Pharmacokinetics of tetrahydrobiopterin following oral loadings with three single dosages in patients with phenylketonuria

Gramer, Gwendolyn; Garbade, Sven F.; Blau, Nenad

doi:10.1007/s10545-008-0955-1

Cited by 13 publications

(9 citation statements)

References 12 publications

(17 reference statements)

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“…B + P max levels and BH 4 response were not associated (Gramer et al 2009). Tyrosine levels and Phe/Tyr ratios did not show any significant changes following BH 4 application (data not shown).…”

Section: Identical Genotypesmentioning

confidence: 80%

Blood phenylalanine concentrations in patients with PAH‐deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: Assessing responsiveness in a model of statistical process control

Gramer

Garbade

Burgard

2009

J of Inher Metab Disea

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Tetrahydrobiopterin (BH(4)) cofactor loading is a standard procedure to differentiate defects of BH(4) metabolism from phenylalanine hydroxylase (PAH) deficiency. BH(4) responsiveness also exists in PAH-deficient patients with high residual PAH activity. Unexpectedly, single cases with presumed nil residual PAH activity have been reported to be BH(4) responsive, too. BH(4) responsiveness has been defined either by a >or=30% reduction of blood Phe concentration after a single BH(4) dose or by a decline greater than the individual circadian Phe level variation. Since both methods have methodological disadvantages, we present a model of statistical process control (SPC) to assess BH(4) responsiveness. Phe levels in 17 adult PKU patients of three phenotypic groups off diet were compared without and with three different single oral dosages of BH(4) applied in a double-blind randomized cross-over design. Results are compared for >or=30% reduction and SPC. The effect of BH(4) by >or=30% reduction was significant for groups (p < 0.01) but not for dose (p = 0.064), with no interaction of group with dose (p = 0.24). SPC revealed significant effects for group (p < 0.01) and the interaction for group with dose (p < 0.05) but not for dose alone (p = 0.87). After one or more loadings, seven patients would be judged to be BH(4) responsive either by the 30% criterion or by the SPC model, but only three by both. Results for patients with identical PAH genotype were not very consistent within (for different BH(4) doses) and between the two models. We conclude that a comparison of protein loadings without and with BH(4) combined with a standardized procedure for data analysis and decision would increase the reliability of diagnostic results.

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Section: Identical Genotypesmentioning

confidence: 80%

Blood phenylalanine concentrations in patients with PAH‐deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: Assessing responsiveness in a model of statistical process control

Gramer

Garbade

Burgard

2009

J of Inher Metab Disea

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“…One was clearly not eligible for inclusion (Nwose 2008) and the remaining three were potentially eligible for inclusion in a future version and their progress has been monitored (Gropmann 2011; NCT01376908; NCT01114737). (Gramer 2009;Utz 2012). Both the trials were not eligible for inclusion.…”

Section: Results Of the Searchmentioning

confidence: 99%

Sapropterin dihydrochloride for phenylketonuria

Somaraju¹,

Merrin

2015

Cochrane Database of Systematic Reviews

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“…As BH 4 levels decrease with time after the load [17,21], the effect on Phe would also show time dependency. Plasma concentrations of BH 4 were not assessed, but as Phe concentrations were available, the time profile of the amount of BH 4 in a (virtual) compartment, driving the effect, could be inferred from the kinetic of the pharmacodynamic response according to a kinetic pharmacodynamic (K-PD) modeling approach (slightly modified after [22].…”

Section: Methodsmentioning

confidence: 99%

Tetrahydrobiopterin (BH4) responsiveness in neonates with hyperphenylalaninemia: A semi-mechanistically-based, nonlinear mixed-effect modeling

Trefz

Lichtenberger

Blau

et al. 2015

Molecular Genetics and Metabolism

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Pharmacokinetics of tetrahydrobiopterin following oral loadings with three single dosages in patients with phenylketonuria

Cited by 13 publications

References 12 publications

Blood phenylalanine concentrations in patients with PAH‐deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: Assessing responsiveness in a model of statistical process control

Blood phenylalanine concentrations in patients with PAH‐deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: Assessing responsiveness in a model of statistical process control

Sapropterin dihydrochloride for phenylketonuria

Tetrahydrobiopterin (BH4) responsiveness in neonates with hyperphenylalaninemia: A semi-mechanistically-based, nonlinear mixed-effect modeling

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