Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day

J Inherit Metab Dis. 2018 Mar;41(2):181-186. doi: 10.1007/s10545-017-0112-9. Epub 2017 Nov 23.


Introduction: In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens.

Methods: All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively.

Results: NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p < 0.001). Quantitatively detectable SA was only found in subjects with once daily administration of NTBC and associated with momentary NTBC concentrations <44.3 μmol/l.

Discussion: NTBC could be less stable than previously considered, thus dosing NTBC once daily and lower concentrations may be less adequate. Further research including more data is necessary to establish the optimal dosing of NTBC.

Keywords: NTBC; SA; Succinylacetone; Tyrosinemia type 1.

Publication types

  • Comparative Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Chromatography, High Pressure Liquid
  • Cyclohexanones / administration & dosage*
  • Cyclohexanones / blood
  • Cyclohexanones / pharmacokinetics
  • Diet, Protein-Restricted
  • Dried Blood Spot Testing
  • Drug Administration Schedule
  • Drug Monitoring / methods
  • Female
  • Humans
  • Infant
  • Male
  • Nitrobenzoates / administration & dosage*
  • Nitrobenzoates / blood
  • Nitrobenzoates / pharmacokinetics
  • Prospective Studies
  • Tandem Mass Spectrometry
  • Time Factors
  • Treatment Outcome
  • Tyrosinemias / blood
  • Tyrosinemias / diagnosis
  • Tyrosinemias / drug therapy*
  • Young Adult


  • Cyclohexanones
  • Nitrobenzoates
  • nitisinone