WIDAPLIK
Clinical safety rating: caution
Comprehensive clinical and safety monograph for WIDAPLIK (WIDAPLIK).
WIDAPLIK is a small-molecule inhibitor of cyclin-dependent kinase 12 (CDK12). By selectively inhibiting CDK12, it interferes with the phosphorylation of RNA polymerase II, leading to reduced expression of DNA damage response genes and promoting apoptosis in cancer cells.
| Metabolism | Primarily metabolized by CYP3A4 and CYP3A5. Minor contributions from CYP2C8 and CYP2D6. |
| Excretion | Primarily renal excretion as unchanged drug (approximately 70%) with 20% as inactive metabolites; 10% via feces. |
| Half-life | Terminal elimination half-life is 12 hours (range 10–14 h) in healthy adults; prolonged to 24–36 h in moderate renal impairment (CrCl 30–50 mL/min). |
| Protein binding | 98% bound to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 0.8 L/kg (0.6–1.0 L/kg), indicating extensive extravascular distribution. |
| Bioavailability | Oral: 75% (range 70–80%); intravenous: 100%. |
| Onset of Action | Oral: 30–60 minutes; intravenous: within 5 minutes. |
| Duration of Action | 12 hours for oral administration; 6–8 hours for intravenous (dose-dependent). |
50 mg orally twice daily.
| Dosage form | TABLET |
| Renal impairment | GFR >=60 mL/min: no adjustment; GFR 30-59: 25 mg twice daily; GFR <30: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: 25 mg twice daily; Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established; use not recommended in patients <18 years. |
| Geriatric use | Start at 25 mg twice daily; titrate based on renal function and tolerability. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for WIDAPLIK (WIDAPLIK).
| Breastfeeding | Excreted into breast milk; M/P ratio 1.2. Due to potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during WIDAPLIK therapy and for 1 month after last dose. |
| Teratogenic Risk | WIDAPLIK is contraindicated in pregnancy due to high risk of fetal harm. First trimester: Major congenital malformations including neural tube defects and cardiac anomalies in up to 25% of exposed pregnancies. Second and third trimesters: Fetal growth restriction, oligohydramnios, and neonatal renal impairment. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Concomitant use with strong CYP3A4 inhibitors or inducers.","Severe hepatic impairment (Child-Pugh class C)."]
| Precautions | ["Hepatotoxicity: Elevations in liver enzymes (ALT, AST) and bilirubin; monitor liver function prior to initiation and periodically during treatment.","Severe cutaneous adverse reactions (SCARs): Including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN); discontinue if symptoms occur.","Hemorrhagic events: Fatal hemorrhagic events reported; use with caution in patients with bleeding risk.","Thromboembolic events: Increased risk of venous thromboembolism; consider prophylactic anticoagulation."] |
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| Fetal Monitoring |
| Pregnancy test before initiation, monthly during therapy, and 1 month after discontinuation. If exposure occurs, immediate referral to maternal-fetal medicine. Fetal ultrasound and echocardiogram at 18-20 weeks gestation. |
| Fertility Effects | WIDAPLIK causes reversible infertility in females due to ovarian failure and in males due to azoospermia; fertility may not return after discontinuation. Contraception required during treatment. |