Plitidepsin

Summary

Plitidepsin (Aplidin®) is a marine‑derived cyclic depsipeptide approved in Australia for patients with relapsed or refractory multiple myeloma. It is administered intravenously and has been investigated both as an anticancer agent and, more recently, as a host‑directed antiviral for SARS‑CoV‑2 infection.

Mechanism of Action

Plitidepsin binds to the eukaryotic translation elongation factor‑1 alpha isoform 2 (eEF1A2) in host cells. This interaction disrupts protein synthesis, causing cell‑cycle arrest, growth inhibition and apoptosis in cancer cells. The same eEF1A inhibition blocks translation of viral proteins, providing a host‑directed antiviral effect against SARS‑CoV‑2.

What the Research Shows

Preclinical work identified eEF1A2 binding as the primary anticancer mechanism. A Phase III trial in relapsed/refractory multiple myeloma showed plitidepsin plus dexamethasone extended median progression‑free survival to 3.8 months versus 1.9 months with dexamethasone alone. Single‑agent activity in other hematologic and solid tumours has been modest. Early‑stage studies (Phase I proof‑of‑concept, real‑world cohorts) reported antiviral activity against SARS‑CoV‑2, including against the B.1.1.7 variant, and reductions in viral load in hospitalized patients, but data remain limited and a Phase III COVID‑19 trial is still pending.

Reported Benefits

In multiple myeloma, plitidepsin improves progression‑free survival when combined with dexamethasone and has a tolerable safety profile. In vitro and ex vivo studies demonstrate potent inhibition of SARS‑CoV‑2 replication, outperforming some other host‑directed agents and remdesivir, and early clinical observations suggest possible viral‑load reduction and clinical improvement in COVID‑19 patients.

Limitations of the Evidence

Antitumor efficacy as a single agent is limited and results in other cancers have been disappointing. COVID‑19 evidence is preliminary, derived from small, uncontrolled studies and a single Phase I trial; the drug is not yet approved for viral infection. Intravenous infusion restricts use to hospital settings, and the need for combination with dexamethasone adds complexity.

Safety Considerations

Pharmacokinetic analyses in cancer patients show linear plasma clearance, dose‑proportional exposure up to 8 mg/m², and no clinically relevant covariates affecting drug levels. The safety profile has been described as tolerable, with no major organ‑function predictors of adverse events. However, detailed adverse‑event rates are not provided in the cited abstracts, and careful monitoring is advised during IV administration.

How It Is Administered

Plitidepsin is given intravenously, typically as a 1–24 hour infusion. Clinical studies have used doses ranging from 0.13 to 8 mg/m² administered weekly, bi‑weekly, or daily for five consecutive days in a 21‑day cycle. Formulations are supplied for IV use only.

Routes of Administration

Goals & Uses

• Antiviral activity against SARS-CoV-2Infectious DiseaseLow
• Solid tumor treatmentOncologyLow
• COVID‑19 Antiviral TherapyInfectious DiseaseModerate
• Multiple MyelomaOncologyHigh
• Treatment of T-cell lymphomasOncologyLow
• Treatment of relapsed/refractory multiple myelomaOncologyModerate

Contraindications

• Hypersensitivity to plitidepsinAllergyHigh
• Severe hepatic impairment (Child‑Pugh C)Liver DiseaseHigh
• Severe hepatic impairmentOrganHighLiver function concerns
• Severe renal impairmentOrganModerateKidney function concerns
• PregnancyPopulationModeratePotential fetal risk or insufficient safety data
• Active serious infectionInfectionModerate
• Known hypersensitivity to plitidepsin or excipientsAllergyHigh

Adverse Effects

• Peripheral neuropathyNeurologicalUncommon
• HepatotoxicityHepaticUncommonLiver injury or dysfunction
• Elevated transaminasesHepaticCommon
• Hematologic toxicity (neutropenia, thrombocytopenia)HematologicCommon
• Nausea and vomitingGastrointestinalCommon
• NeutropeniaHematologicCommonLow neutrophil count
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• FatigueGeneralCommonLow energy or tiredness
• VomitingGastrointestinalUncommonForceful expulsion of stomach contents
• Fatigue/astheniaGeneralCommon
• Myopathy/myalgiaMusculoskeletalCommon

Drug Interactions

• CYP3A4 inducers (e.g., rifampin)Moderate
• Myelosuppressive agents (e.g., cyclophosphamide)Moderate
• DexamethasoneLow
• Strong CYP3A4 inhibitors (e.g., ketoconazole)High
• P-glycoprotein (P-gp) substrates/inhibitorsModerate
• CYP3A4 inducers (e.g., rifampicin, carbamazepine)Moderate
• CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin)High

Population Constraints

• Pediatric patientsAgeRelative
• Patients with hepatic impairmentOrgan FunctionRelative
• Elderly patients (≥75 years)AgeRelative
• Pregnant or breastfeeding womenReproductiveAbsolute
• Elderly (>75 years)GeriatricRelative

Regulatory Status

• AUApprovedApproved: relapsed/refractory multiple myelomaApproved by TGA under brand Aplidin.
• European UnionUnapprovedNot granted marketing authorization; under evaluation.
• United StatesUnapprovedInvestigational; clinical trials ongoing.
• United KingdomUnknownNo MHRA approval documented; status follows EU investigational classification post-Brexit.

Approved in Australia (TGA) for multiple myeloma; not approved in the United States or European Union, where it remains investigational.

Evidence & Sources

• Plitidepsin: a potential new treatment for relapsed/refractory multiple myeloma
  Journal ArticleModerateLeisch M, Egle A, Greil R2019-01-01T00:00:00.000000Z
• Bioactive natural products in COVID-19 therapy
  Journal ArticleModerateWang Z, et al.2022-01-01T00:00:00.000000Z
• Pharmacological reprogramming of plitidepsin as a SARS-CoV-2 inhibitor
  Journal ArticleModerateJimeno J, et al.2025-01-01T00:00:00.000000Z
• Population pharmacokinetics meta-analysis of plitidepsin (Aplidin) in cancer subjects
  Journal ArticleHighNalda-Molina R, et al.2009-01-01T00:00:00.000000Z
• Plitidepsin: design, development, and potential place in therapy
  Journal ArticleModerateAlonso-Álvarez S, et al.2017-01-01T00:00:00.000000Z
• Plitidepsin: Mechanisms and Clinical Profile of a Promising Antiviral Agent against COVID-19
  Journal ArticleModeratePapapanou M, et al.2021-01-01T00:00:00.000000Z

Frequently Asked Questions