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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 03; 41(2):181-186.JI

Abstract

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.

Authors+Show Affiliations

Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.Department of Metabolic Diseases, Birmingham Children's Hospital, Birmingham, UK.Department of Dietetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.Department of Metabolic Diseases, Birmingham Children's Hospital, Birmingham, UK.Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.Department of Metabolic Diseases, Birmingham Children's Hospital, Birmingham, UK.Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands. f.j.van.spronsen@umcg.nl.

Pub Type(s)

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

Language

eng

PubMed ID

29170874

Citation

Kienstra, Nienke S., et al. "Daily Variation of NTBC and Its Relation to Succinylacetone in Tyrosinemia Type 1 Patients Comparing a Single Dose to Two Doses a Day." Journal of Inherited Metabolic Disease, vol. 41, no. 2, 2018, pp. 181-186.
Kienstra NS, van Reemst HE, van Ginkel WG, et al. 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;41(2):181-186.
Kienstra, N. S., van Reemst, H. E., van Ginkel, W. G., Daly, A., van Dam, E., MacDonald, A., Burgerhof, J. G. M., de Blaauw, P., McKiernan, P. J., Heiner-Fokkema, M. R., & van Spronsen, F. J. (2018). Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day. Journal of Inherited Metabolic Disease, 41(2), 181-186. https://doi.org/10.1007/s10545-017-0112-9
Kienstra NS, et al. 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;41(2):181-186. PubMed PMID: 29170874.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day. AU - Kienstra,Nienke S, AU - van Reemst,Hannah E, AU - van Ginkel,Willem G, AU - Daly,Anne, AU - van Dam,Esther, AU - MacDonald,Anita, AU - Burgerhof,Johannes G M, AU - de Blaauw,Pim, AU - McKiernan,Patrick J, AU - Heiner-Fokkema,M Rebecca, AU - van Spronsen,Francjan J, Y1 - 2017/11/23/ PY - 2017/05/15/received PY - 2017/10/29/accepted PY - 2017/10/25/revised PY - 2017/11/25/pubmed PY - 2018/12/27/medline PY - 2017/11/25/entrez KW - NTBC KW - SA KW - Succinylacetone KW - Tyrosinemia type 1 SP - 181 EP - 186 JF - Journal of inherited metabolic disease JO - J. Inherit. Metab. Dis. VL - 41 IS - 2 N2 - 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. SN - 1573-2665 UR - https://www.unboundmedicine.com/medline/citation/29170874/Daily_variation_of_NTBC_and_its_relation_to_succinylacetone_in_tyrosinemia_type_1_patients_comparing_a_single_dose_to_two_doses_a_day_ L2 - https://doi.org/10.1007/s10545-017-0112-9 DB - PRIME DP - Unbound Medicine ER -