title: Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders.
abstract: Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data from four Phase II/III trials that collectively enrolled patients ages 2 months to 72 years. Dose simulations were performed with particular attention to phenylacetic acid (PAA), which has been associated with adverse events in non-UCD populations. The final model described metabolite levels in plasma and urine for both drugs and was characterized by (a) partial presystemic metabolism of phenylbutyric acid (PBA) to PAA and/or PAGN, (b) slower PBA absorption and greater presystemic conversion with glycerol phenylbutyrate, (c) similar systemic disposition with saturable conversion of PAA to PAGN for both drugs, and (d) body surface area (BSA) as a significant covariate accounting for age-related PK differences. Dose simulations demonstrated similar PAA exposure following mole-equivalent PBA dosing of both drugs and greater PAA exposure in younger patients based on BSA.
authors.affiliation: Pharsight Corp., Cary, NC, USA.
authors.forename: Jon P R
authors.initials: JP
authors.lastname: Monteleone
authors.forename: M
authors.initials: M
authors.lastname: Mokhtarani
authors.forename: G A
authors.initials: GA
authors.lastname: Diaz
authors.forename: W
authors.initials: W
authors.lastname: Rhead
authors.forename: U
authors.initials: U
authors.lastname: Lichter-Konecki
authors.forename: S A
authors.initials: SA
authors.lastname: Berry
authors.forename: C
authors.initials: C
authors.lastname: Lemons
authors.forename: K
authors.initials: K
authors.lastname: Dickinson
authors.forename: D
authors.initials: D
authors.lastname: Coakley
authors.forename: B
authors.initials: B
authors.lastname: Lee
authors.forename: B F
authors.initials: BF
authors.lastname: Scharschmidt
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D005260:Female; D005973:Glutamine / Q000031:analogs & derivatives / Q000652:urine; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008954:Models, Biological; D009584:Nitrogen / Q000652:urine; D010654:Phenylbutyrates / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic; D035583:Rare Diseases / Q000188:drug therapy / Q000378:metabolism; D056806:Urea Cycle Disorders, Inborn / Q000188:drug therapy* / Q000378:metabolism* / Q000652:urine
chemical_list: D010654:Phenylbutyrates; D005973:Glutamine; C003089:phenylacetylglutamine; D009584:Nitrogen; D005990:Glycerol; C570223:glycerol phenylbutyrate