Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders

Yoko Nakajima; Shuhei Osaka; Tadahaya Mizuno; Katsuyuki Yokoi; Satoshi Nakano; Saeko Hirai; Yuka Hiraoka; Yoshiki Miura; Mitsuyoshi Suzuki; Hiroyuki Kusuhara; Hisamitsu Hayashi

doi:10.1016/j.ymgmr.2021.100799

Influence of food on pharmacokinetics and pharmacodynamics of 4-phenylbutyrate in patients with urea cycle disorders

Mol Genet Metab Rep. 2021 Sep 4:29:100799. doi: 10.1016/j.ymgmr.2021.100799. eCollection 2021 Dec.

Authors

Affiliations

¹ Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan.
² Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Science, The University of Tokyo, Japan.
³ Department of Pediatrics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁴ Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Abstract

Urea cycle disorders (UCDs), inborn errors of hepatocyte metabolism, cause hyperammonemia and lead to neurocognitive deficits, coma, and even death. Sodium 4-phenylbutyrate (NaPB), a standard adjunctive therapy for UCDs, generates an alternative pathway of nitrogen deposition through glutamine consumption. Administration during or immediately after a meal is the approved usage of NaPB. However, we previously found that preprandial oral administration enhanced its potency in healthy adults and pediatric patients with intrahepatic cholestasis. The present study evaluated the effect of food on the pharmacokinetics and pharmacodynamics of NaPB in five patients with UCDs. Following an overnight fast, NaPB was administered orally at 75 mg/kg/dose (high dose, HD) or 25 mg/kg/dose (low dose, LD) either 15 min before or immediately after breakfast. Each patient was treated with these four treatment regimens with NaPB. With either dose, pre-breakfast administration rather than post-breakfast administration significantly increased plasma PB levels and decreased plasma glutamine availability. Pre-breakfast LD administration resulted in a greater attenuation in plasma glutamine availability than post-breakfast HD administration. Plasma levels of branched-chain amino acids decreased to the same extent in all tested regimens. No severe adverse events occurred during this study. In conclusion, preprandial oral administration of NaPB maximized systemic exposure of PB and thereby its efficacy on glutamine consumption in patients with UCDs.

Keywords: AAs, amino acids; AUC0–4, area under the plasma concentration–time curve from time 0 to 4 h; Amino acids; BCAA, branched-chain amino acids; CI, confidence interval; Clinical study; Cmax, the maximum plasma concentration; HD, high dose; Kel, elimination rate constant; LD, low dose; NaPB, sodium 4-phenylbutyrate; PA, 4-phenylacetate; PAG, 4-phenylacetylglutamine; PB, 4-phenylbutyrate; PD, pharmacodynamics; PFIC, progressive familial intrahepatic cholestasis; PK, pharmacokinetics; Pharmacokinetics; SD, standard deviation; Tmax, time to reach Cmax; UCDs, urea cycle disorders.; Urea cycle disorders; iAUC0–4, incremental area under the curve from time 0 to 4 h after breakfast.