Exposures of Phenylacetic Acid and Phenylacetylglutamine Across Different Subpopulations and Correlation with Adverse Events
| Autor: | Carmen Mak, Jack Tseng, Xiaofeng Wang, Nagaraju Poola, Regis A. Vilchez |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Cirrhosis Glutamine Renal function Gastroenterology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Ammonia Internal medicine medicine Humans Pharmacology (medical) Original Research Article Glycerol phenylbutyrate Adverse effect Hepatic encephalopathy Phenylacetates Pharmacology business.industry medicine.disease 030104 developmental biology Phenylacetylglutamine Phenylacetate chemistry Urea cycle 030211 gastroenterology & hepatology business |
| Zdroj: | Clinical Pharmacokinetics |
| ISSN: | 1179-1926 |
| Popis: | Background Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the l-ornithine salt of phenylacetate, is under development for hepatic encephalopathy. Objective This analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program. Methods Phenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child–Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis. Results Phenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child–Pugh C than in Child–Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy. Conclusions Dose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01047-5. |
| Databáze: | OpenAIRE |
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