Gimeracil: A Pivotal Pharmacokinetic Modulator and DNA Repair Inhibitor Defining Modern Oral Fluoropyrimidine Therapy

1.0 Executive Summary

Gimeracil is a small molecule pyridine derivative that functions as a pivotal component of the oral anticancer agent known as S-1 or Teysuno. While not an antineoplastic agent in its own right, Gimeracil is a critical biochemical modulator that enables the therapeutic efficacy and shapes the safety profile of the combination product. Its primary and most well-characterized mechanism of action is the potent, selective, and reversible inhibition of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme responsible for the catabolism of 5-fluorouracil (5-FU). By preventing the rapid degradation of 5-FU, Gimeracil dramatically increases its bioavailability and prolongs its systemic exposure, allowing for therapeutic concentrations to be achieved with a significantly lower oral dose of the 5-FU prodrug, tegafur. This pharmacokinetic modulation is the central principle of the S-1 regimen, designed to replicate the efficacy of continuous intravenous 5-FU infusion in a convenient oral formulation while mitigating certain toxicities.

Beyond its role as a pharmacokinetic enhancer, emerging evidence has identified a secondary, direct pharmacological action for Gimeracil: the inhibition of DNA double-strand break repair via the homologous recombination pathway. This function positions Gimeracil as a potential radiosensitizer, capable of enhancing the cytotoxic effects of radiation therapy by preventing cancer cells from repairing the induced DNA damage. This dual mechanism suggests a broader therapeutic potential than previously understood, particularly in the context of combined-modality chemoradiotherapy.

Clinically, Gimeracil is exclusively administered as part of the fixed-dose combination S-1/Teysuno, alongside tegafur and oteracil. This tripartite formulation has established itself as a standard of care for advanced gastric cancer in Japan and Europe, where large-scale clinical trials have demonstrated its non-inferiority to infused 5-FU with a more favorable safety profile, particularly with respect to myelosuppression. The regimen has also gained approval in Europe for metastatic colorectal cancer in patients who are intolerant to other fluoropyrimidines due to hand-foot syndrome or cardiotoxicity, a niche defined by its distinct safety advantages over capecitabine. The global regulatory history of Gimeracil is complex, with broad adoption in Asia and Europe but a lack of approval in the United States, reflecting differing regulatory philosophies and the challenges of translating therapies across ethnically diverse populations with distinct pharmacogenomic profiles. Gimeracil's primary renal excretion pathway makes patient kidney function a critical determinant of safety, necessitating careful dose adjustments. Ultimately, Gimeracil represents a sophisticated example of rational drug design, where precise biochemical modulation of a classic cytotoxic agent's pharmacology has created a valuable and differentiated therapeutic option in the oncology armamentarium.

2.0 Physicochemical Profile and Molecular Identification

A comprehensive understanding of Gimeracil's pharmacological and clinical properties begins with its fundamental chemical identity. As a small molecule, its structure, mass, and physical characteristics dictate its formulation, stability, and behavior in biological systems.

2.1 Nomenclature and Chemical Identifiers

Gimeracil is identified by a consistent set of systematic names, common synonyms, and unique registry numbers across chemical and pharmacological databases, ensuring unambiguous reference in research and clinical contexts.

Its primary systematic name, following IUPAC conventions, is 5-chloro-4-hydroxy-2(1H)-pyridinone.[1] It is also frequently referred to by the tautomeric name 5-chloro-2,4-dihydroxypyridine.[2] In scientific literature and among suppliers, it is widely known by several synonyms, most notably CDHP (an abbreviation for 5-chloro-2,4-dihydroxypyridine), Gimestat, and 5-Chlorodihydropyrimidine.[1]

The molecule is cataloged under several key global identifiers:

• CAS (Chemical Abstracts Service) Number: 103766-25-2.[1]
• DrugBank Accession Number: DB09257.[4]
• PubChem Compound ID (CID): 54679224.[11]
• ChEMBL ID: CHEMBL1730601.[13]

These identifiers provide a standardized means of accessing detailed information about the compound in various public and proprietary databases.

2.2 Molecular Formula, Weight, and Structure

Gimeracil is a heterocyclic compound belonging to the chloropyridine chemical class.[2] Its elemental composition and mass are precisely defined.

• Molecular Formula: The empirical formula for Gimeracil is C5​H4​ClNO2​.[1]
• Molecular Weight: The average molecular weight is calculated to be 145.54 g/mol.[3]
• Monoisotopic Mass: The exact monoisotopic mass is 144.9930561 Da, a value critical for high-resolution mass spectrometry analysis.[3]

The two-dimensional structure of the molecule can be represented by standardized line notations:

• SMILES (Simplified Molecular Input Line Entry System): C1=C(C(=CNC1=O)Cl)O or OC1=CC(=O)C(Cl)=CN1.[8]
• InChI (International Chemical Identifier) Key: ZPLQIPFOCGIIHV-UHFFFAOYSA-N, a hashed representation that serves as a unique structural fingerprint.[1]

2.3 Physical and Chemical Properties

Gimeracil's physical state and solubility are key determinants of its handling, storage, and formulation into a final medicinal product.

• Appearance: At room temperature, Gimeracil is a solid, described as a white to almost white or light yellow crystalline powder.[2]
• Melting Point: It has a high melting point of approximately 274 °C, at which it undergoes decomposition.[2]
• Solubility: The solubility profile of Gimeracil is characterized by poor aqueous solubility, which has significant implications for its route of administration and formulation. It is highly soluble in organic solvents like dimethyl sulfoxide (DMSO), with reported solubilities ranging from 5 mg/mL to 29 mg/mL, and dimethylformamide (DMF) at 20 mg/mL. In contrast, its solubility is very low in ethanol (<1 mg/mL) and water (<1 mg/mL), where it is described as slightly soluble or insoluble.[1] This lipophilic nature necessitates its formulation as a solid oral dosage form, as creating a stable intravenous solution would be challenging.
• Storage and Stability: As a solid powder, Gimeracil is stable for extended periods, with recommendations for storage at -20°C for up to 3 years.[9] Stock solutions prepared in DMSO can be stored at -20°C for up to 3 months or at -80°C for one year.[9]

The fundamental physicochemical properties of Gimeracil are consolidated in Table 1, providing a comprehensive reference for the molecule's identity.

Property	Value	Source(s)
Systematic Name	5-chloro-4-hydroxy-2(1H)-pyridinone	1
Synonyms	CDHP, Gimestat, 5-Chlorodihydropyrimidine	1
CAS Number	103766-25-2	9
DrugBank ID	DB09257	4
PubChem CID	54679224	11
Molecular Formula	C5​H4​ClNO2​	4
Average Molecular Weight	145.54 g/mol	4
Monoisotopic Mass	144.9930561 Da	3
Appearance	White to light yellow crystalline powder	2
Melting Point	274 °C (decomposes)	2
Solubility (DMSO)	25-29 mg/mL	1
Solubility (Water)	<1 mg/mL (Slightly soluble to insoluble)	6
SMILES	OC1=CC(=O)C(Cl)=CN1	12
InChI Key	ZPLQIPFOCGIIHV-UHFFFAOYSA-N	1
Table 1: Key Chemical and Physical Properties of Gimeracil

3.0 Pharmacology and Dual Mechanisms of Action

Gimeracil exerts its therapeutic influence through two distinct and significant mechanisms. The first, its primary function, is the modulation of fluoropyrimidine pharmacokinetics through potent enzyme inhibition. The second, an emerging area of research, involves the direct interference with cellular DNA repair processes, positioning it as a potential radiosensitizer. Together, these actions define Gimeracil as a multifaceted agent that enhances conventional chemotherapy from both a pharmacokinetic and a pharmacodynamic perspective.

3.1 Primary Mechanism: Dihydropyrimidine Dehydrogenase (DPD) Inhibition

The foundational role of Gimeracil within the S-1/Teysuno combination therapy is to act as a potent inhibitor of dihydropyrimidine dehydrogenase (DPD; gene name DPYD).[4] DPD is the initial and rate-limiting enzyme in the catabolic pathway of pyrimidines, including the widely used chemotherapeutic agent 5-fluorouracil (5-FU).[21]

3.1.1 Biochemical Action and Pharmacological Consequence

Gimeracil functions as a competitive and reversible inhibitor of DPD.[4] It exhibits a high binding affinity for the enzyme's active site, with a reported inhibitor constant (

Ki​) of 0.36 µM.[1] In rat liver extracts, it demonstrates a 50% inhibitory concentration (

IC50​) of 0.1 µM for the degradation of 5-FU.[1]

Normally, over 80% of an administered dose of 5-FU is rapidly catabolized by DPD, primarily in the liver, into inactive metabolites such as 5,6-dihydro-5-fluorouracil (DHFU).[22] This rapid clearance limits the bioavailability and therapeutic efficacy of 5-FU, particularly when administered orally, and necessitates continuous intravenous infusions to maintain therapeutic drug levels.[25]

By competitively binding to and blocking DPD, Gimeracil effectively halts this rapid degradation process.[22] This enzymatic blockade leads to two critical pharmacological consequences:

1. Increased Bioavailability of 5-FU: The concentration of active 5-FU in the plasma is significantly increased.
2. Prolonged Half-Life of 5-FU: The systemic exposure, measured as the area under the concentration-time curve (AUC), is substantially prolonged.[4]

The inhibition of DPD by Gimeracil is reversible, a key feature for safety and controlled dosing. Pharmacodynamic studies in humans show that plasma uracil concentrations, a biomarker for DPD activity, peak at 4 hours after a dose of Teysuno and return to baseline levels within approximately 48 hours, indicating that the enzymatic inhibition resolves as Gimeracil is cleared from the body.[4]

3.1.2 Therapeutic Impact in the S-1 Formulation

This mechanism of DPD inhibition is the cornerstone of the S-1/Teysuno therapeutic strategy. The formulation combines Gimeracil with tegafur, an oral prodrug of 5-FU.[21] Gimeracil's presence allows a much lower dose of tegafur to produce sustained, therapeutically effective concentrations of 5-FU that mimic a continuous intravenous infusion.[4] Studies have shown that mean 5-FU Cmax and AUC values are approximately 3-fold higher after Teysuno administration compared to tegafur alone, even though the tegafur dose in Teysuno was 16-fold lower.[4] This biochemical modulation is pivotal because it aims to improve the therapeutic index of 5-FU by enhancing its cytotoxic effects against cancer cells while simultaneously allowing for a lower overall drug dose, which can reduce the incidence and severity of certain dose-related adverse effects.[22]

3.2 Secondary Mechanism: Radiosensitization via DNA Repair Inhibition

In addition to its well-established role in pharmacokinetics, Gimeracil has been shown to possess a second, direct antitumor mechanism: the inhibition of DNA repair. Specifically, research indicates that Gimeracil inhibits the early steps of homologous recombination (HR), a major cellular pathway responsible for the high-fidelity repair of DNA double-strand breaks (DSBs).[7]

3.2.1 Molecular Action on Homologous Recombination

DSBs are among the most lethal forms of DNA damage and can be induced by ionizing radiation and certain chemotherapeutic agents. The HR pathway is a complex process that uses a sister chromatid as a template to flawlessly repair the break. Studies have demonstrated that Gimeracil interferes with this process by restraining the formation of nuclear foci of key HR proteins, including Rad51 and replication protein A (RPA).[7] Concurrently, it increases the number of foci of proteins involved in the initial damage recognition and processing steps, such as Nbs1, Mre11, and Rad50, suggesting that the repair process is initiated but stalls at a critical early stage.[7] This targeted disruption of HR sensitizes cells to agents that cause DSBs. Gimeracil has been shown to enhance radiation-induced cell death in human colorectal cancer cells and sensitizes cells in the S-phase of the cell cycle more than those in G0/G1.[1]

3.2.2 Therapeutic Implications

This secondary mechanism positions Gimeracil as a potential radiosensitizer. The clinical efficacy observed in treatment regimens that combine S-1 with radiation may not be solely attributable to the radiosensitizing properties of 5-FU. Instead, a synergistic effect may be at play, where 5-FU enhances the initial damage caused by radiation, and Gimeracil subsequently prevents the cancer cells from effectively repairing that damage. This dual action could lead to greater tumor cell killing than would be predicted from either agent alone. This property opens new avenues for research, suggesting that S-1-based chemoradiotherapy could be a particularly effective strategy and that Gimeracil itself may have therapeutic value in combination with other DNA-damaging agents or PARP inhibitors, independent of its role in 5-FU modulation.

4.0 Comprehensive Pharmacokinetic and Pharmacodynamic Profile

The clinical utility and safety of Gimeracil are fundamentally governed by its pharmacokinetic (PK) profile—its absorption, distribution, metabolism, and excretion (ADME)—which dictates its concentration in the body over time. Its pharmacodynamic (PD) effect is directly linked to these concentrations, as the extent and duration of DPD inhibition are dependent on Gimeracil exposure.

4.1 Absorption

Following oral administration as part of the S-1/Teysuno capsule, Gimeracil is rapidly absorbed from the gastrointestinal tract.[22] Clinical studies in cancer patients have consistently shown that the time to reach maximum plasma concentration (

Tmax​) is short, with median values ranging from 1.0 to 3.3 hours after a single dose.[30]

The presence of food significantly impacts Gimeracil's absorption. Administration of Teysuno under fed conditions results in a decrease in the total systemic exposure (AUC) of Gimeracil by approximately 25% compared to administration in a fasted state.[31] This food effect necessitates standardized administration guidelines; to ensure consistent absorption and predictable DPD inhibition, patients are instructed to take the capsules at least one hour before or one hour after a meal.[31]

4.2 Distribution

Once absorbed into the systemic circulation, Gimeracil exhibits modest binding to plasma proteins. In human serum, the protein binding is approximately 32.2% and is not dependent on the drug concentration over the therapeutic range.[31] Although intravenous data in humans are not available, the apparent volume of distribution for Gimeracil has been estimated to be approximately 17 L/m², suggesting it distributes into tissues beyond the plasma volume.[31]

4.3 Metabolism (Biotransformation)

Gimeracil appears to be highly stable in the body and does not undergo significant metabolism. In vitro studies using human liver homogenates (S9 fraction) and human liver microsomes have shown that Gimeracil is stable and does not exert any relevant inhibitory effects on the activity of major cytochrome P450 (CYP) isoforms, including CYP1A1/2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.[31] Furthermore, evaluations in primary human hepatocyte cultures indicated that Gimeracil has little to no inductive effect on CYP1A2, CYP2B6, or CYP3A4/5 metabolic activities.[31] This metabolic inertness suggests a low potential for drug-drug interactions mediated by the CYP450 enzyme system, which simplifies its use in combination with other agents.

4.4 Excretion

The primary route of elimination for Gimeracil is renal excretion. A substantial portion of the administered dose, ranging from 65% to 72%, is excreted unchanged in the urine.[4] This high degree of renal clearance indicates that the kidneys are the main organ responsible for removing the drug from the body. Consistent with its rapid absorption, Gimeracil also has a relatively short elimination half-life (

t1/2​), with values reported to range from 2.7 to 4.1 hours across different studies.[4] This short half-life contributes to the reversibility of its DPD-inhibiting effect.

4.5 Pharmacokinetic Variability and Special Populations

The pharmacokinetic profile of Gimeracil is subject to variability based on patient-specific factors, most notably renal function and, in the context of the S-1 regimen, ethnicity-related pharmacogenomics.

• Renal Impairment: The heavy reliance on renal clearance makes kidney function the single most critical factor influencing Gimeracil exposure. A direct relationship exists between a patient's creatinine clearance and their ability to eliminate Gimeracil. In patients with renal impairment, Gimeracil clearance is reduced, leading to higher and more prolonged plasma concentrations. This, in turn, causes more profound and sustained DPD inhibition, resulting in elevated, and potentially toxic, concentrations of 5-FU.[31] This causal chain explains why the S-1/Teysuno regimen is contraindicated in patients with severe renal impairment or those requiring dialysis, and why specific dose reductions are mandated for patients with moderate renal impairment.[21]
• Ethnic Differences: While Gimeracil's own pharmacokinetics are comparable between Asian and Caucasian populations, the overall pharmacokinetics of the S-1 regimen are significantly influenced by ethnic differences in the metabolism of tegafur.[31] Tegafur is converted to 5-FU by the CYP2A6 enzyme. Polymorphisms in the CYP2A6 gene that result in reduced enzyme activity are more prevalent in Asian populations. This can lead to different rates of 5-FU formation and overall exposure between Asian and Western patients, necessitating the development of different dosing regimens for these populations to achieve a similar balance of efficacy and safety.[25]

Table 2 summarizes the key human pharmacokinetic parameters for Gimeracil derived from clinical studies of the S-1/Teysuno formulation.

Parameter	Value (Mean ± SD or Median)	Study Condition	Source(s)
Tmax​ (Time to Peak)	1.0 - 3.3 hours	Single Oral Dose	30
Cmax​ (Peak Concentration)	452 ± 102 ng/mL	Single 50 mg Dose (Tegafur)	31
	305 ± 116 ng/mL	Multiple 30 mg/m² Doses	31
	143.1 ± 51.4 ng/mL	Single Dose (Korean Patients)	30
AUC (Total Exposure)	1884 ± 640 ng·hr/mL (AUC0−inf​)	Single 50 mg Dose (Tegafur)	31
	1483 ± 527 ng·hr/mL (AUC0−12h​)	Multiple 30 mg/m² Doses	31
	529.4 ± 143.3 ng·hr/mL (AUC0−t​)	Single Dose (Korean Patients)	30
t1/2​ (Elimination Half-Life)	3.1 - 4.1 hours	Single Oral Dose	4
	2.7 ± 0.4 hours	Single Dose (Korean Patients)	30
% Excreted Unchanged (Urine)	65% - 72%	Single Oral Dose	4
Protein Binding	32.2%	In vitro (Human Serum)	31
Volume of Distribution (Apparent)	17 L/m²	Estimated	31
Table 2: Summary of Human Pharmacokinetic Parameters for Gimeracil (from S-1/Teysuno Studies)

5.0 The S-1 (Teysuno) Formulation: A Synergistic Tripartite Combination

Gimeracil is not administered as a standalone agent but is exclusively available as part of a sophisticated, fixed-dose combination product known as S-1 (or Teysuno in Europe). This formulation represents a prime example of rational drug design, where multiple components with distinct pharmacological roles work in concert to optimize the therapeutic profile of a parent cytotoxic drug. The entire system is designed to deliver 5-FU orally with enhanced efficacy and an improved safety profile compared to traditional fluoropyrimidine therapies.[21]

5.1 Rationale and Composition

The central challenge that S-1 was designed to overcome is the poor and erratic oral bioavailability of 5-FU, which is subject to extensive and variable first-pass metabolism by DPD in the gut and liver.[23] The S-1 formulation addresses this by combining a 5-FU prodrug with two different enzyme inhibitors that modulate its activity at both systemic and local levels.

The product is composed of three active substances formulated in a precise molar ratio of 1:0.4:1 [21]:

1. Tegafur (FT)
2. Gimeracil (CDHP)
3. Oteracil (administered as Oteracil Potassium or Potassium Oxonate, OXO)

This specific ratio is the result of extensive preclinical optimization to achieve the desired balance of systemic efficacy and localized toxicity mitigation. The sub-stoichiometric amount of Gimeracil (0.4 moles) relative to tegafur (1 mole) is a critical design feature. It is calibrated to provide a sufficient level of DPD inhibition to significantly increase 5-FU exposure and efficacy, but not to cause complete enzymatic blockade, which could lead to excessive and unmanageable toxicity, similar to that seen in patients with congenital DPD deficiency.[21]

5.2 Role of Each Component

Each of the three components in the S-1 formulation has a distinct and complementary function:

• Tegafur: This component serves as the oral prodrug of 5-FU. After absorption, tegafur is gradually converted into active 5-FU within the body, primarily through the action of the liver enzyme cytochrome P450 2A6 (CYP2A6).[21] This slow conversion process helps to maintain prolonged concentrations of 5-FU, contributing to the goal of mimicking a continuous infusion.
• Gimeracil: As detailed in Section 3.1, Gimeracil is the systemic DPD inhibitor. Its function is to protect the 5-FU generated from tegafur from rapid catabolism. By blocking DPD, Gimeracil ensures that the 5-FU remains in the bloodstream and tumor tissues at therapeutic concentrations for a longer duration, thereby maximizing its cytotoxic potential.[4]
• Oteracil (Potassium Oxonate): This component acts as a local toxicity modulator. Oteracil is an inhibitor of the enzyme orotate phosphoribosyltransferase (OPRT), which is involved in the intracellular activation (phosphorylation) of 5-FU to its cytotoxic metabolites.[21] Due to its low membrane permeability, oteracil is poorly absorbed systemically and remains concentrated within the gastrointestinal tract. Here, it selectively inhibits OPRT, reducing the local activation of 5-FU in the healthy gut mucosa. This targeted action effectively diminishes the direct damage to gastrointestinal cells, thereby mitigating the incidence and severity of common 5-FU-related toxicities such as diarrhea and stomatitis.[21]

5.3 The "Self-Rescuing" Therapeutic Concept

The integrated action of these three components has led to S-1 being described as a "self-rescuing" or "biochemically modulated" therapeutic agent.[28] This concept highlights the dual nature of the formulation's design:

• Systemic Potentiation: Gimeracil enhances the systemic antitumor activity of 5-FU.
• Local Rescue: Oteracil provides a localized "rescue" for healthy gastrointestinal tissue from that same activity.

This intelligent design aims to uncouple the systemic therapeutic effects from the local toxic effects, effectively widening the therapeutic window of 5-FU. By increasing the concentration of 5-FU in the tumor while simultaneously decreasing its concentration and activity in the gut, the S-1 formulation strives to achieve a more favorable balance between efficacy and tolerability than can be achieved with other fluoropyrimidine agents.

6.0 Clinical Efficacy Across Oncological Indications

The clinical development of S-1/Teysuno, enabled by Gimeracil, has established its efficacy across a range of solid tumors, particularly in gastrointestinal malignancies. Its primary approval for advanced gastric cancer has been followed by successful investigations in colorectal, pancreatic, and other cancers, solidifying its role in modern oncology.

6.1 Advanced Gastric Cancer

Advanced gastric cancer is the cornerstone indication for S-1/Teysuno, with robust clinical data supporting its use as a first-line therapy.[21] The standard regimen is S-1 in combination with a platinum agent, typically cisplatin.[25]

The regulatory approvals and establishment as a standard of care are supported by two pivotal Phase III trials:

• The SPIRITS Trial: Conducted in Japan, this trial compared S-1 plus cisplatin against S-1 monotherapy. The combination arm demonstrated significantly superior outcomes, including a higher overall response rate (ORR) (54% vs. 31%), longer progression-free survival (PFS) (6.0 vs. 4.0 months), and longer overall survival (OS) (median 13.0 vs. 11.0 months). These results firmly established S-1 plus cisplatin as the standard first-line treatment for advanced gastric cancer in Japan.[25]
• The FLAGS Trial: This large, global Phase III study was crucial for Western approval. It compared S-1 plus cisplatin against the established standard of infused 5-FU plus cisplatin in a non-Asian patient population. The trial was designed for superiority but did not meet this primary endpoint. However, a post-hoc analysis demonstrated non-inferiority in terms of OS (median 8.6 months for S-1/cisplatin vs. 7.9 months for 5-FU/cisplatin). Crucially, the S-1 arm showed a significantly better safety profile. This balance of equivalent efficacy and improved tolerability formed the basis for its approval by the European Medicines Agency (EMA).[33]

Beyond the pivotal trials, S-1 continues to be investigated in novel combinations for gastric cancer, including regimens with oxaliplatin, irinotecan, and immunotherapy agents like camrelizumab, in various Phase 1 and 2 clinical trials.[45]

6.2 Metastatic Colorectal Cancer (mCRC)

In the European Union, S-1/Teysuno holds a specific and important indication for the treatment of mCRC. It is approved either as a monotherapy or in combination with oxaliplatin or irinotecan (with or without bevacizumab) for patients who are unable to continue treatment with another fluoropyrimidine (such as capecitabine or infused 5-FU) due to the development of severe hand-foot syndrome (HFS) or cardiovascular toxicity.[40]

This indication highlights a key strategic positioning for S-1. Rather than competing directly with established first-line therapies, it serves as a critical alternative that allows patients to remain on effective fluoropyrimidine-based treatment when the toxicities of standard options become dose-limiting. The significantly lower incidence of HFS with S-1 compared to capecitabine is the primary driver for this indication, as detailed further in Section 7.0. Expert consensus guidelines also recommend S-1 as a standard of care option in various lines of therapy for colorectal cancer.[26]

6.3 Pancreatic Cancer

S-1 has demonstrated significant activity in pancreatic cancer and is an approved and commonly used treatment in Japan and other Asian countries.[26] Multiple Phase 2 studies in Asian populations have shown promising overall response rates (21–38%) and median survival times (6–9 months) with S-1 monotherapy.[51]

Numerous clinical trials have explored its role further, evaluating S-1 alone, in combination with gemcitabine, or with targeted agents like nimotuzumab.[51] A recent real-world study registered as NCT06779318 is currently investigating the role of S-1 as a maintenance therapy for patients with resected pancreatic cancer at high risk of recurrence, highlighting its ongoing relevance in this challenging disease.[54]

6.4 Head and Neck Squamous Cell Carcinoma (SCCHN)

Gimeracil, as part of the S-1 formulation, has shown promising activity in SCCHN and is an area of active clinical investigation.[21] Several clinical trials have evaluated its use in different settings:

• Adjuvant Therapy: The NCT00336947 trial compared adjuvant S-1 against tegafur-uracil in patients with previously treated stage III or IV SCCHN.[55]
• Combination with Targeted Therapy: The NCT03096184 and NCT03267121 trials investigated S-1 in combination with the multi-targeted tyrosine kinase inhibitor apatinib for patients with recurrent/metastatic or locally advanced SCCHN, respectively.[56]
• Induction Chemotherapy: A recent study analyzed the efficacy and safety of S-1 as part of a triplet induction regimen with nab-paclitaxel and a platinum agent (cisplatin or nedaplatin) for hypopharyngeal cancer, reporting a high objective response rate of 89.5%.[59]

6.5 Other Investigational Settings

The clinical development of S-1 extends to several other major solid tumors, with notable progress in lung and breast cancer.

• Non-Small Cell Lung Cancer (NSCLC): S-1 has been extensively studied in Japan, where it has demonstrated efficacy comparable to standard platinum-based doublets as both first- and second-line therapy, often with a more favorable toxicity profile, particularly lower rates of alopecia and severe neutropenia.[6] Based on these data, it has received regulatory approval for this indication in Taiwan.[61]
• Breast Cancer: A landmark Phase III study in Japan, the POTENT trial, produced significant results for adjuvant therapy. The trial demonstrated that adding one year of S-1 to standard endocrine therapy significantly improved invasive disease-free survival (iDFS) in patients with hormone receptor-positive (HR+), HER2-negative breast cancer at high risk of recurrence. At a median follow-up of 51.4 months, the recurrence rate was 10.6% in the S-1 arm versus 15.9% in the endocrine-therapy-alone arm, corresponding to a hazard ratio of 0.63.[62] This led to an additional approval for this indication in Japan.[63] A separate Phase 3 trial (NCT01655992) comparing S-1 to capecitabine in metastatic breast cancer was terminated early.[64]

7.0 Comparative Clinical Assessment Against Fluoropyrimidine Standards

The clinical value of S-1/Teysuno is best understood through direct comparison with the two other fluoropyrimidine standards in oncology: continuously infused 5-fluorouracil (5-FU) and the oral prodrug capecitabine. These comparisons reveal a nuanced profile where S-1 offers distinct advantages in safety and convenience but does not universally demonstrate superior efficacy.

7.1 S-1 vs. Infused 5-Fluorouracil (5-FU)

The primary goal in developing S-1 was to create an oral agent that could replicate the efficacy of infused 5-FU with greater convenience and improved tolerability.

• Gastric Cancer (FLAGS Trial): The head-to-head comparison in the FLAGS trial provides the most definitive evidence in a non-Asian population. As noted previously, the S-1 plus cisplatin regimen was found to be non-inferior to 5-FU plus cisplatin in terms of overall survival (median 8.6 vs. 7.9 months) and progression-free survival (median 4.8 vs. 5.5 months).[42] The key distinction was the safety profile. The S-1 arm exhibited a statistically significant and clinically meaningful reduction in the rates of severe (Grade 3-4) myelosuppression. Key differences included:
• Neutropenia: 32% with S-1 vs. 64% with 5-FU
• Thrombocytopenia: 8% with S-1 vs. 14% with 5-FU
• Leucopenia: 14% with S-1 vs. 33% with 5-FU
• Febrile Neutropenia: 5% with S-1 vs. 14% with 5-FU.[33]

Furthermore, treatment-related deaths were significantly lower in the S-1 arm (2.5% vs. 4.9%).44 This demonstrates that Gimeracil's modulation successfully translates the efficacy of infused 5-FU into an oral form with a superior hematological safety profile.

• Colorectal Cancer: While direct head-to-head trials are less prominent, infused 5-FU regimens like FOLFOX (5-FU, leucovorin, oxaliplatin) remain a global standard of care for colorectal cancer.[23] S-1 offers an oral alternative, which is a significant advantage in terms of patient convenience and avoidance of central venous access complications.[26]

7.2 S-1 vs. Capecitabine

The comparison between the two major oral fluoropyrimidines, S-1 and capecitabine, is particularly important for clinical decision-making. The choice between them is highly dependent on the specific clinical context, as their relative efficacy and safety profiles differ by indication and disease stage.

• Metastatic Colorectal Cancer (SALTO Trial): The Dutch SALTO study provides the most robust head-to-head evidence in mCRC.
• Efficacy: The trial demonstrated comparable efficacy between the two agents. The median PFS was not significantly different, at 8.4 months for S-1 versus 8.2 months for capecitabine.[66]
• Safety (Primary Endpoint): The study met its primary endpoint by showing a dramatic and statistically significant reduction in Hand-Foot Syndrome (HFS) with S-1. Investigator-assessed all-grade HFS was observed in 45% of patients on S-1 compared to 73% on capecitabine. More importantly, the incidence of debilitating Grade 3 HFS was over five times lower with S-1 (4% vs. 21%).[66] This profound safety advantage in a dose-limiting toxicity for capecitabine is the primary rationale for S-1's use in this setting.
• Adjuvant Colorectal Cancer (JCOG0910 Trial): In contrast to the metastatic setting, a large Japanese Phase III trial (JCOG0910) evaluating S-1 versus capecitabine as adjuvant therapy for stage III colorectal cancer yielded different results.
• Efficacy: The trial was terminated early because S-1 failed to demonstrate non-inferiority to capecitabine. The 3-year disease-free survival (DFS) was 77.9% for S-1 versus 82.0% for capecitabine (HR 1.23). Based on these results, the study concluded that S-1 is not recommended as adjuvant therapy for this patient population in Japan, where capecitabine remains a standard of care.[69] This finding underscores that the relative efficacy of these two drugs cannot be extrapolated across different stages of disease.
• Advanced Gastric Cancer: A meta-analysis of several randomized trials directly comparing S-1-based and capecitabine-based regimens for advanced gastric cancer found no significant differences in efficacy outcomes, including ORR, PFS, and OS.[71] However, the safety profiles were distinct. Consistent with the SALTO trial, capecitabine was associated with a significantly higher incidence of HFS (pooled relative risk of 3.41). Conversely, some analyses suggested a higher incidence of Grade 3-4 neutropenia with S-1-based regimens.[71]

This body of evidence reveals a complex relationship. In the palliative metastatic setting, where long-term treatment and quality of life are paramount, S-1's comparable efficacy and superior HFS profile make it an excellent alternative to capecitabine. However, in the curative-intent adjuvant setting, where maximizing the chance of cure is the primary goal, the available evidence from the JCOG0910 trial favors capecitabine due to its superior efficacy. This highlights the critical importance of selecting fluoropyrimidine therapy based on the specific clinical context and treatment goals.

Clinical Setting	Trial	Efficacy Outcome	Key Safety Finding (S-1 vs. Capecitabine)	Conclusion	Source(s)
Metastatic Colorectal Cancer	SALTO (Phase III)	Non-inferior PFS: Median 8.4 vs. 8.2 months (HR 0.99)	Significantly less HFS: Grade 3: 4% vs. 21%	S-1 is a valid alternative with a superior HFS safety profile.	67
Adjuvant Colorectal Cancer	JCOG0910 (Phase III)	Inferior DFS: 3-year DFS: 77.9% vs. 82.0% (HR 1.23)	Less HFS: Grade 3/4: <1% vs. 16% More Diarrhea: Grade 3/4: 8% vs. 4%	S-1 is not non-inferior and is not recommended in this setting.	69
Table 3: Comparative Efficacy and Safety of S-1 vs. Capecitabine in Metastatic and Adjuvant Colorectal Cancer

8.0 Safety, Tolerability, and Risk Management Profile

The safety profile of Gimeracil is intrinsically linked to that of the S-1/Teysuno combination product it enables. The adverse events observed are a composite of the effects of systemic 5-FU exposure, which Gimeracil potentiates, and the specific modulatory effects of its companion agent, oteracil. A thorough understanding of this profile, including common toxicities, contraindications, and drug interactions, is essential for its safe clinical use.

8.1 Common Adverse Events

Clinical trials have consistently characterized the spectrum of adverse events (AEs) associated with S-1/Teysuno therapy. When used in combination with cisplatin for gastric cancer, the most frequently reported severe (Grade 3 or higher) AEs are hematological.[21]

• Hematologic Toxicities: Myelosuppression is a dose-limiting toxicity. The most common events are neutropenia, anemia, leukopenia, and thrombocytopenia. Febrile neutropenia, a serious complication, is also reported.[27]
• Gastrointestinal Toxicities: Diarrhea, nausea, vomiting, and stomatitis are very common, although the incidence of severe GI events is mitigated by the oteracil component. Anorexia (decreased appetite) and abdominal pain are also frequently observed.[27]
• Constitutional Symptoms: Fatigue and lack of energy are very common side effects.[21]
• Ocular Disorders: A notable class effect of fluoropyrimidines that is observed with S-1 is an increased incidence of lacrimal disorders, including increased lacrimation (watery eyes), dry eye, and acquired dacryostenosis (blockage of the tear duct).[33]
• Dermatologic Toxicities: Hand-foot syndrome (palmar-plantar erythrodysesthesia) can occur, but as established in Section 7.0, its incidence and severity are significantly lower than with capecitabine.[33] Rashes and alopecia are also possible.[34]

8.2 Contraindications

The safe use of S-1/Teysuno is predicated on avoiding its administration in patient populations at high risk for severe toxicity. The contraindications are directly linked to the pharmacology of its components, particularly Gimeracil and 5-FU.

• Dihydropyrimidine Dehydrogenase (DPD) Deficiency: This is an absolute contraindication. Patients with a known complete or partial deficiency of the DPD enzyme are at risk of life-threatening or fatal toxicity due to their inability to catabolize 5-FU. Pre-treatment screening for DPD deficiency through phenotype or genotype testing is recommended.[21]
• Severe Renal Impairment: Because Gimeracil is primarily cleared by the kidneys, its use is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) or those requiring dialysis. Accumulation of Gimeracil in these patients would lead to excessive DPD inhibition and dangerous levels of 5-FU.[21]
• Severe Myelosuppression: The regimen should not be initiated in patients with pre-existing severe bone marrow suppression, defined as severe leukopenia, neutropenia, or thrombocytopenia.[21]
• Pregnancy and Breastfeeding: S-1/Teysuno is contraindicated during pregnancy and breastfeeding due to the potential for fetal harm.[21]
• Concomitant DPD Inhibitors: Co-administration with other potent DPD inhibitors, such as the antiviral agents sorivudine or brivudine, is strictly contraindicated due to the risk of a fatal drug-drug interaction.[31]
• Hypersensitivity: A history of severe and unexpected reactions to fluoropyrimidine therapy or known hypersensitivity to any of the active substances is a contraindication.[21]

8.3 Drug Interactions

The potential for drug-drug interactions must be carefully considered.

• Pharmacodynamic Interactions: Co-administration with other cytotoxic agents can lead to additive or synergistic toxicities, particularly myelosuppression.[27]
• Pharmacokinetic Interactions: The most critical interactions are those that affect Gimeracil's clearance. Drugs that impair renal function, such as nonsteroidal anti-inflammatory drugs (NSAIDs), can decrease the excretion of Gimeracil, leading to higher systemic levels and increased 5-FU-related toxicity.[27] A large number of other medications, including acetaminophen, amoxicillin, and allopurinol, are listed as potentially decreasing the excretion rate of Gimeracil, which could result in higher serum levels.[4]

8.4 Material Safety Data

When handled as a pure chemical substance for research purposes, Gimeracil carries specific hazard warnings. The GHS classification indicates it is harmful if swallowed (H302), causes skin irritation (H315), causes serious eye irritation (H319), and may cause respiratory irritation (H335).[18] However, the final formulated product, Tegafur/gimeracil/oteracil potassium, is not classified as a hazardous substance or mixture under GHS guidelines.[19] Nonetheless, as an antineoplastic agent, it should be handled with appropriate personal protective equipment, including gloves and safety goggles, in a well-ventilated area.[19]

9.0 Global Regulatory Landscape and Market Access

The regulatory journey of Gimeracil, as part of the S-1/Teysuno formulation, provides a compelling case study in the complexities of global drug development and approval. Its path has been marked by early and broad adoption in Asia, a more measured, data-driven acceptance in Europe, and a lack of approval in the United States, reflecting different regulatory philosophies, market dynamics, and population genetics.

9.1 Japan (Pharmaceuticals and Medical Devices Agency - PMDA)

Japan is the country of origin for S-1, which was developed by Taiho Pharmaceutical Co., Ltd..[27]

• First Approval: S-1 received its first global approval from the Japanese government in 1999 for the treatment of gastric cancer.[25] This approval was based on strong domestic Phase II data showing high response rates.[25]
• Broad Adoption and Standard of Care: Following its initial approval, S-1 rapidly became a cornerstone of treatment for gastric cancer in Japan and is considered a standard of care, particularly in combination with cisplatin.[25] Over the subsequent years, its approval has expanded significantly, and it is now indicated for a wide range of solid tumors, including colorectal cancer, head and neck cancer, non-small cell lung cancer, inoperable or recurrent breast cancer, pancreatic cancer, and biliary tract cancer.[63] This broad acceptance reflects its extensive clinical development within the Japanese healthcare system.

9.2 Europe (European Medicines Agency - EMA)

The introduction of S-1 into the European market, under the trade name Teysuno, occurred more than a decade after its Japanese debut.

• Gastric Cancer Approval (2011): Teysuno was first granted marketing authorization by the European Commission in March 2011 for the treatment of adults with advanced gastric cancer when given in combination with cisplatin.[21] This approval was based on the pivotal FLAGS trial, where the EMA's Committee for Medicinal Products for Human Use (CHMP) concluded that despite the trial not meeting its primary endpoint of superiority over 5-FU/cisplatin, the demonstration of non-inferior efficacy combined with a significantly better safety profile resulted in a positive benefit-risk balance.[41]
• Colorectal Cancer Approval (2022): In January 2022, the EMA expanded Teysuno's indication to include the treatment of patients with metastatic colorectal cancer for whom it is not possible to continue treatment with another fluoropyrimidine due to the development of hand-foot syndrome or cardiovascular toxicity.[49] This approval was a strategic expansion based on data highlighting Teysuno's distinct safety advantages over capecitabine.

9.3 United States (Food and Drug Administration - FDA)

Despite significant clinical development and approvals in other major markets, S-1/Teysuno is not approved for use in the United States.[75]

• Orphan Drug Designation: The combination of tegafur/gimeracil/oteracil was granted Orphan Drug Designation by the FDA on July 20, 2006, for the treatment of gastric cancer.[66] This designation provides incentives for the development of drugs for rare diseases but does not guarantee approval.
• Lack of Approval: The failure to secure FDA approval likely stems from a combination of factors. The FLAGS trial's inability to demonstrate superior efficacy over an existing, widely available standard (infused 5-FU) represents a high hurdle in the US regulatory environment. Furthermore, the pharmacokinetic complexities related to ethnic differences in CYP2A6 metabolism may have raised concerns about ensuring a consistent and safe dosing strategy for the highly heterogeneous US population.

9.4 Other Key Regions

S-1 has achieved regulatory approval and is in clinical use in numerous other countries, particularly in Asia.

• South Korea (Ministry of Food and Drug Safety - MFDS): S-1 is approved and is a standard treatment option. A bioequivalence study for a generic formulation of S-1 was successfully conducted in Korean gastric cancer patients, meeting the regulatory requirements of the MFDS.[30]
• Taiwan (Taiwan Food and Drug Administration - TFDA): Marketed as TS-1®, the drug is approved for multiple indications, including gastric cancer, pancreatic cancer, and notably, for locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy.[61]
• China (National Medical Products Administration - NMPA): S-1 is used in clinical practice and is the subject of ongoing clinical trials in China, such as studies combining it with anlotinib and oxaliplatin (SOX regimen) for gastric cancer, indicating its availability and integration into the country's oncology research landscape.[80]
• India (Central Drugs Standard Control Organisation - CDSCO): The combination was approved on February 1, 2022, for advanced gastric cancer when given in combination with cisplatin.[75]

The divergent regulatory paths of S-1/Teysuno highlight the different evidentiary standards and clinical priorities of global health authorities. Japan's early embrace was driven by strong local data for a prevalent national cancer. The EMA's approval reflects a pragmatic assessment of the overall benefit-risk profile, valuing the improved safety and oral convenience. The FDA's more stringent stance underscores a high bar for non-superiority claims, especially for complex combination products in a market with established alternatives.

Regulatory Body	Country/Region	Approval Status	Key Approved Indications	Date of First Approval	Source(s)
PMDA	Japan	Approved	Gastric, Colorectal, Breast, Pancreatic, NSCLC, Head & Neck, Biliary Tract Cancer	1999	25
EMA	European Union	Approved	Advanced Gastric Cancer; Metastatic Colorectal Cancer (after intolerance to other fluoropyrimidines)	March 2011	21
FDA	United States	Not Approved	Orphan Drug Designation for Gastric Cancer (July 2006)	N/A	75
MFDS	South Korea	Approved	Gastric Cancer, other malignancies	N/A	78
TFDA	Taiwan	Approved	Gastric Cancer, Pancreatic Cancer, NSCLC	N/A	61
CDSCO	India	Approved	Advanced Gastric Cancer	Feb 2022	75
Table 4: Global Regulatory Approval Status of S-1/Teysuno

10.0 Concluding Analysis and Future Perspectives

Gimeracil stands as a testament to the power of biochemical modulation in cancer therapy. It is not merely an adjuvant but the central enabling component of the S-1/Teysuno therapeutic platform. Its development and clinical application have provided valuable lessons in rational drug design, the importance of pharmacogenomics in globalizing treatments, and the evolving criteria by which regulatory agencies assess the value of new oncologic agents.

10.1 Synthesis of Gimeracil's Role

The primary contribution of Gimeracil to oncology is its successful translation of the efficacy of continuously infused 5-FU into a convenient and well-tolerated oral dosage form. By precisely inhibiting DPD, Gimeracil solves the fundamental pharmacokinetic challenge that has historically limited the use of oral 5-FU. This modulation allows the S-1 regimen to achieve a unique clinical profile: efficacy that is non-inferior to the intravenous standard but with a safety profile that is often superior, particularly regarding myelosuppression compared to infused 5-FU and hand-foot syndrome compared to capecitabine. Gimeracil's story is not one of discovering a new cytotoxic mechanism but of intelligently refining an old one, shifting the paradigm from developing novel killing agents to optimizing the pharmacology of existing ones to widen the therapeutic window.

10.2 Future Research Directions

The multifaceted nature of Gimeracil opens several promising avenues for future research and clinical development.

• Exploiting the Radiosensitizing Mechanism: The discovery that Gimeracil inhibits homologous recombination-mediated DNA repair is a significant development that has yet to be fully exploited clinically. Future trials should be specifically designed to test the hypothesis that S-1 provides a synergistic benefit with radiation that is greater than the sum of its parts (5-FU radiosensitization plus Gimeracil-mediated DPD inhibition). This could lead to new indications or establish S-1 as a preferred partner for radiotherapy in cancers where this modality is a cornerstone of curative-intent treatment, such as rectal cancer, cervical cancer, or specific subsets of head and neck cancer.
• Novel Combinations: The favorable tolerability profile of the S-1 backbone makes it an attractive partner for combination with novel agents. Ongoing research combining S-1 with immunotherapy checkpoint inhibitors (e.g., camrelizumab, nivolumab) and targeted agents (e.g., apatinib) is a logical and promising path forward.[46] Gimeracil's role in providing a manageable fluoropyrimidine foundation could be key to developing effective and tolerable multi-drug regimens.
• Addressing Unmet Needs in Special Populations: The distinct safety profile of S-1, particularly its low incidence of severe HFS, makes it an ideal candidate for further study in patient populations who are vulnerable to the toxicities of other agents. This includes elderly or frail patients who may not tolerate intensive infused chemotherapy or the dermatological toxicity of capecitabine. Trials focused on these populations could solidify S-1's niche as a preferred agent for maintaining treatment intensity while preserving quality of life.

10.3 Final Perspective

Gimeracil is a sophisticated pharmacological tool that has fundamentally altered the landscape of oral fluoropyrimidine therapy. Its journey from a DPD inhibitor to a potential DNA repair modulator illustrates the continued potential for discovery even within established therapeutic classes. The global experience with S-1/Teysuno—from its rapid adoption in Japan to its nuanced, toxicity-driven positioning in Europe and its non-approval in the US—serves as a powerful reminder of the complex interplay between clinical data, population genetics, and regulatory science. Gimeracil is more than a component; it is the key that unlocks a therapy defined by a delicate and deliberate balance of efficacy, safety, and patient convenience, embodying a modern approach to cancer drug development.

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