AST-120 (Kremezin): A Comprehensive Monograph on the Oral Carbon Adsorbent for Chronic Kidney Disease and Beyond

Introduction and Drug Profile

Overview of AST-120

AST-120 is an orally administered intestinal sorbent developed and innovated by Kureha Corporation in Japan.[1] Marketed under the brand name Kremezin®, it represents a unique therapeutic approach within the field of nephrology.[4] Its primary approved indication in several Asian countries is to slow the progression of chronic kidney disease (CKD), delay the initiation of maintenance dialysis, and ameliorate the systemic symptoms of uremia in patients with progressive CKD.[4] Pharmacologically, it is classified as an adsorbent for chronic kidney disease, functioning not through systemic absorption but by sequestering specific molecules within the gastrointestinal lumen.[9]

The development of AST-120 was driven by the understanding that the accumulation of certain gut-derived uremic toxins plays a direct role in the pathophysiology of CKD progression and its associated cardiovascular complications. By targeting the precursors of these toxins at their source within the intestine, AST-120 aims to interrupt a key pathological feedback loop where the consequences of renal failure (toxin accumulation) actively contribute to further renal and systemic damage. This upstream intervention distinguishes it from renal replacement therapies like dialysis, which attempt to clear toxins after they have entered the systemic circulation.

Physicochemical Properties

The therapeutic function of AST-120 is intrinsically linked to its distinct physicochemical characteristics. It is formulated as black, odorless, spherical particles of engineered carbon, with a highly consistent diameter ranging from 0.2 to 0.4 mm.[2] These particles are composed almost entirely of carbon (approximately 96%) and are designed to be insoluble in water and common organic solvents, ensuring they remain within the gastrointestinal tract without being absorbed into the body.[4]

A defining feature of AST-120 is its highly porous structure, which results in an exceptionally large surface area, documented to exceed 1600 m2/g.[4] This vast and widely distributed porosity creates an extensive and highly efficient binding surface, optimized for the selective adsorption of low molecular weight substances from the complex environment of the intestinal lumen.[4] The precise engineering of these pores is fundamental to the drug's mechanism and selectivity, allowing it to target small-molecule toxins while sparing larger, essential molecules.

Comparison with Activated Charcoal

While AST-120 is a carbon-based adsorbent, it is structurally and functionally distinct from conventional activated charcoal.[10] Standard activated charcoal is a broad-spectrum adsorbent, a property that makes it effective in cases of acute poisoning but presents significant challenges for chronic, long-term use. Its non-specific binding can lead to the adsorption of essential nutrients, vitamins, and co-administered medications, raising concerns about malnutrition and therapeutic interference.

AST-120 was specifically engineered to overcome these limitations. It exhibits a superior adsorption capacity for certain acidic and basic organic compounds that are known to accumulate in patients with renal failure when compared to standard activated charcoal.[2] More importantly, its unique pore structure confers a degree of molecular selectivity. AST-120 has a demonstrably lower adsorption capability for larger molecules, such as the digestive enzymes amylase, pepsin, lipase, and chymotrypsin.[4] This selectivity is a critical clinical advantage, as it minimizes interference with normal digestive processes and reduces the risk of nutrient malabsorption during long-term therapy. This deliberate engineering to favor the binding of small uremic toxin precursors (e.g., indole, with a molecular weight of approximately 117 Da) over much larger protein enzymes (e.g., pepsin, with a molecular weight of approximately 35 kDa) is the key innovation that makes AST-120 suitable for chronic administration in diseases like CKD.

Table 1: Key Physicochemical and Pharmacological Properties of AST-120

Property	Description	Source(s)
Generic Name	Spherical Carbon Adsorbent	9
Brand Name(s)	Kremezin®	4
Drug Class	Intestinal Sorbent / Adsorbent for Chronic Kidney Disease	4
Composition	Porous spherical particles composed of approximately 96% carbon.	2
Physical Form	Black, odorless, fine granules or spherical particles.	10
Particle Diameter	0.2–0.4 mm	4
Surface Area	Exceeds 1600 m2/g	4
Solubility	Insoluble in water and common organic solvents.	4
Primary Mechanism	Adsorption of low molecular weight uremic toxin precursors in the GI tract.	4
Key Adsorbed Molecules	Indole (precursor to Indoxyl Sulfate), p-Cresol (precursor to p-Cresyl Sulfate).	5
Comparison to Activated Charcoal	Superior adsorption for certain uremic toxins; lower adsorption for digestive enzymes (e.g., amylase, pepsin, lipase), making it more selective for chronic use.	4

Pharmacodynamics and Mechanism of Action

Primary Mechanism: Adsorption of Uremic Toxin Precursors

The pharmacodynamic activity of AST-120 is executed entirely within the lumen of the gastrointestinal (GI) tract. As an insoluble carbon adsorbent, it is not absorbed into the systemic circulation and therefore exerts no direct systemic pharmacological effects.[5] Its therapeutic benefit is derived from its ability to function as a high-affinity molecular sieve, selectively adsorbing specific low molecular weight substances and preventing their entry into the body.[4]

The primary targets of AST-120 are indole and p-cresol.[5] These aromatic compounds are not ingested but are generated endogenously within the colon. They are the metabolic byproducts of protein fermentation by the gut microbiota, arising from the breakdown of the amino acids tryptophan (to indole) and tyrosine and phenylalanine (to p-cresol).[8] In a healthy individual, these compounds are absorbed, metabolized, and efficiently cleared by the kidneys. However, in patients with CKD, their impaired clearance leads to systemic accumulation and toxicity.

AST-120 intervenes at the earliest point in this pathological pathway. As it transits through the GI tract, its vast porous surface area binds indole and p-cresol, sequestering them within the carbon matrix.[5] This physical adsorption prevents the precursors from being absorbed across the intestinal wall into the bloodstream. By interrupting this crucial absorption step, AST-120 effectively blocks the subsequent metabolic conversion of these precursors into their more toxic forms. Specifically, it prevents the hepatic conversion of absorbed indole into indoxyl sulfate (IS) and the conjugation of absorbed p-cresol into p-cresyl sulfate (PCS) in the intestinal submucosa and liver.[5] The AST-120 particles, now laden with the adsorbed toxin precursors, continue their transit through the digestive system and are ultimately eliminated from the body via fecal excretion.[5] This mechanism represents a proactive strategy of toxin removal, targeting the source of production rather than attempting to clear the toxins after they have accumulated systemically.

The Pathophysiological Role of Target Uremic Toxins

The clinical rationale for AST-120 is predicated on the well-established toxicity of its ultimate targets, indoxyl sulfate (IS) and p-cresyl sulfate (PCS). These compounds are among the most extensively studied protein-bound uremic toxins.[5] In patients with CKD, their serum concentrations rise dramatically due to diminished renal tubular secretion.[18] Because a large fraction of circulating IS and PCS is bound to albumin, they are poorly removed by conventional hemodialysis or hemodiafiltration, allowing them to persist at high levels even in patients receiving renal replacement therapy.[18]

An extensive body of evidence implicates IS and PCS as direct contributors to the progression of both CKD and its most lethal comorbidity, cardiovascular disease.[5] Their accumulation creates a vicious cycle, whereby the toxins generated as a consequence of kidney failure actively promote further kidney damage. The mechanisms of their nephrotoxicity are multifactorial and include the induction of oxidative stress through the generation of reactive oxygen species, the promotion of pro-inflammatory and pro-fibrotic pathways (such as stimulating transforming growth factor-β1), and the direct causation of glomerulosclerosis and tubulointerstitial fibrosis.[6]

Beyond the kidney, these toxins exert pleiotropic and deleterious effects on numerous organ systems. They are known to promote endothelial dysfunction, vascular smooth muscle cell proliferation, and vascular calcification, all of which are key drivers of the accelerated atherosclerosis and high cardiovascular mortality seen in CKD patients.[4] Furthermore, these toxins are implicated in a range of other uremic complications, including bone metabolism disorders, insulin resistance, and debilitating symptoms such as uremic pruritus.[20] More recent research has also linked them to neurological sequelae, including cognitive impairment and emotional disorders, suggesting they may cross the blood-brain barrier and induce neuroinflammation.[11] By lowering the systemic burden of IS and PCS, AST-120 is hypothesized to mitigate these widespread pathological processes.

Ancillary and Investigational Mechanisms

While the adsorption of indole and p-cresol is the primary and best-understood mechanism of AST-120, ongoing research suggests its therapeutic effects may be broader.

One area of investigation involves the adsorption of advanced glycation end products (AGEs). AGEs are harmful compounds formed when sugars react with proteins or fats, and their accumulation is accelerated in both diabetes and CKD. The diet is a major source of exogenous AGEs. Preclinical studies have shown that AST-120 can bind to diet-derived AGEs, such as carboxymethyllysine (CML), within the GI tract.[24] This suggests that AST-120 may reduce the body's total AGE load, potentially providing an additional mechanism for reducing the systemic inflammation and oxidative stress that drive complications in both CKD and diabetes.[14]

Another novel line of inquiry explores the potential of AST-120 in functional bowel disorders, particularly Irritable Bowel Syndrome (IBS).[4] This hypothesis stems from the recognition that AST-120's adsorptive capacity is not limited to uremic toxin precursors. The pathophysiology of IBS involves altered gut motility, increased intestinal permeability, and visceral hypersensitivity, which are thought to be driven by a variety of low-grade inflammatory mediators and altered bile acid signaling. Compelling data suggest that AST-120 may be able to adsorb mast cell-derived mediators and modulate the farnesoid X receptor (FXR), a critical bile acid sensor that maintains intestinal homeostasis.[4] By sequestering these non-uremic inflammatory molecules and influencing gut signaling pathways, AST-120 could theoretically mitigate key symptoms of IBS, such as abdominal pain and bloating. This expands the potential application of the drug's fundamental mechanism to a different, gut-centric pathology.

Clinical Evidence in Chronic Kidney Disease (CKD)

The clinical development of AST-120 is characterized by a significant divergence in evidence, with early, targeted trials in Japan yielding positive results that supported its approval, while subsequent large, multinational pivotal trials failed to meet their primary endpoints. A critical analysis of this history is essential to understand the drug's current standing in nephrology.

Foundational Clinical Trials in Japan (Pre-Market, 1982-1986)

The initial approval of AST-120 in Japan in 1991 was based on two key Phase III, double-blind, placebo-controlled trials conducted in the 1980s.[7] These trials are notable for their design and the evolution of their methodology.

The first Phase III trial (1982-1983) enrolled 156 patients with advanced CKD (serum creatinine [sCr] 5–8 mg/dL) and treated them with either AST-120 or placebo for 24 weeks.[7] This initial study did not demonstrate a statistically significant benefit for AST-120 on its primary endpoints, which included global improvement ratings and hemodialysis scores.[5] However, a crucial observation was made during a post-hoc analysis. When investigators isolated a subset of patients who exhibited clear evidence of rapid disease progression at baseline (defined by a significantly negative slope of the reciprocal of serum creatinine, or 1/Cr, over time), a significant attenuation of this decline was observed in the AST-120-treated group.[7] This finding suggested that the drug's effect might be most readily detectable in patients whose kidney function was actively and rapidly deteriorating.

Informed by this result, the second Phase III trial (1984-1986) was redesigned with a more sophisticated, two-phase approach.[7] The trial incorporated a 24-week, pre-randomization observation period. Only patients who demonstrated a significant increase in sCr (≥1.2 mg/dL) during this observation period—thereby confirming their status as "rapid progressors"—were eligible to enter the 24-week double-blind treatment phase.[7] In this enriched population of patients with demonstrably progressive disease, the results were markedly different from the first trial. AST-120 treatment led to a highly significant attenuation of the 1/Cr slope compared to placebo.[5] Furthermore, global improvement ratings, which took into account both renal function changes and uremic symptoms, were significantly superior in the AST-120 group.[5] These foundational trials established a critical principle that would echo throughout the drug's history: the clinical efficacy of AST-120 appeared to be contingent on the underlying rate of disease progression in the study population.

The EPPIC-1 and EPPIC-2 Trials: A Critical Analysis

In an effort to gain regulatory approval in the United States and Europe, two large-scale, multinational, randomized, double-blind, placebo-controlled Phase III trials were conducted: Evaluating Prevention of Progression in Chronic Kidney Disease 1 and 2 (EPPIC-1 and EPPIC-2; NCT00500682 and NCT00501046).[10] These trials enrolled a combined total of 2,035 patients with moderate to severe CKD, who were randomized to receive either a high dose of AST-120 (9 g/day) or a matching placebo, in addition to the contemporary standard of care.[1]

Despite their large scale and rigorous design, the EPPIC trials failed to meet their primary composite endpoint, which was the time to dialysis initiation, kidney transplantation, or doubling of serum creatinine.[10] In both the individual trials and a pooled analysis of the data, there was no statistically significant difference between the AST-120 and placebo groups for this hard clinical outcome.[10]

A deep analysis of the trial data reveals several key factors that likely contributed to this outcome. The most significant factor was a fundamental miscalculation in the trial's assumptions about disease progression. The power calculations for the studies were based on an estimated median time to the primary endpoint of 124 weeks in the placebo group. However, the actual observed median time to the endpoint was substantially longer: 189.0 weeks in EPPIC-1 and 170.3 weeks in EPPIC-2.[5] This indicates that the enrolled patient population, as a whole, had a much more gradual rate of CKD progression than anticipated. This slower-than-expected event rate severely diminished the statistical power of the studies to detect a therapeutic benefit, as the "room for improvement" was much smaller than planned. Unlike the successful second Japanese trial, the EPPIC studies did not employ an observation period to enrich the population with rapid progressors, resulting in a heterogeneous cohort where many patients had relatively stable disease.[10]

A second major confounding factor was patient adherence. The 9 g/day dose of AST-120 required a very high pill burden (30 capsules per day), and the known gastrointestinal side effects, such as constipation, likely posed a significant challenge for long-term adherence.[2] While reported compliance based on pill counts was high, this method is often unreliable. The potential for poor adherence in a rigorous intent-to-treat (ITT) analysis could mask a true drug effect.

Despite the failure of the primary endpoint, insights can be gleaned from secondary and post-hoc analyses. For instance, while not a primary endpoint, the rate of decline in estimated glomerular filtration rate (eGFR) was significantly slower in the AST-120 group compared to placebo in the EPPIC-2 trial and in the pooled analysis of both studies.[5] This suggests that AST-120 did exert a measurable biological effect on the rate of renal function loss, even if it did not translate to a statistically significant benefit on the hard composite endpoint within the trial's timeframe. Furthermore, post-hoc subgroup analyses hinted at efficacy in specific populations. An analysis of patients from the United States and another analysis of patients with high compliance rates (defined as ≥67%) both showed a statistically significant delay in the time to the primary endpoint in the AST-120 group.[2] These findings reinforce the conclusions from the early Japanese trials: that the benefits of AST-120 are most likely to be realized in well-defined, adherent patient populations with actively progressing disease.

Other Significant CKD Trials

Beyond the pivotal Japanese and EPPIC trials, other studies have contributed to the complex evidence base for AST-120.

• CAP-KD (Japan): The Collaborative study on the Administration of Kremezin in patients with Progressive chronic Kidney Disease was a post-marketing trial in Japan. It demonstrated that in patients already receiving standard-of-care with renin-angiotensin system (RAS) inhibitors, the addition of AST-120 significantly suppressed the rate of eGFR decline over a one-year observation period.[5]
• K-STAR (Korea): The Kremezin Study against Renal Disease Progression in Korea was a prospective, randomized controlled trial. Similar to the EPPIC trials, K-STAR did not show a significant difference between the AST-120 and control groups on its primary endpoint.[5] Also similar to EPPIC, the rate of renal function decline in the control group was slower than expected, likely due to the effectiveness of modern standard medical care, which again limited the statistical power to show a benefit.[5] Post-hoc analyses of the K-STAR data have suggested that sustained use of AST-120 may be associated with improved cardiovascular outcomes.[27]
• Korean Observational Study: A retrospective analysis of 195 Korean patients with CKD evaluated renal function for six months before and for at least six months after the initiation of AST-120 therapy. The study found that the slope of renal deterioration, as measured by both 1/sCr and eGFR, was significantly blunted after patients started taking AST-120, providing real-world evidence of its potential to slow CKD progression.[6]

Meta-Analyses and Systematic Reviews

Multiple meta-analyses have been conducted to synthesize the available data. These analyses consistently confirm that AST-120 is highly effective at achieving its primary biochemical goal: significantly lowering serum levels of indoxyl sulfate.[19]

However, the evidence for hard clinical endpoints remains mixed. A comprehensive network meta-analysis published in 2021, which included 15 randomized controlled trials (RCTs) with a total of 3,763 patients, found no significant difference in all-cause mortality among various treatment strategies.[29] It also concluded that fixed low-dose and high-dose AST-120 regimens were not superior to no AST-120 treatment with respect to major renal outcomes.[29] However, this same analysis uncovered a critical nuance. When examining studies that employed a

"tailored-dose" strategy, where the dosage was adjusted based on patient characteristics or response, this approach was associated with significantly lower event rates for both end-stage renal disease and the composite renal outcome.[29] This finding strongly suggests that a one-size-fits-all dosing strategy may be suboptimal and that individualized therapy could be key to unlocking the clinical benefits of AST-120.

Preclinical Evidence from Animal Models

In stark contrast to the equivocal results from human clinical trials, the preclinical evidence for AST-120 in animal models of CKD is overwhelmingly and consistently positive.[28] A 2024 meta-analysis of animal studies systematically reviewed the data and found that treatment with AST-120 was associated with statistically significant improvements in all major markers of renal function. These included lower serum creatinine levels, lower blood urea nitrogen (BUN) levels, greater creatinine clearance rates, and reduced proteinuria.[19] Beyond markers of renal function, these animal models also demonstrate that AST-120 effectively reduces oxidative stress, attenuates renal inflammation and fibrosis, and improves dyslipidemia associated with CKD.[21] This profound disconnect between the robustly positive preclinical data and the inconsistent human clinical data highlights a significant translational gap. While the fundamental mechanism of IS reduction and its downstream benefits are clearly demonstrable in controlled animal models, the clinical impact in humans is modulated by a complex interplay of factors including patient heterogeneity, dietary variations, gut microbiome differences, the high efficacy of modern standard of care, and, critically, patient adherence to a challenging medication regimen.

Table 2: Summary of Major Clinical Trials of AST-120 in Chronic Kidney Disease

Trial Name	Years	Region	N	Patient Population	Dosing	Primary Endpoint(s)	Key Outcomes & Conclusions	Source(s)
Japan Phase III-2	1984–1986	Japan	244	Progressive CKD (sCr 5-8 mg/dL) selected after 24-week observation period for rapid progression.	4.2 g/day, increased to 6.0 g/day.	Change in 1/sCr slope, uremic symptoms, global improvement.	Positive: AST-120 showed a highly significant attenuation of the 1/sCr slope and superior global improvement vs. placebo. Established efficacy in rapid progressors.	5
EPPIC-1 & EPPIC-2	2007–2012	Multinational (North America, Europe, etc.)	2035	Moderate to severe CKD (sCr 2.0-5.0 mg/dL for men, 1.5-5.0 mg/dL for women).	9 g/day	Composite of dialysis initiation, kidney transplantation, or doubling of sCr.	Negative: No significant difference between AST-120 and placebo. Disease progression in the placebo group was much slower than expected.	10
CAP-KD	Post-2000s	Japan	460	CKD patients with sCr <5.0 mg/dL, already on RAS inhibitors.	6 g/day	Change in eGFR.	Positive: AST-120 significantly suppressed the decline in eGFR over one year compared to control.	5
K-STAR	~2010s	Korea	465	Progressive CKD.	6 g/day	Composite of dialysis initiation, transplantation, or 50% reduction in eGFR.	Negative: No significant difference in the primary endpoint. Progression in the control group was slow. Post-hoc analyses suggested cardiovascular benefits.	5
US Phase II	~2000s	USA	N/A	Moderate to severe CKD with elevated serum indoxyl sulfate.	2.7 g/day, 6.3 g/day, 9.0 g/day.	Change in serum indoxyl sulfate, uremic symptoms.	Positive: Showed a significant dose-dependent reduction in serum indoxyl sulfate levels and a decrease in uremia-related malaise.	8

Emerging and Investigational Therapeutic Applications

While the primary development focus for AST-120 has been on slowing the progression of CKD, research has expanded to investigate its potential for managing specific complications of uremia and other conditions with related pathophysiology. This research suggests that the drug's value may extend beyond altering long-term renal outcomes to providing tangible, symptom-oriented benefits.

Management of Uremic Pruritus

Uremic pruritus, or severe itching, is a common, debilitating, and often undertreated symptom affecting a large proportion of patients with advanced CKD and end-stage renal disease (ESRD), particularly those on hemodialysis.[20] It is strongly associated with a poor quality of life, sleep disturbances, depression, and even increased mortality.[20] The pathophysiology is complex but is believed to be linked to the systemic accumulation of uremic toxins, including indoxyl sulfate, which can induce a state of chronic systemic inflammation.[20]

A recent prospective, randomized clinical trial (NCT04639674) specifically evaluated the efficacy of AST-120 for this indication in hemodialysis patients.[23] The study demonstrated that a four-week course of treatment with AST-120 at a dose of 6 g/day resulted in a statistically significant decrease in the severity of uremic pruritus, as measured by the Visual Analog Scale (VAS) for itch intensity.[20] This clinical improvement was accompanied by significant reductions in the serum levels of both indoxyl sulfate and the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α).[20] This finding is significant as it provides a clear mechanistic link between the drug's primary action (adsorption of toxin precursors), its downstream biochemical effects (reduced systemic IS and inflammation), and a tangible clinical benefit (symptom relief). This evidence suggests a potential paradigm shift for AST-120, repositioning it from a disease-modifying agent for pre-dialysis patients to a potent symptomatic therapy for the dialysis population, where quality of life is a primary therapeutic goal.

Neurological and Cognitive Complications of CKD

There is growing recognition of a "kidney-brain axis," where the systemic environment of CKD negatively impacts neurological function. Uremic toxins like indoxyl sulfate are implicated in this process, contributing to cognitive and emotional disorders such as anxiety and depression.[11] These toxins are capable of crossing the blood-brain barrier and inducing neuroinflammation.

Preclinical research has explored the potential of AST-120 to mitigate these effects. A study using a 5/6 nephrectomy rat model of CKD investigated the impact of AST-120 treatment on neurological outcomes.[11] The results showed that rats treated with AST-120 exhibited an alleviation of cognitive deficits and anxiety-like behaviors compared to untreated CKD rats. Histological examination of the brain revealed that this behavioral improvement was associated with a reduction in markers of neuroinflammation, specifically a decreased coexpression of aquaporin-4 (a water channel involved in brain edema) and glial fibrillary acidic protein (GFAP, a marker of astrocyte activation) in the hippocampus. These neuroprotective effects were correlated with the successful reduction of serum IS levels by AST-120.[11] While these findings are preclinical, they open a promising new avenue of research into whether targeting gut-derived uremic toxins could be a viable strategy for protecting brain health in patients with CKD.

Potential Role in Irritable Bowel Syndrome (IBS)

The therapeutic rationale for AST-120 is also being explored in the context of non-renal, gut-centric disorders such as Irritable Bowel Syndrome (IBS).[4] This investigation is based on a logical extension of the drug's known mechanism of action within the gastrointestinal lumen. IBS is a functional bowel disorder characterized by altered gut motility, secretion, and visceral hypersensitivity.[4]

The theoretical basis for using AST-120 in IBS is multifactorial. The hypothesis posits that AST-120 could provide benefit by adsorbing a range of non-uremic, pro-inflammatory molecules present in the gut lumen, such as mediators released from mast cells, which are known to be involved in IBS pathophysiology.[4] Additionally, compelling data suggest that AST-120 may modulate the farnesoid X receptor (FXR), a nuclear receptor that acts as a key sensor for bile acids and is indispensable for maintaining intestinal homeostasis.[4] By influencing bile acid signaling and removing inflammatory mediators, AST-120 could potentially improve intestinal barrier function (reduce permeability), decrease visceral sensitivity (reduce pain signaling), and normalize gut motility. At present, this remains a preclinical concept that requires rigorous clinical validation to determine if these theoretical benefits translate into meaningful improvements for patients with IBS.

Prescribing Information and Clinical Administration

This section consolidates practical clinical information regarding the use of AST-120, including dosing, administration, safety profile, and key management considerations. This information is primarily derived from its use in Asian countries where it is an approved medication.

Dosage and Administration

The dosing of AST-120 has varied between clinical trials and approved labeling, but a standard regimen has been established in clinical practice.

• Approved Dosage: The standard approved dose in Japan, Korea, the Philippines, and Taiwan is 6 g per day.[2] This is typically administered in three divided doses of 2 g each.[6]
• Clinical Trial Dosages: A range of doses has been evaluated in clinical studies. Early Japanese trials that established its efficacy used escalating doses, starting at 3.6 g/day and increasing to 5.4 g/day or even 7.2 g/day based on tolerability and investigator discretion.[7] A dose-ranging Phase II study conducted in the United States evaluated 2.7 g/day, 6.3 g/day, and 9.0 g/day, finding a dose-dependent reduction in serum indoxyl sulfate and concluding that 9 g/day was the optimal dose for that population.[8] The large multinational EPPIC trials subsequently used this higher 9 g/day dose.[1]
• Administration Guidelines: Proper administration is critical to ensure efficacy and minimize interactions. AST-120 should be taken between meals.[6] The most important administration instruction relates to its adsorbent nature. To prevent AST-120 from binding to other orally administered medications and reducing their absorption and efficacy, it must be taken separately. It is recommended that patients wait for a period of 30 minutes to 1 hour after taking other medications before taking their dose of AST-120.[6] This temporal separation is the primary strategy for managing potential drug-drug interactions.

Safety and Tolerability Profile

Because AST-120 is not systemically absorbed, it is generally considered to have a favorable safety profile, with adverse effects being confined to the gastrointestinal tract.[5]

• Common Adverse Reactions: The most frequently reported side effects are directly related to its physical presence and adsorbent properties within the gut. These include constipation, loss of appetite (anorexia), nausea, vomiting, and a sensation of abdominal bloating or fullness.[2]
• Serious Adverse Reactions: The most clinically significant and dose-limiting adverse effect is severe constipation. In some patients, this can be pronounced enough to necessitate dose reduction or complete discontinuation of the therapy.[2] Other less common adverse reactions that have been reported include skin rash and itching (pruritus).[12]

Contraindications, Warnings, and Precautions

The use of AST-120 is restricted in certain patient populations due to its mechanism of action.

• Contraindication: AST-120 is strictly contraindicated in patients with a known or suspected transit disorder of the digestive tract, such as a bowel obstruction, as the drug could potentially exacerbate the condition.[16]
• Warnings and Precautions: Caution should be exercised when prescribing AST-120 to patients with pre-existing gastrointestinal conditions, such as active peptic ulcers or esophageal varices.[16] It should also be used with caution in patients with a known predisposition to constipation, as they are at higher risk of developing this side effect.[16] The safety and efficacy of AST-120 have not been formally established in special populations, and its use in pregnant or lactating women, children, and the elderly requires careful clinical judgment and monitoring.[16]

Drug Interactions

The drug interaction profile of AST-120 is primarily pharmacokinetic and physical, not metabolic.

• Mechanism of Interaction: AST-120 does not interact with metabolic enzyme systems like the cytochrome P450 pathway. Instead, its potential for interaction stems from its fundamental mechanism of action: adsorption. It can physically bind to other orally administered drugs within the GI lumen, thereby preventing their absorption and reducing their systemic bioavailability and therapeutic effect.[6]
• Management: This interaction is managed not by avoiding specific drugs, but by implementing a strategy of temporal separation of dosing. As outlined in the administration guidelines, ensuring a sufficient time interval (at least 30-60 minutes) between the intake of other medications and AST-120 is the key to mitigating this risk.[12] This principle applies universally to all co-administered oral therapies.

Patient Adherence

A major practical challenge in the clinical use of AST-120 is patient adherence. This issue is significant enough to be considered a primary determinant of its real-world effectiveness.

• Barriers to Adherence: The primary barriers are the high treatment burden and the side effect profile. The standard 6 g/day dose requires patients to consume a large volume of fine granules, and the 9 g/day dose used in the EPPIC trials involved taking 30 capsules daily.[2] This, combined with the high incidence of gastrointestinal side effects like constipation and bloating, can make long-term adherence difficult for many patients.[2]
• Clinical Impact of Non-Adherence: The issue of adherence is not merely one of convenience; it has a direct impact on observed clinical efficacy. As the post-hoc analysis of the EPPIC trials revealed, a statistically significant therapeutic benefit was only observed in the subgroup of patients who maintained a high rate of compliance.[26] This demonstrates that inconsistent use of the drug is likely to lead to a lack of therapeutic effect. Reports from Japan suggest that adherence can be low in real-world clinical practice, with some estimates suggesting up to 70% of patients experience adherence problems.[2]
• Strategies for Improvement: Recognizing this challenge, efforts are being explored to improve the patient experience and enhance adherence. These include structured patient support and education programs, as well as the development of more palatable and convenient formulations, such as oblate-coated granules or orally disintegrated tablets that may be easier to ingest.[2] The success of AST-120 therapy in an individual patient is therefore highly dependent on proactive management of side effects and a strong patient-physician partnership to overcome the challenges of the treatment regimen.

Global Regulatory Landscape and Market Access

The regulatory history of AST-120 is a tale of two distinct paths, resulting in a global market where the drug is a long-established standard of care in several Asian countries but remains an unapproved investigational agent in the United States and Europe. This disparity is a direct reflection of evolving evidentiary standards for drug approval and the critical role of clinical trial design.

Approvals in Asia

AST-120 has been approved and marketed for decades in several countries in Asia, where it is an established component of conservative management for pre-dialysis CKD.

• Japan (PMDA): The Pharmaceuticals and Medical Devices Agency (PMDA) of Japan granted the first approval for AST-120 (Kremezin®) in 1991.[1] The approved indication is for the "improvement of uremic symptoms and for prolonging the time to initiation of dialysis in patients with chronic renal failure (progressive)".[3] This approval was based on the positive results of the second Japanese Phase III trial, which successfully demonstrated a slowing of renal function decline (measured by 1/Cr slope) in a carefully selected population of patients with rapidly progressing disease.[7]
• Korea (MFDS): Following Japan, the Ministry of Food and Drug Safety (MFDS) in South Korea approved AST-120 in 2004 (some sources cite 2005) for the same indication of treating uremic symptoms and delaying dialysis initiation in progressive CKD.[4]
• Taiwan (TFDA): The Taiwan Food and Drug Administration (TFDA) granted approval in 2007, also for the same indication as in Japan and Korea.[5]
• Philippines (FDA): The Food and Drug Administration of the Philippines approved AST-120 in 2010.[4] The product registration for Kremezin® remains active, with the indication listed as "Improvement in uremic symptoms & prolonging the time to initiation of dialysis in chronic renal failure (progressive)".[9]

Status in the United States (FDA) and Europe (EMA)

In stark contrast to its status in Asia, AST-120 is not approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for the treatment of chronic kidney disease.[35]

The primary reason for this non-approval is the definitive failure of the large-scale, multinational EPPIC-1 and EPPIC-2 trials to meet their pre-specified primary endpoints.[10] These trials were specifically designed and conducted to meet the rigorous regulatory standards of the FDA and EMA, which in the 2000s required demonstration of a benefit on hard clinical outcomes (like time to dialysis) in large, diverse patient populations. The negative results of these pivotal trials effectively closed the regulatory pathway for a broad CKD indication in these regions.

Interestingly, AST-120 has had some interaction with the FDA. In 2008, it was granted Orphan Drug Designation for the treatment of pouchitis, an inflammatory condition of the ileal pouch that can occur after colectomy.[38] This designation is unrelated to its use in CKD and highlights an alternative therapeutic avenue that was explored, though no further development for this indication has been publicly reported. Numerous clinical trials involving AST-120 have been conducted in the U.S. under Investigational New Drug (IND) applications, including the EPPIC trials and earlier phase studies, but no New Drug Application (NDA) for a CKD indication has been successfully submitted and approved.[10]

Future Perspectives

The future of AST-120 in Western markets is uncertain but not entirely closed. A path to approval would almost certainly require new, successful clinical trials. Drawing lessons from the past, any future trial aimed at slowing CKD progression would need a fundamentally different design from the EPPIC studies. It would require robust patient enrichment strategies to exclusively enroll individuals with a high, prospectively-verified risk of rapid progression, thereby maximizing the potential to observe a treatment effect.[5] Furthermore, such a trial would need to address the critical issue of adherence, perhaps by utilizing novel, more patient-friendly formulations and incorporating adherence-support programs.[2]

An alternative and potentially more viable strategy could be to pursue approval for more targeted, niche indications where there is emerging positive evidence. The successful randomized trial in uremic pruritus provides a strong foundation for seeking an indication for the management of this specific, burdensome symptom in ESRD patients.[20] This would shift the drug's value proposition from long-term disease modification to near-term quality of life improvement, a different but equally valid therapeutic goal.

Table 3: Global Regulatory Approval Status of AST-120 (Kremezin®)

Country/Region	Regulatory Agency	Approval Status	Year of First Approval	Approved Indication(s)	Basis for Decision (Brief)	Source(s)
Japan	PMDA	Approved	1991	Improvement of uremic symptoms and prolonging the time to initiation of dialysis in patients with progressive chronic renal failure.	Positive Phase III trials in a selected population of rapid progressors, showing a significant slowing of renal function decline (1/sCr slope).	3
Korea	MFDS	Approved	2004 / 2005	Improvement of uremic symptoms and prolonging the time to initiation of dialysis in patients with progressive chronic renal failure.	Based on Japanese data and subsequent local studies.	4
Taiwan	TFDA	Approved	2007	Improvement of uremic symptoms and prolonging the time to initiation of dialysis in patients with progressive chronic renal failure.	Based on Japanese data and regional clinical experience.	5
Philippines	FDA	Approved	2010	Improvement of uremic symptoms and prolonging the time to initiation of dialysis in patients with progressive chronic renal failure.	Based on existing international approvals and data.	4
USA	FDA	Not Approved (for CKD)	N/A	N/A	Failure of the pivotal EPPIC-1 and EPPIC-2 trials to meet their primary endpoints for slowing CKD progression.	10
European Union	EMA	Not Approved (for CKD)	N/A	N/A	Failure of the pivotal EPPIC-1 and EPPIC-2 trials to meet their primary endpoints for slowing CKD progression.	10

Synthesis and Expert Conclusion

Reconciling the Disparate Evidence

The extensive body of evidence surrounding AST-120 presents a complex and, at first glance, contradictory picture. The central challenge is to reconcile its proven and consistent biochemical efficacy, the positive outcomes in early targeted clinical trials and preclinical models, and the definitive failure of the large, multinational pivotal trials designed to confirm its benefit. A nuanced analysis reveals that these disparate findings are not necessarily mutually exclusive. Rather, they suggest that the clinical efficacy of AST-120 is highly context-dependent.

The drug consistently and effectively reduces systemic levels of the uremic toxin precursor indole, leading to lower circulating levels of indoxyl sulfate. This is its undisputed primary pharmacological effect. The translation of this biochemical effect into a measurable clinical benefit on hard renal endpoints, however, appears to be contingent on two critical factors: the patient's underlying rate of disease progression and their ability to adhere to the treatment regimen. The early Japanese trials succeeded because they were designed, whether intentionally or through post-hoc discovery, to isolate the signal of efficacy within the noise of patient heterogeneity by focusing on rapid progressors. The EPPIC trials failed, in large part, because they tested the drug in a broad, heterogeneous population whose overall rate of progression was too slow to allow the drug's modest effect to become statistically significant within the study's timeframe.

Therefore, the most accurate conclusion is not that AST-120 is "ineffective," but that its benefit in slowing CKD progression is likely concentrated in a specific patient phenotype: the individual with a documented, high rate of eGFR decline who is also motivated and able to tolerate and adhere to a challenging, long-term therapeutic regimen.

The Role of AST-120 in Modern Nephrology

Based on the available evidence, the role of AST-120 in modern nephrology varies significantly by geographic region and clinical context.

• In Asia (Japan, Korea, etc.): In regions where it holds regulatory approval, AST-120 remains a therapeutic option within the armamentarium for the conservative management of pre-dialysis CKD. Its use is most rationally applied to patients who, despite standard-of-care (e.g., RAS inhibition, blood pressure and glycemic control), continue to exhibit a rapid decline in renal function. Prescribing physicians must engage in careful patient selection and provide comprehensive counseling regarding the treatment burden, potential side effects (especially constipation), and the critical importance of adherence and spaced dosing with other medications.
• In the US and Europe: In regions where it is not approved, AST-120 does not have a role in standard clinical practice. Its primary value is academic, serving as an important case study in the challenges of nephrology drug development. It underscores the critical importance of patient selection and enrichment strategies in clinical trial design and highlights the translational gap between preclinical promise and clinical reality.
• Emerging Niche Applications: The positive results from the trial on uremic pruritus may signal a new and important clinical niche for AST-120. This shifts the therapeutic focus from the ambitious and difficult-to-prove goal of modifying long-term disease progression to the more tangible and achievable goal of improving quality of life by palliating a severe and burdensome symptom. This application is particularly relevant for patients already on dialysis, for whom slowing CKD progression is no longer a relevant endpoint, but symptom control is paramount.

Recommendations for Future Research

The journey of AST-120 has provided valuable lessons that should guide future research. The following areas represent the most logical and promising paths forward:

1. Redesigned CKD Progression Trials: Any future attempt to demonstrate a benefit in slowing CKD progression in Western populations must incorporate stringent enrichment strategies. This would involve a prospective run-in or observation period to identify and exclusively enroll patients with a documented high rate of eGFR decline, thereby replicating the successful design of the second Japanese Phase III trial.
2. Formulation Development: The adherence barrier is a critical and unresolved issue. Investment in the development and clinical testing of more patient-friendly formulations—such as orally disintegrated tablets, smaller capsules, or more palatable granules—is essential to improve tolerability and adherence, which would in turn provide a more accurate assessment of the drug's true efficacy.
3. Confirmation of Symptomatic Benefits: The promising findings in uremic pruritus require confirmation in larger, robust, multi-center randomized controlled trials. This represents the most viable near-term path to a potential new indication. Research could also be expanded to other burdensome uremic symptoms that may be linked to toxin accumulation.
4. Exploration of Neurological and Gut-Brain Axis Effects: The preclinical data suggesting a neuroprotective effect are intriguing and warrant further investigation. Future studies could incorporate cognitive and quality-of-life endpoints to explore whether reducing the systemic uremic toxin load translates into measurable benefits for brain health in CKD patients.

In conclusion, AST-120 is a pharmacologically active agent with a well-defined mechanism of action. Its clinical history is a powerful illustration of the principle that a drug's effectiveness is a product not only of its mechanism but also of the context in which it is used—the right drug, for the right patient, at the right time. While its role in the broad-based prevention of CKD progression remains unproven by modern standards, its potential in carefully selected rapid progressors and as a targeted therapy for debilitating uremic symptoms like pruritus ensures that it remains a subject of significant clinical and scientific interest.

Works cited

1. KUREHA CORPORATION Outcome of Global Phase III (EPPIC) Studies, accessed September 11, 2025, https://www.kureha.co.jp/en/release/pdf/20121010en.pdf
2. Importance of AST-120 (Kremezin®) Adherence in a Chronic Kidney Disease Patient with Diabetes | Case Reports in Nephrology and Dialysis | Karger Publishers, accessed September 11, 2025, https://karger.com/cnd/article/8/2/107/68474/Importance-of-AST-120-KremezinR-Adherence-in-a
3. "Kremezin®", Drug for Chronic Renal Failure Transfer of Marketing Rights in Japan, accessed September 11, 2025, https://www.mt-pharma.co.jp/e/news/assets/pdf/e_MTPC_K110111.pdf
4. The role of AST-120 and protein-bound uremic toxins in irritable ..., accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4530433/
5. Review of the efficacy of AST-120 (KREMEZIN®) on renal function in chronic kidney disease patients - PMC - PubMed Central, accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6374968/
6. Effects of Oral Adsorbent AST-120 (Kremezin on the Progression of Chronic Kidney Disease, accessed September 11, 2025, https://www.krcp-ksn.org/upload/pdf/2904450.pdf
7. Review of the efficacy of AST-120 (KREMEZIN) on renal function in chronic kidney disease patients - ResearchGate, accessed September 11, 2025, https://www.researchgate.net/publication/330959763_Review_of_the_efficacy_of_AST-120_KREMEZIN_on_renal_function_in_chronic_kidney_disease_patients
8. AST-120 for the management of progression of chronic kidney disease | IJNRD, accessed September 11, 2025, https://www.dovepress.com/ast-120-for-the-management-of-progression-of-chronic-kidney-disease-peer-reviewed-fulltext-article-IJNRD
9. Human Drugs View - FDA Verification Portal, accessed September 11, 2025, https://verification.fda.gov.ph/drug_productsview.php?showdetail=®istration_number=DR-XY37669
10. Randomized Placebo-Controlled EPPIC Trials of AST-120 in CKD ..., accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4483576/
11. AST-120 Protects Cognitive and Emotional Impairment in Chronic Kidney Disease Induced by 5/6 Nephrectomy - MDPI, accessed September 11, 2025, https://www.mdpi.com/2076-3425/14/11/1043
12. KREMEZIN Fine Granules 2g | Kusuri-no-Shiori(Drug Information Sheet), accessed September 11, 2025, https://www.rad-ar.or.jp/siori/english/search/result?n=32559
13. AST-120 for the management of progression of chronic kidney disease - PMC, accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3912158/
14. The role of AST-120 and protein-bound uremic toxins in irritable bowel syndrome: A therapeutic perspective - ResearchGate, accessed September 11, 2025, https://www.researchgate.net/publication/281519241_The_role_of_AST-120_and_protein-bound_uremic_toxins_in_irritable_bowel_syndrome_A_therapeutic_perspective
15. AST-120: A NOVEL DRUG TO PREVENT PROGRESSION OF CKD?, accessed September 11, 2025, https://bns-hungary.hu/documents/20bns/2013bns_0829_0900.pdf
16. KREMEZIN, Spherical Carbon Adsorbent 2g 1 Sachet [Prescription ..., accessed September 11, 2025, https://www.watsons.com.ph/kremezin-spherical-carbon-adsorbent-2g-1-sachet-prescription-required/p/BP_50005505
17. Review of the efficacy of AST-120 (KREMEZIN®) on renal function in chronic kidney disease patients - Taylor & Francis Online, accessed September 11, 2025, https://www.tandfonline.com/doi/abs/10.1080/0886022X.2018.1561376
18. Pharmacological Actions of Indoxyl Sulfate and AST-120 That Should Be Recognized for the Strategic Treatment of Patients with Ch, accessed September 11, 2025, https://www.dovepress.com/article/download/60013
19. The Ability of AST-120 to Lower the Serum Indoxyl Sulfate Level Improves Renal Outcomes and the Lipid Profile in Diabetic and Nondiabetic Animal Models of Chronic Kidney Disease: A Meta-Analysis - MDPI, accessed September 11, 2025, https://www.mdpi.com/2072-6651/16/12/544
20. AST-120 improved uremic pruritus by lowering indoxyl sulfate and inflammatory cytokines in hemodialysis patients - Aging-US, accessed September 11, 2025, https://www.aging-us.com/article/205580/text
21. Early and delayed effects of AST-120 on chronic cyclosporine nephropathy | Nephrology Dialysis Transplantation | Oxford Academic, accessed September 11, 2025, https://academic.oup.com/ndt/article/26/5/1502/1893276
22. AST-120 improved uremic pruritus by lowering indoxyl sulfate and inflammatory cytokines in hemodialysis patients - Aging-US, accessed September 11, 2025, https://www.aging-us.com/article/205580/pdf
23. Study Details | NCT04639674 | AST-120 in Hemodialysis Patients ..., accessed September 11, 2025, https://clinicaltrials.gov/study/NCT04639674
24. Oral administration of AST-120 (Kremezin) is a promising therapeutic strategy for advanced glycation end product (AGE)-related disorders - PubMed, accessed September 11, 2025, https://pubmed.ncbi.nlm.nih.gov/17331665/
25. Full article: Review of the efficacy of AST-120 (KREMEZIN®) on renal function in chronic kidney disease patients - Taylor & Francis Online, accessed September 11, 2025, https://www.tandfonline.com/doi/full/10.1080/0886022X.2018.1561376
26. The effects of AST-120 on chronic kidney disease progression in the United States of America: a post hoc subgroup analysis of randomized controlled trials, accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5045594/
27. Diagram of participant enrollment and analysis, the Kremezin study against renal disease progression in Korea (K-STAR). - ResearchGate, accessed September 11, 2025, https://www.researchgate.net/figure/Diagram-of-participant-enrollment-and-analysis-the-Kremezin-study-against-renal-disease_fig1_315719674
28. The Ability of AST-120 to Lower the Serum Indoxyl Sulfate Level ..., accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11679735/
29. Efficacy of AST-120 for Patients With Chronic Kidney Disease: A Network Meta-Analysis of Randomized Controlled Trials - PMC - PubMed Central, accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8350440/
30. Efficacy of AST-120 for Patients With Chronic Kidney Disease: A Network Meta-Analysis of Randomized Controlled Trials - Frontiers, accessed September 11, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.676345/full
31. A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (Kremezin) in patients with moderate to severe CKD - PubMed, accessed September 11, 2025, https://pubmed.ncbi.nlm.nih.gov/16564934/
32. AST-120 improved uremic pruritus by lowering indoxyl sulfate and inflammatory cytokines in hemodialysis patients - PMC - PubMed Central, accessed September 11, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10968676/
33. The Effects of AST-120 on Endothelial Dysfunction in Patients With Chronic Kidney Disease, accessed September 11, 2025, https://www.clinicaltrials.gov/study/NCT01157260
34. Review of the efficacy of AST-120 (KREMEZIN®) on renal function in chronic kidney disease patients - PubMed, accessed September 11, 2025, https://pubmed.ncbi.nlm.nih.gov/30732506/
35. Accelerated assessment | European Medicines Agency (EMA), accessed September 11, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/accelerated-assessment
36. European Medicines Agency (EMA), accessed September 11, 2025, https://www.ema.europa.eu/en/medicines
37. Extensions of marketing authorisations: questions and answers | European Medicines Agency (EMA), accessed September 11, 2025, https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/variations-including-extensions-marketing-authorisations/extensions-marketing-authorisations-questions-answers
38. New FDA Orphan Drugs - Index - Medscape, accessed September 11, 2025, https://www.medscape.com/index/section_3081_0