Glycerol phenylbutyrate
Fuentes regulatorias consultadas
Indicaciones aprobadas
- Terapia adyuvante crónica de trastornos del ciclo de la urea que no se pueden tratar solo con restricción proteica y/o suplementación de aminoácidos.
Contraindicaciones
Absolutas
- Hipersensibilidad al principio activo; tratamiento de hiperamonemia aguda.
Advertencias clínicas
- Advertencia mayor · No es tratamiento de la hiperamonemia aguda; incluso durante el tratamiento puede aparecer hiperamonemia aguda, incluida encefalopatía hiperamonémica. — AEMPS CIMA, Ravicti, ficha técnica 1151062001, secciones 4.3 y 4.4
- Advertencia mayor · En somnolencia, confusión, náuseas o letargo inexplicados con amonio normal o bajo, medir fenilacetato y el cociente fenilacetato/fenilacetilglutamina; si el fenilacetato supera 500 microgramos/ml y el cociente es mayor de 2,5, considerar reducir la dosis o aumentar la frecuencia. — AEMPS CIMA, Ravicti, ficha técnica 1151062001, sección 4.4
- Advertencia mayor · Monitorizar estrechamente el amonio en insuficiencia pancreática o malabsorción intestinal, porque puede disminuir la absorción y el control del amonio. — AEMPS CIMA, Ravicti, ficha técnica 1151062001, sección 4.4
Interacciones medicamentosas
- ModeradaMidazolam y otros sustratos predominantes de CYP3A4
Mecanismo: Fenilbutirato de glicerol y/o sus metabolitos son inductores débiles de CYP3A4; redujeron aproximadamente 32 % la exposición sistémica a midazolam en estado estacionario.
Recomendación: Revisar eficacia de los sustratos de CYP3A4, incluidos algunos anticonceptivos orales, y considerar alternativas o seguimiento si se reduce su efecto terapéutico.
https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
- ModeradaInhibidores de lipasa y tratamientos de reposición de enzimas pancreáticas
Mecanismo: Fenilbutirato de glicerol se hidroliza por lipasas digestivas a ácido fenilbutírico y glicerol.
Recomendación: Usar con precaución; monitorizar el control del amonio cuando pueda alterarse la hidrólisis digestiva.
https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
- ModeradaCorticoesteroides
Mecanismo: Los corticoesteroides pueden aumentar la degradación proteica corporal y la concentración de amonio.
Recomendación: Monitorizar estrechamente la concentración de amonio durante la administración concomitante.
https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
- ModeradaÁcido valproico y haloperidol
Mecanismo: Ácido valproico y haloperidol pueden inducir hiperamonemia.
Recomendación: Monitorizar estrechamente la concentración de amonio si su uso es necesario en pacientes con trastornos del ciclo de la urea.
https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
- ModeradaProbenecid
Mecanismo: Probenecid puede inhibir la excreción renal de metabolitos del fenilbutirato de glicerol, incluida la fenilacetilglutamina y el ácido fenilacético.
Recomendación: Tener en cuenta esta interacción al interpretar la fenilacetilglutamina urinaria y ajustar la dosis; monitorizar estrechamente el amonio plasmático.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=15c4da9f-f5e0-4628-b55f-3730be3e1c39https://cima.aemps.es/cima/dochtml/ft/1151062001/FT_1151062001.html
Eventos adversos
Comunes (≥1%)
Diarrea · Flatulencia · Cefalea · Disminución del apetito · Vómitos · Fatiga · Náuseas
Raros pero graves
Encefalopatía hiperamonémica · Neurotoxicidad por fenilacetato
Embarazo y lactancia
No usar durante el embarazo ni en mujeres con capacidad de concebir que no utilicen anticoncepción eficaz, salvo que la situación clínica requiera tratamiento. En lactancia, decidir entre interrumpirla o interrumpir el tratamiento según beneficios para madre y niño.
Bibliografía reciente (PubMed)
Hepatic encephalopathy (HE) is one of the reversible complications of chronic liver disease, associated with a higher mortality rate. In current clinical practice, treatment with rifaximin and lactulose/lactitol is the first line of treatment in HE. With the advance in pathophysiology, a new class of ammonia lowering drugs has been revealed to overcome the hurdle and disease burden. The mechanism of the novel agents differs significantly and includes the alteration in intestinal microbiota, intestinal endothelial integrity, oxidative stress, inflammatory markers, and modulation of neurotoxins. Most of the trials have reported promising results in the treatment and prevention of HE with fecal microbiota transplantation, albumin, probiotics, flumazenil, polyethylene glycol, AST-120, glycerol phenylbutyrate, nitazoxanide, branched-chain amino acid, naloxone, and acetyl-l-carnitine. However, their clinical use is limited due to the presence of major drawbacks in their study design, sample size, safety profile, bias, and heterogenicity. This study will discuss the novel therapeutic targets for HE in liver cirrhosis patients with supporting clinical trial data.
Later-onset urea cycle disorders (UCD) are characterized by variable clinical presentation and unpredictable metabolic decompensation. Current management often relies on a reactive approach, with treatment initiated after clinical manifestations. Glycerol phenylbutyrate (GPB) is widely used for ammonia control in UCD. However, its role in later-onset forms remains incompletely defined, particularly regarding timing of initiation. Available evidence suggests that hyperammonemia-related neurological injury may occur even in apparently stable patients, raising concerns about the adequacy of a wait-and-see strategy. This work provides a clinical perspective integrating current evidence together with personal experience to explore the potential role of pre-emptive GPB therapy in later-onset UCD. The limitations of current approaches are discussed, highlighting the discrepancy between apparent biochemical stability and ongoing neurological risk. We suggest that a proactive treatment strategy may reduce the risk of neurological complications in selected patients with later-onset UCD. We propose a shift from reactive to pre-emptive management, positioning GPB as a potential tool in this context.
Hyperammonaemia is a key pathological feature of liver disease and the primary driver of hepatic encephalopathy (HE). However, the relative roles of increased ammonia production and reduced clearance are poorly understood as is the action of ammonia-targeting drugs for HE. We aimed to quantify whole-body ammonia metabolism in healthy persons and patients with cirrhosis and to validate our method by examining the effects of glycerol phenylbutyrate and lactulose + rifaximin treatment. Ten healthy men and ten male patients with cirrhosis were investigated by 90-minute constant ammonia infusion to achieve steady-state plasma ammonia. Whole-body ammonia clearance was calculated as infusion rate divided by steady-state concentration increase and ammonia production was calculated as clearance multiplied by baseline ammonia concentration. Participants were re-investigated after the ammonia-targeting interventions. In healthy persons, ammonia clearance was 3.5 (3.1-3.9) L/min and ammonia production was 49 (35-63) μmol/min. Phenylbutyrate increased clearance by 11% (4-19%, p = 0.009). In patients with cirrhosis, ammonia clearance was 20% lower at 2.7 (2.1-3.3) L/min (p = 0.02) and production was nearly threefold higher at 131 (102-159) μmol/min (p <0.0001). Lactulose + rifaximin reduced production by 20% (2-37%, p = 0.03). The infusion was generally well-tolerated apart from in one hyperammonaemic patient, with cirrhosis and possible bleeding unrelated to the infusion, who developed clinical HE that reverted when infusion was discontinued. Whole-body ammonia clearance and production may be measured separately using the described technique. This technique identified a lower clearance and a higher production of ammonia in patients with cirrhosis, and showed that phenylbutyrate increases clearance, whereas lactulose + rifaximin reduces production. High blood ammonia plays a key role in cirrhosis-related brain dysfunction. However, the relative roles of reduced ammonia clearance