PRALATREXATE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for PRALATREXATE (PRALATREXATE).
Folate analogue metabolic inhibitor that competitively inhibits dihydrofolate reductase (DHFR), disrupting DNA synthesis and cell proliferation.
| Metabolism | Not extensively metabolized; undergoes minimal hepatic metabolism via CYP450 enzymes; primarily excreted unchanged in urine. |
| Excretion | Renal excretion accounts for approximately 70-80% of the administered dose as unchanged drug; biliary/fecal elimination is minimal (<10%). |
| Half-life | Terminal elimination half-life is approximately 12–19 hours in patients with normal renal function, supporting a weekly dosing interval. |
| Protein binding | Approximately 45–55% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Mean volume of distribution is about 40–60 L/m², indicating extensive extravascular distribution (estimated 0.6–1.2 L/kg in adults). |
| Bioavailability | Intravenous administration only; oral bioavailability is negligible (<5%) due to poor absorption and is not a clinical route. |
| Onset of Action | Intravenous administration: Onset of clinical effect (antitumor activity) is typically observed within 2–4 weeks after initiation of therapy. |
| Duration of Action | Duration of action is approximately 7 days, consistent with weekly dosing; sustained folate analog effect persists until drug clearance. |
30 mg/m2 intravenously over 3-5 minutes on days 1, 8, and 15 of a 28-day cycle.
| Dosage form | SOLUTION |
| Renal impairment | For creatinine clearance (CrCl) 30-59 mL/min: reduce dose to 20 mg/m2. For CrCl 15-29 mL/min: reduce dose to 15 mg/m2. Not recommended for CrCl <15 mL/min. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose to 20 mg/m2. Child-Pugh Class C: avoid use. |
| Pediatric use | Not established; safety and efficacy in pediatric patients have not been studied. |
| Geriatric use | No specific dose adjustment recommended, but monitor renal function closely due to age-related decline in CrCl. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for PRALATREXATE (PRALATREXATE).
| Breastfeeding | No data on human milk excretion, but due to the drug's molecular weight (moderate) and its folate antagonist properties, potential for infant toxicity is high. M/P ratio not available. Breastfeeding is contraindicated during therapy and for at least 1 week after the last dose. |
| Teratogenic Risk | Pralatrexate is a folate analog metabolic inhibitor; based on its mechanism and findings in animal studies (teratogenicity, embryolethality, and developmental delays at doses below the clinical dose), it is contraindicated in pregnancy. First trimester: High risk of major malformations (neural tube defects, craniofacial, cardiovascular). Second and third trimesters: Fetal growth restriction, oligohydramnios, and fetal death. Pralatrexate carries a boxed warning for fetal harm. |
■ FDA Black Box Warning
Increased risk of severe or fatal mucositis, especially in patients with impaired renal function; contraindicated in patients with creatinine clearance less than 30 mL/min.
| Serious Effects |
CrCl < 30 mL/min; severe mucositis; hypersensitivity to pralatrexate or any component of the formulation.
| Precautions | Monitor renal function, liver function, and blood counts; fatal mucositis; tumor lysis syndrome; bone marrow suppression; dermatologic reactions; secondary malignancies. |
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| Fetal Monitoring | Monitor complete blood count (CBC) with differential, hepatic function, renal function, and mucositis assessment prior to each dose. Also monitor for pleural effusion and ascites. During pregnancy, serial ultrasounds for fetal growth, anatomy, and amniotic fluid index are recommended if inadvertent exposure occurs. |
| Fertility Effects | Pralatrexate may cause amenorrhea and gonadal dysfunction. In males, sperm production may be impaired (oligospermia, azoospermia). Long-term effects on fertility are not established; risk associated with folic acid antagonism. Preclinical data show ovarian toxicity and testicular atrophy at clinically relevant doses. |