Darinaparsin
Also known as: Arsenic‑glutathione conjugate, DAR, Darinastat, DMAG, S-dimethylarsino-glutathione, S-dimethylarsino‑glutathione, ZIO-101
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Summary
Darinaparsin is an organoarsenic drug composed of dimethylated arsenic linked to glutathione. It is approved in Japan for the treatment of relapsed or refractory peripheral T‑cell lymphoma (PTCL) and is administered intravenously. Clinical studies have shown modest response rates in this difficult‑to‑treat disease, with a safety profile that includes cytopenias and hypertension.
Mechanism of Action
After intravenous infusion, darinaparsin is processed at the cell surface by γ‑glutamyltranspeptidase, generating dimethylarsino‑cysteine that enters tumor cells via a cystine transporter. Inside the cell it accumulates in mitochondria, disrupts mitochondrial function, raises intracellular reactive oxygen species, and triggers apoptosis and cell‑cycle arrest. The drug therefore exploits the high γ‑GT and cystine‑transporter expression of many cancer cells to deliver arsenic‑mediated cytotoxicity.
What the Research Shows
Pre‑clinical work demonstrated broad antitumor activity of darinaparsin across hematologic and solid tumor models, with mechanisms distinct from arsenic trioxide. A phase I trial in refractory solid tumours identified a maximum tolerated dose of 300 mg/m² daily for five days every four weeks and reported stable disease in a minority of patients. The pivotal Asian phase II study enrolled 65 patients with relapsed/refractory PTCL, delivering 300 mg/m² over one hour daily for five days in a 21‑day cycle. Central review showed an overall response rate of 19.3%, rising to 22.2% in the Japanese subgroup, and tumour shrinkage in over 60% of participants. Safety data from the same trial highlighted frequent treatment‑emergent adverse events, most notably grade ≥3 cytopenias and hypertension, which were generally manageable with dose adjustments.
Reported Benefits
In the phase II PTCL trial, darinaparsin achieved an overall response rate of 19.3% and tumour reduction in 62% of patients, indicating antitumour activity where few options exist. The drug’s targeted uptake by tumour cells may contribute to its efficacy across diverse PTCL subtypes, including angioimmunoblastic T‑cell lymphoma, which showed a 29.4% response rate. The safety profile, while notable for cytopenias, was considered clinically acceptable and manageable with standard supportive care.
Limitations of the Evidence
Evidence is limited to a single‑arm, non‑randomised phase II study in an Asian population; no comparative or long‑term survival data are available. The overall response rate, though statistically above a predefined threshold, remains modest, and the drug has only been evaluated in PTCL, with limited data in solid tumours. Safety concerns such as grade ≥3 cytopenias and hypertension may restrict use in patients with pre‑existing marrow compromise. Neurologic toxicities observed at higher doses in solid‑tumour patients highlight a narrow therapeutic window.
Safety Considerations
Nearly all patients (98.5%) experienced treatment‑emergent adverse events. Grade ≥3 events occurring in ≥5% of participants included anemia (15.4%), thrombocytopenia (13.8%), neutropenia (12.3%), leukopenia (9.2%), lymphopenia (9.2%) and hypertension (6.2%). In a phase I solid‑tumour study, neurologic dose‑limiting toxicities (altered mental status, ataxia) emerged at doses ≥420 mg/m², leading to a recommended phase‑II dose of 300 mg/m². Adverse events were generally managed with dose reductions and supportive care.
How It Is Administered
Darinaparsin is supplied as an intravenous injection (DARVIAS® 135 mg). The approved regimen for relapsed/refractory PTCL is 300 mg/m² infused over 1 hour daily for five consecutive days, repeated every 21 days. No oral formulation is currently approved.
Routes of Administration
Goals & Uses
- Induction of tumor cell apoptosis via ROSMechanism/pharmacologyHigh
- Treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL)OncologyHigh
- Myelodysplastic syndromesOncologyLow
- Treatment of acute myeloid leukemia (AML)Hematologic MalignancyModerate
- Peripheral T‑cell lymphomaOncologyModerate
- Acute myeloid leukemiaOncologyModerate
- Treatment of myelodysplastic syndrome (MDS)OncologyLow
Contraindications
- Known hypersensitivity to darinaparsin or arsenic‑containing compoundsAllergyHigh
- QT prolongation / cardiac arrhythmiasCardiacHigh
- Severe hepatic impairment (Child‑Pugh C)Liver DiseaseModerate
- Severe hepatic impairmentOrganHighLiver function concerns
- Hypersensitivity to arsenic compoundsAllergyHigh
- Severe renal impairmentOrganModerateKidney function concerns
- PregnancyPopulationHighPotential fetal risk or insufficient safety data
Adverse Effects
- Peripheral neuropathyNeurologicalUncommon
- QT interval prolongationCardiacUncommon
- Elevated transaminasesHepaticUncommon
- Nausea/vomitingGastrointestinalCommon
- Elevated liver enzymes (hepatotoxicity)HepaticUncommon
- FatigueGeneralCommonLow energy or tiredness
- Cytopenias (neutropenia, thrombocytopenia)HematologicCommon
- MyelosuppressionHematologicUncommon
Drug Interactions
- Arsenic trioxideHigh
- QT-prolonging agents (e.g., fluoroquinolones, antiarrhythmics)High
- Thiol-containing compounds (e.g., N-acetylcysteine, glutathione precursors)Moderate
- Strong CYP3A4 inhibitors (e.g., ketoconazole)Moderate
- Concurrent myelosuppressive chemotherapyHigh
Population Constraints
- Patients with electrolyte abnormalitiesMetabolicRelative
- Pediatric patientsAgeRelative
- Pediatric patients (<12 y)AgeRelative
- Patients with pre-existing peripheral neuropathyNeurologicalRelative
- Pregnant womenReproductiveAbsolute
Regulatory Status
- European UnionInvestigationalClinical trial authorization granted in several member states.
- United StatesInvestigationalIND holder; Phase II/III trials ongoing.
- United KingdomInvestigationalMHRA clinical trial approval; not marketed.
Not approved in any major jurisdiction; currently in Phase II/III clinical trials.
Evidence & Sources
- Journal ArticleModerateKim WS, et al.2023-01-01T00:00:00.000000Z
- Journal ArticleModerateYao K, Sonehara Y, Nagahama F2023-01-01T00:00:00.000000Z
- Journal ArticleModerateNegoro E, et al.2023-01-01T00:00:00.000000Z
- Journal ArticleModerateMann KK, et al.2009-01-01T00:00:00.000000Z
- Journal ArticleModerateFrampton JE2022-01-01T00:00:00.000000Z
- Journal ArticleModerateTsimberidou AM, et al.2009-01-01T00:00:00.000000Z
Frequently Asked Questions
What type of cancer is darinaparsin approved to treat?
Darinaparsin has received regulatory approval in Japan for the treatment of relapsed or refractory peripheral T‑cell lymphoma, a group of aggressive mature T‑cell malignancies.
How is darinaparsin given to patients?
The drug is administered intravenously as a 1‑hour infusion at a dose of 300 mg/m² on five consecutive days, followed by a rest period to complete a 21‑day treatment cycle.
What are the most common serious side effects?
Serious adverse events occurring in at least 5% of patients include anemia, thrombocytopenia, neutropenia, leukopenia, lymphopenia, and hypertension; these are typically managed with dose adjustments and supportive care.
Is darinaparsin effective in solid tumours?
A phase I trial in refractory solid tumours showed limited activity, with some patients achieving stable disease; however, neurologic toxicities at higher doses limited further development in this setting.
How does darinaparsin differ from arsenic trioxide?
Unlike arsenic trioxide, darinaparsin is a glutathione‑conjugated organoarsenic that is processed by γ‑glutamyltranspeptidase and taken up via cystine transporters, leading to mitochondrial disruption and reactive‑oxygen‑species generation rather than the pathways primarily targeted by arsenic trioxide.
What is Darinaparsin?
Darinaparsin is an organoarsenic drug composed of dimethylated arsenic linked to glutathione. It is approved in Japan for the treatment of relapsed or refractory peripheral T‑cell lymphoma (PTCL) and is administered intravenously. Clinical studies have shown modest response rates in this difficult‑to‑treat disease, with a safety profile that includes cytopenias and hypertension.
What is Darinaparsin used for?
Darinaparsin is educationally associated with: Induction of tumor cell apoptosis via ROS, Treatment of relapsed/refractory peripheral T-cell lymphoma (PTCL), Myelodysplastic syndromes, Treatment of acute myeloid leukemia (AML), Peripheral T‑cell lymphoma, Acute myeloid leukemia, Treatment of myelodysplastic syndrome (MDS). Educational only — not medical advice.
How is Darinaparsin administered?
Recorded routes of administration: Intravenous.
What are the potential side effects of Darinaparsin?
Reported adverse effects include: Peripheral neuropathy, QT interval prolongation, Elevated transaminases, Nausea/vomiting, Elevated liver enzymes (hepatotoxicity), Fatigue, Cytopenias (neutropenia, thrombocytopenia), Myelosuppression. This list is not exhaustive — consult a qualified clinician.
Who should avoid Darinaparsin?
Recorded contraindications: Known hypersensitivity to darinaparsin or arsenic‑containing compounds, QT prolongation / cardiac arrhythmias, Severe hepatic impairment (Child‑Pugh C), Severe hepatic impairment, Hypersensitivity to arsenic compounds, Severe renal impairment, Pregnancy. Consult a qualified clinician before use.