G Gramer1, S F Garbade, N Blau, M Lindner. 1. Centre for Paediatric and Adolescent Medicine, Department of General Paediatrics, Division of Metabolic Disorders, Heidelberg, Germany. gwendolyn.gramer@med.uni-heidelberg.de
Abstract
BACKGROUND:Tetrahydrobiopterin (BH(4)) loading has been performed for many years in patients detected by newborn screening for hyperphenylalaninaemia (HPA) to distinguish BH(4) cofactor synthesis or recycling defects from phenylalanine hydroxylase (PAH)-deficient HPA. Previous studies have shown that the pharmacokinetics of BH(4) shows high intra-individual and inter-individual variability. METHODS:Seventeen adult patients with PAH-deficient HPA were classified in one of three phenotypic groups (mild, moderate, classical PKU) according to their response to a standardized protein loading test. Genotype information was available for all participants. In a randomized controlled double-blind design, BH(4) loadings in single oral dosages of 10, 20 and 30 mg BH(4)/kg body weight (bw) were performed to assess BH(4) responsiveness. As part of this study, levels of BH(4) metabolites in dried blood spots were studied to provide information on the pharmacokinetics of BH(4) following oral administration. RESULTS:Levels of biopterin and pterin (B + P) increased significantly with increasing BH(4) dose (p < 0.0001). Maximum B + P levels were reached 4 hours after application of BH(4). There was no significant difference in BH(4) pharmacokinetics between the three phenotypic groups of PKU. Male and female patients showed different levels of BH(4) metabolites following 10 mg BH(4)/kg bw, but not following 20 and 30 mg BH(4)/kg bw. There was no relationship between age of patients and BH(4) pharmacokinetics. There was no correlation between B + P levels and decrease in Phe level (p = 0.69). CONCLUSION:BH(4) pharmacokinetics are variable between patients regarding absolute levels of BH(4) metabolites reached after BH(4) loading, but are similar regarding the interval to individual maximum B + P levels. Levels of B + P increase significantly with increasing BH(4) doses. There is no correlation between B + P levels and decrease in Phe level.
RCT Entities:
BACKGROUND:Tetrahydrobiopterin (BH(4)) loading has been performed for many years in patients detected by newborn screening for hyperphenylalaninaemia (HPA) to distinguish BH(4) cofactor synthesis or recycling defects from phenylalanine hydroxylase (PAH)-deficient HPA. Previous studies have shown that the pharmacokinetics of BH(4) shows high intra-individual and inter-individual variability. METHODS: Seventeen adult patients with PAH-deficient HPA were classified in one of three phenotypic groups (mild, moderate, classical PKU) according to their response to a standardized protein loading test. Genotype information was available for all participants. In a randomized controlled double-blind design, BH(4) loadings in single oral dosages of 10, 20 and 30 mg BH(4)/kg body weight (bw) were performed to assess BH(4) responsiveness. As part of this study, levels of BH(4) metabolites in dried blood spots were studied to provide information on the pharmacokinetics of BH(4) following oral administration. RESULTS: Levels of biopterin and pterin (B + P) increased significantly with increasing BH(4) dose (p < 0.0001). Maximum B + P levels were reached 4 hours after application of BH(4). There was no significant difference in BH(4) pharmacokinetics between the three phenotypic groups of PKU. Male and female patients showed different levels of BH(4) metabolites following 10 mg BH(4)/kg bw, but not following 20 and 30 mg BH(4)/kg bw. There was no relationship between age of patients and BH(4) pharmacokinetics. There was no correlation between B + P levels and decrease in Phe level (p = 0.69). CONCLUSION: BH(4) pharmacokinetics are variable between patients regarding absolute levels of BH(4) metabolites reached after BH(4) loading, but are similar regarding the interval to individual maximum B + P levels. Levels of B + P increase significantly with increasing BH(4) doses. There is no correlation between B + P levels and decrease in Phe level.
Authors: Reuben Matalon; Kimberlee Michals-Matalon; Richard Koch; James Grady; Stephen Tyring; Raymond C Stevens Journal: Mol Genet Metab Date: 2005-09-06 Impact factor: 4.797
Authors: M R Zurflüh; L Fiori; B Fiege; I Ozen; M Demirkol; K H Gärtner; B Thöny; M Giovannini; N Blau Journal: J Inherit Metab Dis Date: 2006-11-07 Impact factor: 4.982