Valspodar
Also known as: Cyclosporin D analogue MDR inhibitor, PSC 833, PSC-833, PSC833, SDZ PSC 833, Valspodar
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Summary
Valspodar (PSC‑833) is a synthetic cyclic peptide derived from cyclosporin D that acts as a multidrug‑resistance (MDR) modulator. It was investigated in research settings as a P‑glycoprotein (P‑gp/ABCB1) inhibitor intended to improve the efficacy of chemotherapy in acute myeloid leukaemia, multiple myeloma, ovarian cancer and solid tumours. The compound was never approved for clinical use and its development was discontinued after mixed trial results and notable toxicity.
Mechanism of Action
Valspodar binds with high affinity to the MDR1‑encoded P‑glycoprotein transporter, blocking its drug‑efflux activity at intestinal, hepatic, blood‑brain barrier and tumour cell membranes. By inhibiting P‑gp, it raises intracellular concentrations of co‑administered chemotherapeutics. The molecule is also a substrate of cytochrome P450 3A (CYP3A), leading to reciprocal pharmacokinetic interactions that can alter both its own and partner drug levels. Unlike cyclosporin A, it lacks immunosuppressive and nephrotoxic activity.
What the Research Shows
Pre‑clinical work showed that valspodar reverses P‑gp‑mediated resistance more potently than cyclosporin A or verapamil. Early phase I/II trials reported achievable plasma levels with reversible cerebellar ataxia as the dose‑limiting toxicity and suggested activity in acute myeloid leukaemia, multiple myeloma and ovarian cancer. A phase III trial in relapsed/refractory multiple myeloma added valspodar to VAD chemotherapy but did not improve response rates, progression‑free survival, or overall survival, while markedly increasing grade ≥ 3 toxicity. Subsequent phase I studies combining oral valspodar with paclitaxel or with liposomal doxorubicin showed safety at reduced chemotherapy doses, modest pharmacokinetic interactions, and limited efficacy, prompting discontinuation of its clinical development.
Reported Benefits
In vitro and animal models consistently demonstrated that valspodar can restore sensitivity of P‑gp‑overexpressing cancer cells to a range of chemotherapeutics. Early clinical studies indicated that plasma concentrations sufficient for MDR reversal are attainable, and reversible ataxia was the main adverse effect, suggesting a manageable safety profile when dosing was carefully controlled. The oral formulation achieved roughly 60 % bioavailability, facilitating combination regimens in trial settings.
Limitations of the Evidence
Phase III data failed to show any therapeutic advantage over standard chemotherapy, and toxicity was substantially higher, requiring dose reductions of co‑administered agents. Pharmacokinetic interactions with drugs such as paclitaxel and doxorubicin complicated dosing. Development was halted, and the compound remains investigational without regulatory approval. Evidence for clinical benefit is therefore limited to early‑phase trials and pre‑clinical observations.
Safety Considerations
The most frequent adverse event was transient, reversible cerebellar ataxia, often dose‑limiting. Grade 3–4 neutropenia and increased hepatic enzymes (hyperbilirubinaemia, transaminitis) were reported in combination studies. Adding valspodar to chemotherapy increased the incidence of grade ≥ 3 toxicity compared with chemotherapy alone. Because valspodar is a CYP3A substrate, it can alter the metabolism of co‑administered drugs, necessitating careful monitoring and dose adjustments.
How It Is Administered
Valspodar has been studied both intravenously and orally. An oral formulation with about 60 % bioavailability was used in phase I trials, administered four times daily for short courses (e.g., 12 doses). In combination regimens, chemotherapy doses were often reduced to mitigate enhanced toxicity. The drug is supplied as a research‑grade compound, not as a marketed pharmaceutical product.
Routes of Administration
Goals & Uses
- Reversal of multidrug resistance in cancerOncology / Pharmacology ResearchModerate
- Improved chemotherapy efficacy in solid tumorsOncology / Solid TumorsLow
- Improved chemotherapy efficacy in AMLOncology / Hematologic MalignancyLow
- Multidrug resistance reversalOncologyModerate
Contraindications
- Severe hepatic impairmentOrganHighLiver function concerns
- Concurrent use with drugs highly dependent on CYP3A4/P-gp for clearanceDrug InteractionHigh
- Hypersensitivity to cyclosporine or its analoguesAllergyHigh
Adverse Effects
- Hypersensitivity reactionsImmunologicRare
- NeurotoxicityNeurologicalUncommon
- Hepatotoxicity (elevated transaminases)HepaticUncommon
- Enhanced chemotherapy toxicity (myelosuppression, neuropathy)Pharmacokinetic Interaction Mediated ToxicityCommon
- Nausea/vomitingGastrointestinalCommon
- Nausea and vomitingGastrointestinalCommon
- Neurotoxicity (tremor, paresthesia)NeurologicalRare
- Hyperbilirubinemia / hepatotoxicityHepaticUncommon
Drug Interactions
- DoxorubicinHigh
- DigoxinLow
- PaclitaxelModerate
- Cyclosporin AModerate
- EtoposideModerate
- VincristineHigh
Population Constraints
- PregnancyReproductive SafetyAbsolute
- Patients with significant hepatic dysfunctionOrgan ImpairmentRelative
- Pediatric patientsAgeRelative
- Pregnant womenReproductiveAbsolute
- Severe hepatic impairmentOrgan ImpairmentRelative
Regulatory Status
- European UnionInvestigationalEvaluated in European clinical trials; not authorized.
- United StatesInvestigationalInvestigational New Drug (IND) filed; never received FDA approval.
- United KingdomInvestigationalNo marketing authorization; used only in research settings.
Development discontinued after mixed efficacy results and safety concerns; not approved in any jurisdiction.
Evidence & Sources
- Journal ArticleModerateRobak T, et al.2011-01-01T00:00:00.000000Z
- Journal ArticleModerateBerg D, et al.1999-01-01T00:00:00.000000Z
- Journal ArticleModerateTai HL2000-01-01T00:00:00.000000Z
- Journal ArticleModerateFriedenberg WR, et al.2006-01-01T00:00:00.000000Z
- Journal ArticleModerateFracasso PM, et al.2023-01-01T00:00:00.000000Z
- Journal ArticleModerateAdvani R, et al.2005-01-01T00:00:00.000000Z
Frequently Asked Questions
What type of compound is valspodar?
Valspodar is a synthetic cyclic peptide analogue of cyclosporin D designed to inhibit the P‑glycoprotein drug‑efflux transporter and thereby reverse multidrug resistance in cancer cells.
Why is valspodar not used in routine cancer treatment?
Phase III clinical testing in multiple myeloma showed no improvement in response or survival, while toxicity was higher than with chemotherapy alone. Development was stopped, and the drug has never received regulatory approval.
What are the main side effects observed with valspodar?
The dose‑limiting toxicity is reversible cerebellar ataxia. Additional adverse events include severe neutropenia, liver enzyme elevations, and increased overall grade ≥ 3 toxicity when combined with chemotherapy.
How does valspodar interact with other drugs?
Valspodar blocks P‑gp at intestinal, hepatic and blood‑brain barrier sites, raising the exposure of co‑administered agents. It is also metabolised by CYP3A, so it can both inhibit and be affected by other CYP3A substrates, often requiring dose adjustments.
Is valspodar available for clinical use?
No. The compound is classified as a research‑only agent and has been withdrawn from development after disappointing trial results. It is not marketed or approved for any therapeutic indication.
What is Valspodar?
Valspodar (PSC‑833) is a synthetic cyclic peptide derived from cyclosporin D that acts as a multidrug‑resistance (MDR) modulator. It was investigated in research settings as a P‑glycoprotein (P‑gp/ABCB1) inhibitor intended to improve the efficacy of chemotherapy in acute myeloid leukaemia, multiple myeloma, ovarian cancer and solid tumours. The compound was never approved for clinical use and its development was discontinued after mixed trial results and notable toxicity.
What is Valspodar used for?
Valspodar is educationally associated with: Reversal of multidrug resistance in cancer, Improved chemotherapy efficacy in solid tumors, Improved chemotherapy efficacy in AML, Multidrug resistance reversal. Educational only — not medical advice.
How is Valspodar administered?
Recorded routes of administration: Intravenous, Oral.
What are the potential side effects of Valspodar?
Reported adverse effects include: Hypersensitivity reactions, Neurotoxicity, Hepatotoxicity (elevated transaminases), Enhanced chemotherapy toxicity (myelosuppression, neuropathy), Nausea/vomiting, Nausea and vomiting, Neurotoxicity (tremor, paresthesia), Hyperbilirubinemia / hepatotoxicity. This list is not exhaustive — consult a qualified clinician.
Who should avoid Valspodar?
Recorded contraindications: Severe hepatic impairment, Concurrent use with drugs highly dependent on CYP3A4/P-gp for clearance, Hypersensitivity to cyclosporine or its analogues. Consult a qualified clinician before use.