Effect of Food on the Pharmacokinetics and Efficacy of 4-Phenylbutyrate in Progressive Familial Intrahepatic Cholestasis

Progressive familial intrahepatic cholestasis (PFIC), a rare inherited recessive liver disease, progresses to liver failure in childhood. There is no effective medical therapy for PFIC. We and other groups have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has novel beneficial effects in two subtypes of PFIC, PFIC1 and PFIC2. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, we performed a multicenter, open-label, single-dose study to investigate the influence of meal timing on the pharmacokinetics of NaPB in PFIC patients. NaPB (150 mg/kg) was administered orally 30 min before, just before, and just after breakfast following overnight fasting. Seven pediatric PFIC patients were enrolled and six completed the study. Compared with postprandial administration, an approved guideline for UCDs, preprandial administration significantly increased the peak plasma concentration and area under the plasma concentration-time curve of 4-phenylbutyrate by 2.5-fold (95% confidential interval (CI), 2.0-3.0; P=0.003) and 2.5-fold (95% CI, 1.7-3.1; P=0.005), respectively. The optimal regimen for NaPB treatment of PFIC was studied over 27 months in two PFIC2 patients. One patient obtained no beneficial effect from 14 months of postprandial oral administration, so was converted to preprandial administration; the other patient commenced with preprandial NaPB dosing. Preprandial oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression in both patients. No adverse events were observed. In conclusion, preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients. Trial Registration Number: The study was registered in the UMIN Clinical Trials Registry at www.umin.ac.jp/ctr/index.htm (UMI25037). Funding Statement: This work was supported by Japan Agency for Medical Research and Development (AMED) under Grant Number JP18ek0109298 to H.H. The funding source does not participate in the study design and execution. Declaration of Interest: The authors state: None. Ethics Approval Statement: This study was approved by the institutional review boards at the University of Tokyo, Juntendo University, and other participating institutions, and was performed in accordance with the amended Declaration of Helsinki. Written informed consent was obtained from the parents of each patient prior to enrollment in the study.