Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis.

Scientific reports 2019 Nov 19

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Progressive familial intrahepatic cholestasis (PFIC), a rare inherited disorder, progresses to liver failure in childhood. We have shown that sodium 4-phenylbutyrate (NaPB), a drug approved for urea cycle disorders (UCDs), has beneficial effects in PFIC. However, there is little evidence to determine an optimal regimen for NaPB therapy. Herein, a multicenter, open-label, single-dose study was performed to investigate the influence of meal timing on the pharmacokinetics of NaPB. 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 regimen 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 2.4-fold (95% CI, 1.7-3.2;P = 0.005). The observational study over 3 years in two PFIC patients showed that preprandial, but not prandial or postprandial, oral treatment with 500 mg/kg/day NaPB improved liver function tests and clinical symptoms and suppressed the fibrosis progression. No adverse events were observed. Preprandial oral administration of NaPB was needed to maximize its potency in PFIC patients.

Citation

Satoshi Nakano, Shuhei Osaka, Yusuke Sabu, Kei Minowa, Saeko Hirai, Hiroki Kondou, Takeshi Kimura, Yoshihiro Azuma, Satoshi Watanabe, Ayano Inui, Kazuhiko Bessho, Hidefumi Nakamura, Hironori Kusano, Atsuko Nakazawa, Ken Tanikawa, Masayoshi Kage, Toshiaki Shimizu, Hiroyuki Kusuhara, Yoh Zen, Mitsuyoshi Suzuki, Hisamitsu Hayashi. Effect of food on the pharmacokinetics and therapeutic efficacy of 4-phenylbutyrate in progressive familial intrahepatic cholestasis. Scientific reports. 2019 Nov 19;9(1):17075