Comprehensive Analysis of the Third-Generation Platinum Antineoplastic Agent: Lobaplatin

Executive Summary

Lobaplatin is a third-generation, organometallic platinum-based antineoplastic agent, classified as a small molecule, that represents a significant evolution in the development of platinum chemotherapy.[1] It functions as a DNA alkylating pro-drug; following intravenous administration and intracellular hydrolysis, it forms highly reactive platinum complexes that create covalent inter- and intra-strand cross-links with DNA. This process inhibits DNA replication and transcription, ultimately leading to cell cycle arrest and apoptosis.[2]

The drug holds exclusive marketing approval in China for the treatment of small cell lung cancer (SCLC), inoperable metastatic breast cancer, and chronic myelogenous leukemia (CML).[2] Clinical trials have demonstrated its non-inferiority to cisplatin in SCLC but with a markedly improved safety profile, and it has shown exceptional promise in triple-negative breast cancer (TNBC), where its addition to neoadjuvant chemotherapy more than doubled the rate of total pathological complete response.[5]

Lobaplatin's primary clinical advantage is its differentiated safety profile compared to first- and second-generation platinum agents. It exhibits significantly lower incidences of nephrotoxicity, neurotoxicity, and severe gastrointestinal toxicity, which are the dose-limiting factors for cisplatin.[3] This improved tolerability is offset by a different primary toxicity: dose-limiting thrombocytopenia.[2] While its global approval is restricted, Lobaplatin's unique profile as a potent and better-tolerated alternative to older platinum agents warrants further investigation, particularly in patient populations intolerant to cisplatin and in settings of platinum resistance.

Chemical Identity and Physicochemical Properties

Nomenclature and Standard Identifiers

Lobaplatin is identified by a range of names and codes that are essential for its unambiguous classification in scientific and regulatory databases.

• Generic Name: Lobaplatin.[1]
• International Nonproprietary Name (INN) Variants: The INN is adapted for different languages, including Lobaplatine (French), Lobaplatino (Spanish), and Lobaplatinum (Latin).[3]
• Systematic (IUPAC) Names: Due to its complex coordination chemistry, several systematic names are used, including cis-platinum and 1,2-diammino-methyl-cyclobutane-platinum (II) lactate.[2]
• Synonyms and Development Codes: Throughout its development and in research literature, it is frequently referred to by its initial research code, D-19466 (also D 19466 or D19466), as well as NSC-741422.[3]
• Brand Name: In the markets where it is available, Lobaplatin is sold under the trade name Dacotin.[17]
• Registry Numbers: Key identifiers for database cross-referencing are as follows:
• CAS Number: 135558-11-1 (A deprecated CAS number, 131374-93-1, is also associated with the compound).[1]
• DrugBank ID: DB13049.[1]
• UNII: OX5XK1JD8C.[2]
• PubChem CID: 10000860.[2]
• ChEBI ID: CHEBI:192744.[2]

Molecular Structure and Formulation

Lobaplatin is an organometallic compound characterized by a central platinum(II) atom coordinated with two distinct ligands, a structural design that is fundamental to its pharmacological profile.[1]

• Core Structure: The molecule's core is a platinum(II) metal center, which is the reactive component responsible for its cytotoxic effects.[18]
• Ligands: The platinum center is coordinated to:

1. A bidentate amine ligand, 1,2-bis(aminomethyl)cyclobutane, which is a stable, non-leaving group that anchors the complex.[19]
2. A bidentate lactic acid ligand, which functions as the leaving group during intracellular activation.[19] The chemical stability of this lactate group is a key structural feature that differentiates Lobaplatin from earlier platinum drugs. Cisplatin's high reactivity and associated toxicities, such as nephrotoxicity, are linked to the relative instability of its chloride ligands, which are easily displaced by water molecules in the bloodstream.[1] The more stable lactate ligand in Lobaplatin hydrolyzes less readily, reducing non-specific reactions with biomolecules and thereby contributing to its lower toxicity profile.[2]

• Stereochemistry: The drug is formulated and administered as an approximate 50/50 diastereometric mixture of its R,R,S- and S,S,S-configurations.[2] While stereoisomers can possess distinct pharmacological and toxicological properties, the available literature does not differentiate the activities of Lobaplatin's individual isomers. This suggests that the isomers may have comparable activity or that their separation was not pursued during development, leaving an open question for future research regarding whether a single isomer could offer an improved therapeutic index.
• Chemical Formula: The molecular formula for Lobaplatin is .[1]
• Molecular Weight: The average molecular weight is approximately 397.33 g/mol, with a monoisotopic mass of 397.096534 Da.[1]
• Structural Identifiers: For precise computational and database identification, the following are used:
• InChIKey: RLXPIABKJFUYFG-DOYDWZMXSA-M.[10]
• SMILES: C[C@@H](C(=O)[O-])[O-].C1C[C@H]([C@@H]1CN)CN.[Pt+2].[10]

Physical and Chemical Properties

• Appearance: Lobaplatin is a white to beige crystalline powder.[20]
• Solubility: It is characterized as a water-soluble platinum compound.[12] Specific solubility values vary but are reported as high as 72.9 mg/mL [1] and  50 mg/mL in water.[22] It is important to note that its activity can be inactivated by DMSO, and it should not be dissolved in sodium chloride solutions, which can induce degradation.[22]
• Stability and Storage: The compound is stable enough for shipment under ambient temperatures. For long-term storage (months to years), a temperature of -20°C is recommended. Prepared stock solutions should be kept at 0-4°C for short-term use or -20°C for long-term storage.[11]
• Melting Point: Lobaplatin melts at 220°C with decomposition.[2]

Comprehensive Pharmacological Profile

Mechanism of Antineoplastic Action

Lobaplatin exerts its anticancer effects through a well-defined mechanism shared by other platinum-based agents, but with distinct chemical properties that influence its activity and safety.[1]

• Classification: It is classified as a DNA alkylating agent and an inhibitor of DNA synthesis.[16]
• Pro-drug Activation: Lobaplatin is a pro-drug, meaning it is administered in a relatively inert state and requires chemical transformation in the body to become cytotoxic.[2]
• Hydrolysis: Upon entering the low-chloride intracellular environment, the lactate leaving group dissociates from the platinum center. This hydrolysis event forms a charged and highly reactive aquated platinum complex, which is the active form of the drug.[2]
• DNA Cross-linking: The activated platinum complex is a strong electrophile that covalently binds to nucleophilic sites on DNA, preferentially at guanine- and adenine-rich sequences.[12] This binding results in the formation of DNA-drug adducts, primarily as intra-strand and inter-strand cross-links between adjacent guanine-guanine (GG) or guanine-adenine (GA) bases.[2]
• Cellular Consequences: These cross-links create a physical distortion in the DNA double helix, which sterically hinders the processes of DNA replication and transcription.[3] The cell's machinery recognizes this extensive and irreparable DNA damage, leading to the activation of signaling pathways that cause cell cycle arrest, typically at the G1 and G2/M checkpoints, and subsequent induction of apoptosis (programmed cell death).[2]
• Apoptotic Pathway Modulation: The apoptotic process is driven by Lobaplatin's influence on key regulatory proteins. It has been shown to upregulate the expression of pro-apoptotic proteins such as Bax and initiator and effector caspases, while downregulating the expression of anti-apoptotic proteins like Bcl-2.[22] Furthermore, Lobaplatin affects the expression of the c-myc oncogene, a critical regulator of both cell proliferation and apoptosis.[2]

Pharmacodynamics

The pharmacodynamic properties of Lobaplatin describe the relationship between drug concentration and its therapeutic and toxic effects on the body.

• Primary Effect: The principal pharmacodynamic effect is a dose-dependent inhibition of tumor cell growth and induction of apoptosis.[15]
• Dose-Limiting Toxicity (DLT): Across numerous clinical trials, the consistent and primary DLT for Lobaplatin is thrombocytopenia.[2] This indicates that the bone marrow, specifically the megakaryocytes responsible for platelet production, is the most sensitive tissue to the drug's cytotoxic effects at clinically relevant doses.
• Maximum Tolerated Dose (MTD): As a single agent, the MTD is generally established at 60 mg/m² administered every 3 to 4 weeks.[2] In combination regimens, such as with docetaxel, the MTD for Lobaplatin may be lower; one Phase I study identified it as 35 mg/m².[24]
• Exposure-Toxicity Relationship: A crucial pharmacodynamic characteristic of Lobaplatin is the strong, direct correlation observed between systemic drug exposure—measured as the Area Under the Curve (AUC) of ultrafilterable (free) platinum—and the degree of thrombocytopenia. This relationship (correlation coefficient, r = 0.72) provides a predictable link between pharmacokinetics and the primary toxicity.[29]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Lobaplatin is defined by its intravenous administration and its strong dependence on renal function for elimination.

• Absorption: As Lobaplatin is administered exclusively via intravenous injection or infusion, oral absorption is not a relevant parameter.[2]
• Distribution: The distribution of platinum following Lobaplatin administration differs based on whether it is free or protein-bound. The mean steady-state volume of distribution () for free platinum is approximately 0.44 L/kg, indicating that the active drug is largely confined to the systemic circulation. In contrast, the  for total platinum is much larger (ranging from 0.64 to 3.95 L/kg), reflecting its extensive and irreversible binding to plasma proteins and subsequent distribution into tissues.[30]
• Metabolism: Lobaplatin does not undergo significant enzymatic metabolism in the liver. Its primary "metabolic" step is the non-enzymatic hydrolysis to its active form within cells.[2] The drug remains largely intact in the plasma until it is cleared from the body.[25]
• Excretion: The primary route of elimination for Lobaplatin and its platinum species is renal excretion via glomerular filtration.[25] The kinetics of this process are biphasic and markedly different for the free versus protein-bound drug:
• Ultrafilterable (Free) Platinum: The active form of the drug is cleared rapidly from the plasma, with a final elimination half-life () of approximately 131 minutes and a clearance of about 125 mL/min/1.73 m².[29]
• Total Platinum: Due to irreversible binding to plasma proteins, the elimination of total platinum is extremely slow, with a terminal half-life of approximately 6.8 days.[29] This long half-life does not represent active drug but rather the slow turnover rate of the proteins to which platinum is bound.[31] While the immediate toxicity is linked to the free fraction, this long-term reservoir of bound platinum represents a systemic burden that could theoretically contribute to cumulative toxicities over multiple cycles, an area that warrants further investigation.
• Influence of Organ Function:
• Renal Function: The pharmacokinetics of Lobaplatin are highly dependent on renal function. Patients with impaired renal function exhibit decreased drug clearance, which leads to a longer half-life and consequently higher systemic exposure (AUC). This increased exposure is directly linked to more severe hematological toxicity.[29] This predictable chain of events—from renal function to clearance, to exposure, to toxicity—allows for a more rational approach to dosing. A specific formula, , was developed based on the strong linear correlation () between creatinine clearance () and ultrafilterable platinum clearance. This enables personalized dose adjustments in patients with a creatinine clearance of  30 mL/min/1.73 m² to target a specific AUC and manage thrombocytopenia.[29]
• Hepatic Function: In contrast to renal impairment, studies have shown that impaired liver function does not significantly alter the pharmacokinetic profile of Lobaplatin.[29]

Clinical Efficacy by Indication: A Review of Key Trials

The clinical utility of Lobaplatin has been established through a series of trials, primarily conducted in China, leading to its approval for specific malignancies. Its investigational use continues to be explored in other cancer types.

Table 4.1: Summary of Key Lobaplatin Clinical Trials
Trial Identifier	Phase	Indication	Regimen(s) Studied	Primary Endpoint(s)	Key Outcome
Phase III (Unnamed) 7	III	Extensive-Stage Small Cell Lung Cancer (ES-SCLC)	Lobaplatin + Etoposide (EL) vs. Cisplatin + Etoposide (EP)	Progression-Free Survival (PFS)	EL was non-inferior to EP for PFS and OS, with a superior safety profile (less nephrotoxicity and vomiting).
ChiCTR-TRC-14005019 5	II	Neoadjuvant Triple-Negative Breast Cancer (TNBC)	Docetaxel + Epirubicin + Lobaplatin (TEL) vs. Docetaxel + Epirubicin (TE)	Total Pathological Complete Response (tpCR)	Addition of Lobaplatin more than doubled the tpCR rate (41.4% vs. 17.8%) and significantly improved 5-year DFS.
NCT03613597 32	II	Limited-Stage Small Cell Lung Cancer (LS-SCLC)	Etoposide + Lobaplatin + TRT vs. Etoposide + Cisplatin + TRT	Survival Outcomes	Completed trial comparing Lobaplatin to cisplatin in combination with thoracic radiotherapy (TRT).
Phase II (Unnamed) 33	II	Locally Advanced Nasopharyngeal Carcinoma (LA-NPC)	Lobaplatin + 5-Fluorouracil (ICT) followed by Lobaplatin + RT (CRT)	Objective Response Rate (ORR)	High ORR (88.1% post-ICT, 100% post-CRT) and favorable 3-year survival rates with tolerable toxicity.

Approved Indications in China

Small Cell Lung Cancer (SCLC)

Lobaplatin is approved for SCLC in China, where it has been positioned as an alternative to cisplatin.[2] A pivotal Phase III randomized trial in 234 patients with previously untreated extensive-stage SCLC (ES-SCLC) directly compared a Lobaplatin-plus-etoposide regimen (EL) against the global standard of cisplatin-plus-etoposide (EP).[7] The results established the non-inferiority of the Lobaplatin-based regimen in terms of efficacy:

• Progression-Free Survival (PFS): Median PFS was 5.1 months for the EL group versus 5.3 months for the EP group ().[7]
• Overall Survival (OS): Median OS was 10.6 months for EL versus 9.7 months for EP ().[7]
• Objective Response Rate (ORR): The ORR showed a trend favoring the EL arm at 67.6% versus 53.9% for the EP arm ().[7]

The most significant finding of this trial was the superior safety and tolerability of the EL regimen. Patients receiving Lobaplatin experienced significantly lower rates of grade 3/4 vomiting (0.8% vs. 11.7%), nausea, and nephrotoxicity (2.5% vs. 11.7%). This was counterbalanced by a higher rate of grade 3/4 thrombocytopenia in the EL group (28.9% vs. 10.8%). Overall quality of life was better in the Lobaplatin arm, establishing it as an effective and better-tolerated first-line option for ES-SCLC.[7]

Metastatic Breast Cancer

Lobaplatin is approved for inoperable metastatic breast cancer, with the most compelling evidence emerging from trials in triple-negative breast cancer (TNBC).[2] A randomized Phase II trial (ChiCTR-TRC-14005019) evaluated the addition of Lobaplatin to a standard neoadjuvant chemotherapy regimen of docetaxel and epirubicin (TE) for TNBC.[5] The results from the 5-year follow-up were striking:

• Total Pathological Complete Response (tpCR): The addition of Lobaplatin more than doubled the tpCR rate, from 17.8% in the TE group to 41.4% in the TEL group (). This is a clinically meaningful improvement in a key surrogate endpoint that is strongly correlated with long-term survival in TNBC.
• Overall Response Rate (ORR): The ORR was significantly higher in the TEL group at 92.9% compared to 74.3% in the TE group ().
• Disease-Free Survival (DFS): The improvement in pathological response translated into a significant long-term survival benefit, with a hazard ratio (HR) for DFS of 0.44 (), indicating a 56% reduction in the risk of disease recurrence or death.
• Overall Survival (OS): A strong trend toward improved OS was observed, with an HR of 0.44 ().

This evidence provides a powerful rationale for the use of Lobaplatin in the neoadjuvant setting for TNBC, a cancer subtype that lacks targeted therapies and relies heavily on effective chemotherapy.

Chronic Myelogenous Leukemia (CML)

Although CML is an approved indication for Lobaplatin in China, there is a notable absence of specific, modern clinical trial data in the available literature to support this use.[2] While Phase II trials for CML were completed historically, their results are not detailed.[36] The contemporary treatment landscape for CML has been transformed by highly effective and targeted tyrosine kinase inhibitors (TKIs), which have rendered cytotoxic chemotherapy largely obsolete for this disease.[37] This discrepancy suggests that the approval may be based on older data from a pre-TKI era, and the practical clinical relevance of Lobaplatin for CML today is likely minimal.

Investigational Uses

Lobaplatin continues to be evaluated in a range of other malignancies:

• Osteosarcoma: It is under investigation as a second-line treatment in combination with gemcitabine and in a neoadjuvant setting with other agents.[1]
• Hepatocellular Carcinoma (HCC): Lobaplatin has been the subject of clinical trials for liver cancer.[1]
• Nasopharyngeal Carcinoma (NPC): A Phase II study combining Lobaplatin with 5-fluorouracil and radiotherapy showed high response rates (100% ORR post-treatment) and encouraging 3-year survival rates (94.9% OS), with manageable toxicity.[33] It is also part of an ongoing Phase III trial.[39]
• Other Tumors: Early-phase trials have explored its activity in esophageal and ovarian cancers, among others.[17]

Safety, Tolerability, and Risk Management

Profile of Adverse Drug Reactions (ADRs)

The safety profile of Lobaplatin is distinct from that of earlier platinum agents, characterized by a shift in primary toxicity from organ systems to the bone marrow.

• Dose-Limiting Toxicity: The most significant and consistently reported DLT is thrombocytopenia, which frequently necessitates dose modifications or treatment delays.[2]
• Hematological Toxicity: Myelosuppression is the most common category of adverse events.[9] This includes:
• Thrombocytopenia (low platelets)
• Neutropenia/Leukopenia (low white blood cells)
• Anemia (low red blood cells)
• Agranulocytosis (a severe deficiency of granulocytes).[2]
• Gastrointestinal Toxicity: Nausea and vomiting are common but are significantly less frequent and severe compared to cisplatin and are typically well-managed with standard antiemetic therapy.[2]
• Nephrotoxicity: Lobaplatin demonstrates a major safety advantage over cisplatin with a significantly lower risk of kidney damage. Consequently, the extensive pre- and post-hydration required for high-dose cisplatin is not necessary with Lobaplatin.[3]
• Neurotoxicity and Ototoxicity: The risks of peripheral neuropathy and hearing damage are also substantially lower than with cisplatin and carboplatin.[3]
• Other ADRs: Other reported side effects include alopecia, fatigue, and hypersensitivity reactions ranging from skin rashes to, rarely, anaphylaxis.[41]

This "toxicity shift" is a critical aspect of Lobaplatin's clinical profile. It is not universally less toxic than its predecessors but rather possesses a different spectrum of toxicities. This allows for more tailored patient selection; for instance, a patient with pre-existing renal dysfunction may be a suitable candidate for Lobaplatin, whereas a patient with poor bone marrow reserve would be at high risk for severe complications.

Contraindications, Warnings, and Precautions

Based on its known toxicities, the use of Lobaplatin is contraindicated or requires significant caution in certain patient populations.

• Contraindications:
• Known hypersensitivity to Lobaplatin or other platinum-containing compounds.[17]
• Severe pre-existing bone marrow suppression.[17]
• Severe pre-existing renal impairment.[17]
• Warnings and Precautions:
• Caution is advised in patients with pre-existing cardiovascular disease, as chemotherapy can potentially exacerbate cardiac conditions.[17]
• Patients with severe functional disorders of the heart or liver should be treated with caution.[43]

Management of Drug-Drug Interactions

Interactions with Lobaplatin primarily involve additive pharmacodynamic effects that can potentiate toxicity.

• Nephrotoxic Agents: Co-administration with other drugs known to cause kidney damage, such as aminoglycoside antibiotics or non-steroidal anti-inflammatory drugs (NSAIDs), may increase the risk of nephrotoxicity, even though Lobaplatin's intrinsic risk is low.[17]
• Myelosuppressive Agents: The risk of severe bone marrow suppression is increased when Lobaplatin is used concurrently with other myelosuppressive chemotherapies or with radiation therapy.[17] Careful monitoring of blood counts is essential.
• Anticoagulants: Due to the high risk of thrombocytopenia, co-administration with anticoagulants like warfarin may increase the risk of bleeding. Close monitoring of coagulation parameters and platelet counts is necessary.[17]
• 5-Fluorouracil (5-FU): Studies show that Lobaplatin has a synergistic interaction with 5-FU, similar to that of cisplatin. A prolonged (e.g., 24-hour) infusion of 5-FU is more effective in combination with Lobaplatin than a short-term bolus application.[44]

Comparative Assessment and Place in Therapy

Lobaplatin's position in oncology is best understood through direct comparison with other platinum agents, highlighting its unique balance of efficacy and toxicity.

Lobaplatin vs. Cisplatin and Carboplatin

Lobaplatin was developed to improve upon the therapeutic index of first-generation (cisplatin) and second-generation (carboplatin) agents.

Table 6.1: Comparative Profile of Platinum Agents
Feature	Cisplatin (1st Gen)	Carboplatin (2nd Gen)	Lobaplatin (3rd Gen)
Primary Efficacy	High, broad-spectrum	Slightly lower than cisplatin in some tumors	Comparable or superior to cisplatin in clinical/preclinical models 2
Dose-Limiting Toxicity	Nephrotoxicity, Neurotoxicity, Ototoxicity	Myelosuppression (Thrombocytopenia)	Myelosuppression (Thrombocytopenia) 2
Nephrotoxicity	High / Severe	Low	Very Low / Not significant 3
Neuro/Ototoxicity	High / Cumulative	Low	Very Low / Not significant 3
Emetogenic Potential	High	Moderate	Low to Moderate 7
Hydration Required	Yes (Extensive)	No	No 24
Activity in Resistant Models	Baseline	Some activity	Overcomes some forms of cisplatin/carboplatin resistance 3

In direct clinical comparisons, Lobaplatin has demonstrated non-inferior efficacy to cisplatin in ES-SCLC while offering a significantly better quality of life due to reduced organ toxicity.[7] Preclinical studies suggest it may have greater intrinsic anticancer activity than both cisplatin and carboplatin.[2] Compared to carboplatin, which also has myelosuppression as its DLT, some data suggest Lobaplatin may have a more favorable therapeutic effect and safety profile, particularly when combined with immunotherapy.[15] A key advantage of Lobaplatin is its activity in preclinical models that are resistant to cisplatin and carboplatin, suggesting it may have a role in treating relapsed or refractory disease.[3]

Lobaplatin vs. Oxaliplatin

Direct comparative data is scarce. However, a preclinical study in colon cancer cell lines demonstrated that Lobaplatin retained inhibitory activity against cells that had developed resistance to oxaliplatin.[47] This finding suggests a lack of complete cross-resistance and points to a potential clinical niche for Lobaplatin in patients with colorectal or other cancers who have progressed on oxaliplatin-based regimens.

Expert Perspective and Future Outlook

Currently, Lobaplatin's place in therapy is as a regional alternative to cisplatin, primarily in China. Its profile makes it an excellent candidate for patients who are poor candidates for cisplatin due to pre-existing renal impairment, hearing loss, or neuropathy. Its robust efficacy data in neoadjuvant TNBC represents its most promising area for global development.

The primary obstacle to its broader use is its limited regulatory approval outside of China. Future research and development should prioritize:

1. Conducting international, multicenter Phase III trials to confirm the exceptional Phase II results in neoadjuvant TNBC.
2. Initiating clinical trials in patient populations with tumors resistant to cisplatin or carboplatin to validate the preclinical findings of non-cross-resistance.
3. Exploring novel combination strategies with targeted agents, such as PARP inhibitors, and further investigating its synergy with immune checkpoint inhibitors.

Developmental and Regulatory History

Lobaplatin's development followed a fragmented path, which helps explain its current regional-specific regulatory status.

• 1990: The compound was first synthesized in Germany by ASTA Pharma and given the research designation D-19466.[2]
• Early 2000s: Following a corporate restructuring, ASTA Pharma discontinued its development. Further development was undertaken by its successor biopharmaceutical company, Zentaris AG (a part of AEterna Laboratories).[2]
• 2003: Zentaris AG signed a licensing agreement with Hainan Tianwang International Pharmaceutical for the manufacturing and marketing of Lobaplatin exclusively in China.[2]
• 2005: The China National Medical Products Administration (NMPA), then known as the CFDA, approved the production of Lobaplatin in China.[48]
• 2010: Lobaplatin received full approval for clinical use in China for its specified indications.[2]

Despite completing Phase II clinical trials in the United States, the European Union, and other regions, development was not pursued to Phase III or regulatory submission in these markets.[36] Consequently, Lobaplatin is not approved by the U.S. FDA or the European Medicines Agency (EMA).[1] This developmental trajectory, where a drug is passed between companies and ultimately licensed for a specific regional market, often occurs when a compound shows clear clinical promise but is not prioritized for global development by its parent company. This history has been the primary factor limiting Lobaplatin's impact on global oncology practice.

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