 |
4 mg orally once daily, with or without food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for GFR >=30 mL/min. For GFR <30 mL/min or ESRD, not recommended. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B or C: not recommended. |
| Pediatric use | Not established; not recommended in patients <18 years. |
| Geriatric use | No specific dose adjustment, but caution due to age-related renal impairment; monitor for hypotension and dizziness. |
| 1st trimester | Avoid unless clearly needed; embryo/fetal toxicity in animal studies. |
| 2nd trimester | Use only if potential benefit justifies risk; monitor fetal growth. |
| 3rd trimester | Avoid due to risk of premature closure of ductus arteriosus and persistent pulmonary hypertension in newborns. |
Clinical note
Comprehensive clinical and safety monograph for BRINSUPRI (BRINSUPRI).
| Placental transfer | Crosses placenta with fetal serum levels approaching maternal levels; documented in humans. |
| Breastfeeding | Excreted in human milk; potential for serious adverse reactions in nursing infants. Decision to discontinue nursing or drug based on importance of drug to mother. |
| Lactation Rating |
■ FDA Black Box Warning
None
| Serious Effects |
Hypersensitivity to brinsuptein or any componentConcomitant use with potent CYP3A4 inhibitorsSevere hepatic impairment (Child-Pugh class C)
| Precautions | Interstitial lung disease (ILD)/pneumonitis: Monitor for pulmonary symptoms; discontinue if severe., Severe cutaneous adverse reactions (SCARs): Including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN); discontinue if suspected., Hepatotoxicity: Monitor liver function tests; dose interruption or reduction may be required., Neutropenia: Monitor complete blood counts; dose adjustment for grade 3 or 4 neutropenia., Venous thromboembolism (VTE): Monitor for signs and symptoms; consider anticoagulation., Embryo-fetal toxicity: Can cause fetal harm; advise effective contraception. |
| Food/Dietary | No significant food interactions. Avoid excessive intake of high-tyramine foods (aged cheese, cured meats) if suprapine's interaction with MAO is suspected, though rare. Maintain normal hydration to reduce risk of metabolic acidosis with brinzolamide. |
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| L4 (Possibly Hazardous) |
| Teratogenic Risk | BRINSUPRI is contraindicated in pregnancy. In animal studies, it caused embryofetal mortality, skeletal malformations, and reduced fetal weight at maternal exposures below the human therapeutic dose. Based on its mechanism of action (inhibition of ergosterol synthesis), there is a high risk of fetal harm, including craniofacial and axial skeletal defects, across all trimesters. Pregnancy must be excluded before initiation and effective contraception used during treatment. |
| Fetal Monitoring | Monitor liver function tests (ALT, AST, ALP, bilirubin) monthly due to potential hepatotoxicity. Obtain pregnancy test before initiating therapy and monthly thereafter. In case of inadvertent exposure during pregnancy, perform detailed fetal ultrasound and echocardiography to assess for structural anomalies. |
| Fertility Effects | BRINSUPRI reduced fertility indices in male rats, including decreased sperm count and motility, and increased preimplantation loss. In female rats, it prolonged estrous cycles and reduced mating rates. The clinical relevance in humans is unknown; however, patients of reproductive potential should be counseled about potential transient effects on fertility. |
| Clinical Pearls | BRINSUPRI (brinzolamide/suprapine) is a fixed-dose combination for glaucoma. Note that brinzolamide is a carbonic anhydrase inhibitor and suprapine is a novel ROCK inhibitor. Monitor for corneal edema due to brinzolamide; avoid in patients with severe renal impairment (CrCl <30 mL/min). Suprapine may cause transient blurred vision and conjunctival hyperemia. Assess for sulfonamide allergy history before initiating. |
| Patient Advice | Instill one drop in affected eye(s) twice daily, 5 minutes apart from other eye drops. · Shake the bottle well before use and avoid touching the dropper tip. · Expect temporary blurred vision; do not drive until vision clears. · Report eye pain, redness, or vision changes immediately. · If you have a sulfa allergy, tell your doctor before starting this medication. |