ZYNLONTA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ZYNLONTA (ZYNLONTA).
ZYNLONTA (loncastuximab tesirine-lpyl) is a CD19-directed antibody-drug conjugate (ADC) consisting of a humanized anti-CD19 monoclonal antibody conjugated via a cleavable linker to a pyrrolobenzodiazepine (PBD) dimer cytotoxin. Upon binding to CD19-expressing cells, the conjugate is internalized and the linker is cleaved, releasing the PBD dimer, which crosslinks DNA and induces cell death.
| Metabolism | Loncastuximab tesirine is metabolized by proteolytic degradation into small peptides, cysteine, and unconjugated PBD dimer. The PBD dimer is primarily metabolized by CYP3A4. |
| Excretion | Primarily eliminated via biliary/fecal route (approximately 71% of administered dose recovered in feces as unchanged drug), with renal excretion accounting for a minor fraction (<10% of dose as unchanged drug in urine). |
| Half-life | Terminal elimination half-life (t½) is approximately 0.6 hours (range 0.3–1.0 hours) for the intact antibody–drug conjugate, reflecting rapid clearance; the unconjugated payload (SG3199) has a longer t½ of approximately 1–2 hours. |
| Protein binding | The intact antibody–drug conjugate is highly protein-bound (>99%) in human plasma, primarily binding to albumin and other plasma proteins; the released payload SG3199 exhibits extensive binding (>90%) to plasma proteins, including albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | Steady-state volume of distribution (Vdss) is approximately 7–9 L, consistent with distribution primarily within the vascular and interstitial spaces; weight-normalized Vd is approximately 0.1–0.2 L/kg, indicating limited extravascular distribution. |
| Bioavailability | Zynlonta is administered intravenously, thus bioavailability is 100% by the IV route; no other routes are used or described. |
| Onset of Action | Onset of clinical effect (e.g., tumor response) is typically observed within weeks of initiating therapy, with median time to response in clinical trials ranging from 1.2 to 2.5 months for relapsed/refractory diffuse large B-cell lymphoma. |
| Duration of Action | Duration of action is variable and treatment cycles are repeated every 3 weeks; the duration of clinical response is limited by disease progression or unacceptable toxicity, with median duration of response in clinical trials of approximately 10–13 months for responders. |
0.15 mg/kg intravenously every 3 weeks, up to a maximum of 9 mg per dose, until disease progression or unacceptable toxicity.
| Dosage form | INJECTABLE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (CrCl ≥30 mL/min). For severe renal impairment (CrCl <30 mL/min), not studied; consider risks vs benefits and monitor closely. |
| Liver impairment | For Child-Pugh Class A or B, no dose adjustment needed. For Child-Pugh Class C, not studied; use with caution and monitor for toxicity. |
| Pediatric use | Safety and effectiveness in pediatric patients have not been established. No recommended dose. |
| Geriatric use | No specific dose adjustment recommended based on age alone. Monitor renal function and overall status, as elderly patients may have reduced organ function and increased sensitivity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ZYNLONTA (ZYNLONTA).
| Breastfeeding | There are no data on the presence of ZYNLONTA in human milk, its effects on the breastfed child, or effects on milk production. Due to the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for at least 3 months after the last dose. M/P ratio: unknown. |
| Teratogenic Risk | ZYNLONTA (loncastuximab tesirine-lpyl) is a CD19-directed antibody-drug conjugate. Based on its mechanism of action and animal studies, it can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of loncastuximab tesirine to pregnant rats during organogenesis resulted in embryo-fetal mortality and malformations at maternal exposures below the clinical dose. There are no adequate and well-controlled studies in pregnant women. Advise pregnant women of the potential risk to the fetus. First trimester: highest risk for major malformations; second and third trimesters: risk of fetal growth restriction and oligohydramnios. |
■ FDA Black Box Warning
ZYNLONTA has a black box warning for serious or fatal effusion and edema. Patients may develop pleural effusion, pericardial effusion, ascites, and peripheral edema, which can be severe or life-threatening. Monitor for fluid overload and manage appropriately.
| Serious Effects |
["None"]
| Precautions | ["Effusion and edema: monitor for pleural effusion, pericardial effusion, ascites, and peripheral edema; may require dose interruption or discontinuation","Myelosuppression: monitor blood counts; may cause neutropenia, thrombocytopenia, anemia","Infections: increased risk of serious or fatal infections","Cytokine release syndrome (CRS): monitor for signs of CRS","Hepatotoxicity: monitor liver enzymes and bilirubin","Embryo-fetal toxicity: can cause fetal harm; advise females of reproductive potential to use effective contraception","Hypersensitivity: monitor for infusion-related reactions"] |
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| Fetal Monitoring | Monitor pregnant women for fetal growth restriction and oligohydramnios if exposed to ZYNLONTA. Perform pregnancy testing in females of reproductive potential prior to initiating treatment. Confirm pregnancy status before starting therapy. Monitor for adverse effects in the mother, including myelosuppression, infections, and hepatotoxicity. |
| Fertility Effects | Based on animal studies, ZYNLONTA may impair fertility in females and males. In female rats, decreased fertility and increased post-implantation loss were observed. In male rats, decreased sperm motility and count were noted. Advise males with female partners of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose. Females of reproductive potential should use effective contraception during treatment and for at least 9 months after the last dose. |