A Comprehensive Monograph on Vindesine (DB00309): From Botanical Origins to Clinical Application and Market Realities

Executive Summary

Vindesine is a second-generation, semisynthetic vinca alkaloid, a potent antineoplastic agent derived from the natural product vinblastine. As a member of the antimicrotubule class of chemotherapeutics, its primary mechanism of action involves the inhibition of tubulin polymerization, which disrupts the formation of the mitotic spindle, leading to cell cycle arrest in metaphase and subsequent apoptosis. This report provides a comprehensive examination of Vindesine, identified by DrugBank ID DB00309 and CAS Number 53643-48-4, synthesizing data from its botanical origins to its current clinical and regulatory standing.

Clinically, Vindesine established a crucial niche in the treatment of various malignancies, most notably as a salvage therapy for acute lymphoblastic leukemia (ALL) in pediatric patients who have developed resistance to the first-generation vinca alkaloid, vincristine. Its activity also extends to lymphomas, melanoma, breast cancer, and lung cancer, typically as a component of combination chemotherapy regimens. The pharmacological profile of Vindesine is distinguished by its high potency and a lack of complete cross-resistance with vincristine, underpinning its value in second-line treatment protocols. However, its therapeutic utility is balanced by significant dose-limiting toxicities, primarily myelosuppression (specifically granulocytopenia) and peripheral neurotoxicity, which require careful clinical management and dose adjustment.

The metabolism of Vindesine is predominantly hepatic, mediated by the CYP3A4 isoenzyme, rendering it highly susceptible to a wide range of drug-drug interactions that can dangerously alter its therapeutic index. Administration is strictly intravenous, with extreme caution required to prevent fatal outcomes from inadvertent intrathecal injection and severe tissue damage from extravasation.

Despite its established clinical efficacy, Vindesine occupies a precarious position in the modern therapeutic landscape. It is not approved for use in the United States and its availability in other regions, including Europe, is inconsistent and appears to be based on national-level authorizations rather than a centralized marketing approval. This marginalization is not a reflection of clinical failure but rather a consequence of pharmaceutical market dynamics affecting older, off-patent generic drugs. The lack of commercial incentive has led to supply chain fragility, a cessation of new clinical research, and its gradual disappearance from contemporary treatment guidelines. Vindesine thus serves as a compelling case study of a clinically valuable medication becoming a "commercially orphaned" agent, where economic factors, rather than scientific or medical merit, dictate its availability to patients.

Introduction: The Vinca Alkaloid Family and the Development of Vindesine

The discovery and development of the vinca alkaloids represent a landmark achievement in the history of cancer chemotherapy, demonstrating the profound therapeutic potential of natural products. This class of drugs originated from phytochemical investigations into the Madagascar periwinkle, Catharanthus roseus, a plant with a rich history in traditional medicine.[1] The journey of Vindesine begins with this botanical heritage and the scientific drive to refine and improve upon the first-generation agents derived from it.

Botanical and Historical Origins

For centuries, extracts of Catharanthus roseus were used in various systems of folklore medicine for ailments ranging from diabetes to hemorrhage and wound healing.[1] In the 1950s, scientific inquiry into its reputed oral hypoglycemic properties was initiated by independent research groups, including one led by Robert Noble and Charles Beer in Canada.[1] These investigations failed to confirm any anti-diabetic effects; instead, they made a serendipitous and far more significant discovery. Animal studies revealed that plant extracts induced severe leukopenia and bone marrow depression, suggesting a potent cytotoxic effect.[3] This observation pivoted the research focus towards oncology, leading to the isolation and characterization of over 120 distinct alkaloids from the plant.[4]

Among these, two dimeric indole alkaloids, vincaleukoblastine (now vinblastine) and leurocristine (now vincristine), demonstrated remarkable antineoplastic activity.[3] Vinblastine was introduced clinically in the early 1960s for Hodgkin's lymphoma and testicular cancer, while vincristine proved highly effective against childhood leukemias.[1] Their success marked a turning point in oncology, establishing that chemotherapy could be curative for certain cancers and cementing the vinca alkaloids as a cornerstone of treatment.[1]

Rationale for Second-Generation Analogues

The clinical success of vinblastine and vincristine was accompanied by distinct and often severe toxicity profiles. Although structurally very similar—differing only by a methyl versus a formyl group on the vindoline nitrogen—their clinical applications and side effects diverged significantly.[7] Vinblastine's dose-limiting toxicity is primarily myelosuppression, whereas vincristine is limited by its profound neurotoxicity.[4] This dichotomy highlighted that minor modifications to the complex vinca alkaloid scaffold could dramatically alter the biological and toxicological properties of the molecule.

This understanding provided the scientific rationale for developing semisynthetic derivatives. The primary goal was to create novel analogues by chemically modifying the parent structures of vinblastine or vincristine. Researchers aimed to produce compounds with an altered spectrum of antitumoral activity, potentially superior efficacy, and, most importantly, a different or more manageable toxicity profile.[10] Vindesine emerged from this effort as a second-generation analogue, specifically designed to modulate the therapeutic index of its parent compound, vinblastine.[8]

Chemical Synthesis and Development

Vindesine is chemically designated as 3-carbamoyl-4-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine, often referred to more simply as desacetylvinblastine amide.[9] It is a semisynthetic derivative created through the chemical modification of naturally sourced vinblastine.[9] The specific modifications—deacetylation at the C-4 position and the conversion of the C-3 methoxycarbonyl group into a primary carboxamide—were targeted changes intended to alter the molecule's interaction with its biological target and its metabolic fate, thereby shifting the balance between efficacy and toxicity.

Early methods for preparing Vindesine suffered from significant disadvantages, including the use of reagents like Raney nickel that were difficult to manage in large-scale production and led to inconsistent yields.[16] The growing clinical interest in Vindesine, particularly for its activity against vincristine-resistant leukemias, created a pressing need for a more robust and reliable manufacturing process.[16] A subsequent patent described a commercially feasible synthesis suitable for large-scale production. This improved process involves reacting 4-desacetyl vinblastine C-3 carboxazide with a trihydrocarbylphosphine to form a novel intermediate, which is then decomposed with acid to yield Vindesine.[16] This development was crucial, as it highlights a critical and often underappreciated aspect of drug development: the transition from a laboratory discovery to a consistently manufacturable pharmaceutical product. Without a reproducible and scalable synthesis, the clinical potential of Vindesine could not have been fully explored or realized for patient use.

Physicochemical Properties and Drug Identification

A precise understanding of Vindesine's chemical and physical properties is fundamental for its formulation, administration, and study. As a complex small molecule, it is characterized by numerous identifiers and specific experimental properties that define its behavior. It is typically formulated as Vindesine sulfate, a salt form that offers enhanced water solubility and stability compared to the free base, which is crucial for its preparation as an intravenous solution.[10] The key identifiers and physicochemical data for Vindesine are consolidated in the table below.

Property Category	Parameter	Value / Identifier	Source(s)
General Identifiers	Common Names	Vindesine, Eldisine	10
	DrugBank ID	DB00309	10
	CAS Number (Base)	53643-48-4	10
	CAS Number (Sulfate)	59917-39-4	10
	PubChem CID	40839	9
	UNII (Base)	RSA8KO39WH	10
	UNII (Sulfate)	CPH2U7DNDY	10
	ATC Code	L01CA03	8
	KEGG ID	D01769	10
	ChEBI ID	CHEBI:36373	10
Chemical Data	Molecular Formula	C43​H55​N5​O7​	10
	Molar Mass	753.941 g·mol⁻¹	9
	IUPAC Name	methyl (5S,7S,9S)- 9-[(2β,3β,4β,5α,12β,19α)- 3-(aminocarbonyl)- 3,4-dihydroxy- 16-methoxy- 1-methyl- 6,7-didehydroaspidospermidin- 15-yl]- 5-ethyl- 5-hydroxy- 1,4,5,6,7,8,9,10-octahydro- 2H- 3,7-methanoazacycloundecino[5,4-b]indole- 9-carboxylate	10
	InChIKey	HHJUWIANJFBDHT-KOTLKJBCSA-N	10
Experimental Properties	Physical Description	White to off-white crystalline powder	9
	Melting Point	230-232 °C	8
	Solubility (Water)	7.00e-02 g/L	9
	Solubility (Other)	Soluble in Chloroform, Dichloromethane, DMSO, Acetone, etc.	19
	LogP	2.9	9
	Dissociation Constants (pKa)	6.04, 7.67	18

Comprehensive Pharmacology

The pharmacological profile of Vindesine is defined by its potent antimitotic activity, which is characteristic of the vinca alkaloid class. Its effects are rooted in a specific molecular interaction with the cellular cytoskeleton, leading to profound disruptions in cell division. Understanding its mechanism of action, pharmacodynamic properties, and pharmacokinetic behavior is essential for its safe and effective clinical use.

A. Mechanism of Action

Vindesine exerts its cytotoxic effects through a multi-step process that begins with binding to tubulin and culminates in the induction of apoptosis in rapidly dividing cells.

Tubulin Binding and Microtubule Disruption

The primary molecular target of Vindesine is tubulin, the globular protein heterodimer that serves as the fundamental building block of microtubules.[8] Specifically, Vindesine binds to the β-tubulin subunit at a site known as the "Vinca-domain," which is distinct from the binding sites of other microtubule-targeting agents like taxanes.[13] The primary target isoform is the Tubulin beta-1 chain.[13] This binding event physically prevents the polymerization of tubulin dimers into functional microtubules, the dynamic filamentous structures that form a critical part of the cellular cytoskeleton.[8] By inhibiting the assembly of these structures and promoting their disassembly, Vindesine effectively disrupts all cellular processes that depend on a dynamic microtubule network.[24]

Mitotic Arrest

The most critical consequence of microtubule disruption occurs during mitosis, the phase of the cell cycle where a cell divides. Microtubules are essential for the formation of the mitotic spindle, the intricate apparatus responsible for aligning and segregating replicated chromosomes into two new daughter cells.[24] By preventing the formation of a functional spindle, Vindesine causes dividing cells to be unable to proceed past the metaphase stage of mitosis.[8] This results in a potent and definitive cell cycle arrest at the metaphase checkpoint, a hallmark of vinca alkaloid activity.[24] While the primary block is in M-phase, some data also suggest the drug is cell-cycle specific for the S-phase, perhaps indicating an additional, less characterized effect on DNA synthesis or repair processes that also rely on microtubule integrity.[8]

Induction of Apoptosis

A cell that is indefinitely arrested in metaphase cannot complete division and is recognized by internal surveillance mechanisms as critically damaged. This prolonged arrest triggers a cascade of intracellular signaling events that culminate in programmed cell death, or apoptosis.[20] This process involves the activation of pro-apoptotic proteins and the inactivation of anti-apoptotic proteins, such as B-cell lymphoma 2 (BCL-2).[25] The induction of apoptosis is the ultimate mechanism by which Vindesine eliminates rapidly proliferating cancer cells, translating its antimitotic action into a therapeutic effect.

B. Pharmacodynamics

Pharmacodynamically, Vindesine is distinguished from its parent compounds by its relative potency and its activity against certain resistant cell lines.

Potency and Comparative Efficacy

In vitro studies have established Vindesine as a highly potent antimitotic agent. At concentrations designed to arrest 10-15% of cells in mitosis, Vindesine is approximately three times more potent than vincristine and nearly ten times more potent than its direct parent, vinblastine.[8] At higher concentrations that arrest 40-50% of cells, it is roughly equipotent with vincristine.[8] A key differentiating feature observed in these studies is that, unlike vinblastine, Vindesine treatment results in very few postmetaphase cells, suggesting it induces a more complete and irreversible mitotic block from which cells cannot escape.[8]

Cross-Resistance

One of the most clinically significant pharmacodynamic properties of Vindesine is its lack of complete cross-resistance with vincristine.[11] Vindesine has demonstrated clear clinical activity in patients with acute lymphoblastic leukemia (ALL) who have relapsed during or after treatment with vincristine-containing chemotherapy regimens.[8] This clinical observation is profoundly important, as it suggests a subtle but critical difference at the molecular level. While the general mechanism of action is shared across the vinca alkaloid class, the precise binding kinetics of Vindesine to tubulin or its interaction with cellular drug efflux mechanisms, such as P-glycoprotein, must be distinct from those of vincristine. This molecular-level distinction is the likely basis for its ability to overcome vincristine resistance, thereby defining its primary clinical role as a valuable second-line or salvage therapeutic agent.

C. Pharmacokinetics (ADME)

The pharmacokinetic profile of Vindesine dictates its absorption, distribution, metabolism, and elimination (ADME), which collectively determine the drug's exposure and duration of action in the body.

Administration and Absorption

Vindesine is administered exclusively by the intravenous (IV) route, ensuring complete and immediate bioavailability in the systemic circulation.[10] Like other vinca alkaloids, it is not absorbed orally.[23]

Distribution

Following intravenous administration, Vindesine distributes extensively from the plasma into body tissues, which is reflected by its large apparent volume of distribution (Vd​) of 5 L/kg.[29] It is moderately bound to plasma proteins, with a binding percentage of 65-75%.[10]

Metabolism

Vindesine undergoes extensive metabolism in the liver.[8] The biotransformation is primarily mediated by the cytochrome P450 3A4 (CYP3A4) isoenzyme, a critical detail that underpins its susceptibility to numerous drug-drug interactions.[10] This metabolic pathway represents a potential "bottleneck" that can be easily inhibited or induced by co-administered medications. Saturation or inhibition of CYP3A4 can lead to decreased clearance of Vindesine, resulting in elevated plasma concentrations and a significantly increased risk of severe, dose-limiting toxicity.

Excretion

The primary route of elimination for Vindesine and its metabolites is through biliary excretion into the feces.[10] A smaller fraction of the drug is excreted via the kidneys into the urine.[10]

Half-Life and Clearance

The elimination of Vindesine from the body follows a multiphasic pattern. The terminal elimination half-life has been reported as 24 hours in several key sources [8], though another study reports a value of 35 hours.[29] This discrepancy may be attributable to differences in study populations or analytical methodologies. The total body clearance is reported to be 2.20 mL/min/kg.[29]

Parameter	Value	Source(s)
Route of Administration	Intravenous	10
Protein Binding	65-75%	10
Volume of Distribution (Vd​)	5 L/kg	29
Metabolism	Hepatic (CYP3A4-mediated)	10
Primary Elimination Pathway	Biliary / Fecal	10
Clearance (CL)	2.20 mL/min/kg	29
Terminal Half-Life (t1/2​)	24 hours / 35 hours	10

Clinical Profile: Efficacy and Therapeutic Applications

Vindesine has demonstrated clinical activity across a spectrum of hematologic malignancies and solid tumors, typically as part of multi-agent chemotherapy regimens. Its most well-defined role is as a second-line agent in the treatment of acute lymphoblastic leukemia, a position directly resulting from its efficacy in patients with vincristine-resistant disease.

Primary Indications

The foremost clinical application of Vindesine is in the treatment of acute lymphoblastic leukemia (ALL), especially childhood ALL that has become resistant to or has relapsed after therapy with vincristine.[8] This specific indication underscores its value as a salvage agent, providing a crucial therapeutic option when first-line treatments have failed. This clinical utility is a direct consequence of its pharmacological property of not sharing complete cross-resistance with vincristine.

Other primary indications where Vindesine has shown utility include the treatment of the blastic crisis of chronic myeloid leukemia (CML), a highly aggressive phase of the disease.[11] It is also indicated for acute erythraemia and acute panmyelosis.[9]

Secondary and Off-Label Indications

Beyond its primary indications, Vindesine has been incorporated into combination chemotherapy protocols for a variety of other cancers. It has shown activity in:

• Malignant Lymphomas: Including both Hodgkin's disease and non-Hodgkin's lymphomas.[9] Its use in the R-ACVBP (Rituximab, Doxorubicin, Cyclophosphamide, Vindesine, Bleomycin, Prednisone) regimen for diffuse large B-cell lymphoma (DLBCL) has been documented, although its unavailability has led to substitutions with vincristine in modified protocols.[30]
• Malignant Melanoma: Particularly in cases unresponsive to other therapies.[10]
• Breast Cancer: For advanced disease that is unresponsive to endocrine surgery or hormonal therapy.[10]
• Lung Cancer: Specifically in non-oat cell (non-small cell) lung cancer.[9] The combination of Vindesine with cisplatin has been noted as one of the more active regimens for this malignancy.[34]

Clinical Trial Evidence

The available data on clinical trials involving Vindesine points to its historical use in intensive, multi-agent protocols. For instance, it was a component in a consolidation therapy step for high-risk ALL in the LAL1308 trial (NCT01156883), administered alongside drugs like dexamethasone, methotrexate, and ifosfamide.[35] It was also included in combination regimens studied for high-risk neuroblastoma (NCT03042429, NCT00002802).[36]

However, a striking and significant finding is the near-total absence of active or recruiting clinical trials for Vindesine in major clinical trial registries. This is in stark contrast to its parent compounds, vincristine and vinblastine, which are integral components in dozens of ongoing, large-scale clinical trials for a wide array of cancers.[37] This disparity is not readily explained by a lack of efficacy, as Vindesine's activity is well-documented in the literature. Instead, it strongly suggests that the drug has fallen out of favor in contemporary clinical research and development. This decline is likely a direct consequence of the market and supply chain issues that have plagued the drug, creating a self-perpetuating cycle: inconsistent availability discourages its inclusion in new research protocols, and the resulting lack of new data further marginalizes it from evolving clinical practice guidelines. This effectively freezes the drug's evidence base in time, accelerating its obsolescence regardless of its intrinsic therapeutic merit.

Dosage, Administration, and Clinical Management

The clinical use of Vindesine requires meticulous attention to dosing, strict adherence to administration protocols to ensure patient safety, and proactive monitoring for toxicity. Its narrow therapeutic index and potential for severe adverse events necessitate management by healthcare professionals experienced in the use of cytotoxic agents.

Standard Dosing Protocols

Vindesine dosage is calculated based on body surface area (m2) and is highly dependent on the specific indication, the patient population (adult vs. pediatric), and its role within a combination chemotherapy regimen.

• Adults: For most indications, such as advanced breast cancer or CML blast crisis, the usual starting dose is 3 mg/m² administered intravenously once a week.[30]
• Pediatrics: For resistant ALL, a higher starting dose of 4 mg/m² once a week is often used.[30]
• Regimen-Specific Dosing: In specific protocols like R-ACVBP for diffuse large B-cell lymphoma, the dose is 2 mg/m² given on days 1 and 5 of a 14-day cycle.[30]

Subsequent doses are adjusted based on the patient's hematologic tolerance, particularly the granulocyte count, prior to each weekly administration. The maximum recommended total weekly dose is 4 mg/m².[13]

Indication	Patient Population	Starting Dose	Schedule	Source(s)
Resistant Acute Lymphoblastic Leukemia	Pediatric	4 mg/m²	Weekly	30
Advanced Breast Cancer	Adult	3 mg/m²	Weekly	30
CML (Blast Crisis)	Adult	3 mg/m²	Weekly	30
Diffuse Large B-Cell Lymphoma (R-ACVBP)	Adult (≤59 years)	2 mg/m²	Days 1 & 5, every 2 weeks	30

Administration Guidelines: A Critical Safety Section

The administration of Vindesine is associated with severe, potentially life-threatening risks if not performed correctly.

FOR INTRAVENOUS USE ONLY

This is the most critical warning associated with all vinca alkaloids. Inadvertent administration of Vindesine by the intrathecal (into the spine) route is a medical emergency and is nearly always fatal.[21] This catastrophic error leads to ascending paralysis and massive, irreversible neurological damage. To mitigate this risk, global health organizations, including the World Health Organization (WHO) and the U.S. Food and Drug Administration (FDA), have issued stringent guidelines. It is now strongly recommended that vinca alkaloids be prepared and dispensed

only in a small-volume intravenous minibag (e.g., 50 mL of 0.9% NaCl or D5W) for infusion, and NEVER in a syringe.[30] The infusion bag must be prominently labeled with warnings such as "FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES".[40]

Preparation and Handling

As a hazardous cytotoxic agent, Vindesine should be prepared and handled only by trained personnel in a designated area, such as a biological safety cabinet, using appropriate personal protective equipment (gowns, double gloves, eye protection).[30] The infusion is typically administered over a short period, such as 5-15 minutes.[21]

Vesicant Properties and Extravasation Management

Vindesine is a potent vesicant, meaning that if it leaks from the vein into the surrounding subcutaneous tissue (extravasation), it can cause severe pain, inflammation, blistering, and tissue necrosis.[13] Proper needle or catheter placement in a large, stable vein must be confirmed before and monitored during administration. If extravasation is suspected (e.g., patient reports pain, stinging, or swelling at the infusion site), the following protocol must be initiated immediately:

1. Stop the infusion immediately.[30]
2. Leave the cannula in place and attempt to aspirate any residual drug from the line and tissue.
3. Administer a local injection of hyaluronidase (e.g., 150 units/mL) through the existing line or subcutaneously around the site to help disperse the drug.[30]
4. Apply moderate, dry heat to the area to further aid dispersion and reduce local toxicity.[30]
5. The remainder of the dose, if any, must be administered through a new IV site in a different vein.[41]

Dose Adjustments and Monitoring

Careful patient monitoring is essential to manage Vindesine's toxicities.

• Myelosuppression: A complete blood count (CBC) with differential must be performed before each dose.[30] The dose should be withheld if the granulocyte count falls below 1,500/mm³ or the platelet count is below 100,000/mm³.[30]
• Neurotoxicity: Patients must be regularly assessed for signs of peripheral neuropathy (e.g., paresthesias, loss of reflexes). The development of significant neurotoxicity may require dose reduction or temporary discontinuation of the drug.[30]
• Hepatic Impairment: Since Vindesine is cleared by the liver, patients with significant hepatic dysfunction require dose modification. A 50% dose reduction is recommended for patients with a direct bilirubin level greater than 3 mg/dL.[42]

Safety and Tolerability Profile

The therapeutic use of Vindesine is fundamentally limited by its toxicity profile, which is characterized by two major dose-limiting toxicities: myelosuppression and neurotoxicity. A thorough understanding of its adverse effects, contraindications, and drug interactions is paramount for patient safety.

A. Dose-Limiting Toxicities

Myelosuppression

The most common dose-limiting toxicity of Vindesine is bone marrow suppression, primarily manifesting as granulocytopenia (a reduction in neutrophils).[8] The nadir, or lowest point of the granulocyte count, typically occurs 3 to 5 days after administration, with recovery usually complete within 7 to 10 days.[30] This places patients at a transient but significant risk of infection. Thrombocytopenia (low platelet count) and anemia (low red blood cell count) can also occur but are generally less frequent and less severe than with vinblastine, especially with weekly dosing schedules.[26]

Neurotoxicity

The second major dose-limiting toxicity is peripheral neuropathy, a cumulative and often debilitating side effect.[8] The neuropathy is primarily sensory and autonomic. Symptoms typically begin with numbness, tingling, or burning sensations (paresthesias) in the fingers and toes in a classic "stocking-glove" distribution.[21] With continued treatment, this can progress to loss of deep tendon reflexes, muscle weakness, and motor impairment, such as difficulty with fine motor tasks (e.g., buttoning clothes), foot drop, and an ataxic gait.[21] Acute jaw pain, a form of trigeminal neuralgia, can also occur within hours of the first dose.[21] Cranial nerve palsies and autonomic dysfunction leading to severe constipation or paralytic ileus are also well-documented neurotoxic effects.[21]

B. Common and Other Adverse Effects

In addition to the dose-limiting toxicities, Vindesine is associated with a range of other adverse effects. A summary is presented in the table below.

System Organ Class	Adverse Reaction	Frequency / Notes
Blood and Lymphatic System Disorders	Granulocytopenia	Very Common; Dose-limiting
	Anemia, Thrombocytopenia	Common
Nervous System Disorders	Peripheral Neuropathy (sensory, motor)	Very Common; Dose-limiting, cumulative
	Paresthesia, Loss of deep tendon reflexes	Very Common
	Jaw pain, Headache, Dizziness	Common
	Seizures	Rare
Gastrointestinal Disorders	Constipation	Very Common; Can be severe
	Nausea and Vomiting	Common
	Abdominal pain/cramps, Stomatitis	Common
	Paralytic ileus	Uncommon but serious
Skin and Subcutaneous Tissue Disorders	Alopecia (Hair Loss)	Very Common; Usually reversible
	Rash	Common
General Disorders and Administration Site Conditions	Asthenia (Fatigue/Weakness)	Common
	Fever, Chills	Common
	Injection Site Reaction (Phlebitis, Cellulitis)	Common; Vesicant
	Extravasation with tissue necrosis	Potentially severe complication
Respiratory, Thoracic and Mediastinal Disorders	Acute Bronchospasm, Dyspnea	Uncommon; Risk increased with Mitomycin-C

C. Contraindications and High-Risk Populations

Vindesine is absolutely contraindicated in the following situations:

• Intrathecal Administration: This route is fatal.[40]
• Charcot-Marie-Tooth Syndrome: Patients with the demyelinating form of this hereditary neuropathy should not receive Vindesine due to the high risk of severe, irreversible neurotoxicity.[13]
• Pregnancy: Vindesine is classified as Pregnancy Category D. It can cause fetal harm and is teratogenic in animal studies. Women of childbearing potential should use effective contraception during and for a period after treatment.[9]

Caution is required in patients with pre-existing neuromuscular disorders, significant hepatic impairment, or active infections.[42]

D. Drug-Drug Interactions

Vindesine's metabolism via CYP3A4 makes it highly vulnerable to pharmacokinetic drug interactions. Concomitant medications must be carefully reviewed before each dose.

Interacting Agent/Class	Mechanism	Clinical Consequence	Management Recommendation
Strong CYP3A4 Inhibitors (e.g., Ketoconazole, Itraconazole, Ritonavir, Clarithromycin, Grapefruit)	Inhibition of Vindesine metabolism	Increased plasma concentration and exposure, leading to a higher risk of severe myelosuppression and neurotoxicity.	Avoid co-administration if possible. If unavoidable, monitor closely for toxicity and consider a significant Vindesine dose reduction.
Strong CYP3A4 Inducers (e.g., Rifampin, Carbamazepine, Phenytoin, Enzalutamide, St. John's Wort)	Induction of Vindesine metabolism	Decreased plasma concentration and exposure, potentially leading to sub-therapeutic levels and reduced anticancer efficacy.	Avoid co-administration. If unavoidable, monitor for lack of therapeutic effect and consider increasing the Vindesine dose.
Other Neurotoxic Agents (e.g., Platinum agents, Taxanes)	Additive pharmacodynamic toxicity	Increased risk and severity of peripheral neuropathy.	Monitor patients with extreme care for signs of worsening neurotoxicity. Dose adjustments of one or both agents may be necessary.
Mitomycin-C	Unknown	Increased risk of acute bronchospasm and shortness of breath, which can occur minutes to hours after administration.	Monitor respiratory function closely when these agents are used together.
Live Attenuated Vaccines	Pharmacodynamic antagonism	Vindesine is immunosuppressive and can diminish the therapeutic effect of the vaccine while increasing the risk of disseminated infection from the vaccine virus.	Avoid administration of live vaccines during and for at least 3 months after completion of chemotherapy.

Regulatory Status and Current Landscape

The current status of Vindesine is a paradox: it is a drug with well-documented clinical efficacy and a defined therapeutic niche, yet it has become increasingly marginalized and unavailable in major pharmaceutical markets. Its trajectory is defined less by its clinical profile and more by the economic and logistical challenges that affect older, off-patent chemotherapeutic agents.

Regulatory History and Approval Status

A comprehensive review of regulatory databases reveals a complex and fragmented global status for Vindesine.

• United States (FDA): There is no evidence that Vindesine has ever received marketing approval from the U.S. Food and Drug Administration (FDA). The drug is explicitly listed as "Not available in the US".[30] This stands in sharp contrast to its parent compounds, vincristine and vinblastine, which have long histories of FDA approval dating back to the 1960s, as well as newer formulations like liposomal vincristine (Marqibo), which was approved in 2012.[4]
• Europe (EMA): There is no indication of a centralized marketing authorization for Vindesine from the European Medicines Agency (EMA). The EMA's public databases contain orphan drug designations for liposomal vincristine but not for Vindesine.[55] However, a Belgian-based manufacturer, Minakem, holds a European Drug Master File (CEP) for the Vindesine sulfate Active Pharmaceutical Ingredient (API), which facilitates its use in drug products authorized at the national level within EU member states.[56] The drug has been marketed in various European and other countries under brand names such as Eldisine, suggesting it has been subject to individual national regulatory approvals rather than a unified EU-wide authorization.[10]

Current Clinical Utility and Market Challenges

Despite its proven value, particularly in treating refractory leukemias, the clinical use of Vindesine has dramatically declined. This is not due to the emergence of a clinically superior agent for its specific niche, but rather to a market failure driven by pharmaceutical economics and supply chain fragility.

The "unavailability of vindesine in many countries" is explicitly cited as the reason for substituting it with vincristine in the established and effective R-ACVBP chemotherapy regimen for DLBCL.[33] This situation forces clinicians to deviate from evidence-based protocols, potentially altering treatment outcomes, due to logistical and commercial constraints rather than medical judgment. This scenario places Vindesine in the category of a "commercially orphaned" drug. As an old, off-patent generic medication, the financial incentives for manufacturers to maintain production, navigate the complex regulatory requirements of multiple countries, and ensure a stable global supply chain are minimal.

This economic reality is not unique to Vindesine. The broader class of vinca alkaloids has faced similar pressures, exemplified by the critical shortage of vincristine in the U.S. in 2019, which occurred after one of only two suppliers made a "business decision" to cease manufacturing.[57] Vindesine, with its smaller market share and more specialized indications, is even more vulnerable to such market forces. The lack of a stable, predictable supply chain has created a negative feedback loop: its unreliability discourages oncologists and cooperative research groups from including it in new clinical trials. Without new research, it cannot be incorporated into updated clinical practice guidelines. This lack of presence in modern guidelines further reduces demand, reinforcing the low commercial incentive for its production. This cycle accelerates the drug's obsolescence, ensuring its clinical role continues to shrink until it may disappear from practice entirely, irrespective of its intrinsic therapeutic value.

Conclusion

Vindesine is a potent, second-generation semisynthetic vinca alkaloid with a well-defined mechanism of action as an inhibitor of microtubule polymerization. Its development was a rational and successful example of medicinal chemistry, modifying a natural product scaffold to create an analogue with a distinct and clinically valuable profile. Its key advantage—a lack of complete cross-resistance with vincristine—carved out an important therapeutic niche for the drug as a salvage agent in refractory hematologic malignancies, particularly childhood acute lymphoblastic leukemia. This clinical utility, however, is counterbalanced by a significant and challenging toxicity profile, dominated by dose-limiting myelosuppression and cumulative neurotoxicity, which necessitates expert clinical management.

Ultimately, the legacy of Vindesine is now defined as much by the failures of the pharmaceutical market as by its clinical successes. Its current status as a drug that is unavailable in the United States and inconsistently supplied elsewhere highlights a critical vulnerability in the global supply of essential, life-saving generic medicines. The gradual disappearance of Vindesine from the oncologist's armamentarium is not the result of being superseded by a superior drug, but rather a consequence of economic forces that render the continued production of low-profit, off-patent drugs untenable for many manufacturers.

Vindesine serves as a poignant cautionary tale. The science behind the drug is sound, and its clinical value, though specialized, is well-established. Yet, its future in medicine is profoundly uncertain, dictated not by patient need or clinical evidence, but by the economic realities of the modern pharmaceutical landscape. Its story underscores the urgent need for new models to ensure the sustained availability of older, essential medicines that remain critical components of cancer care.

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