Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency

Abstract

The oral loading test with tetrahydrobiopterin (BH(4)) is used to discriminate between variants of hyperphenylalaninaemia and to detect BH(4)-responsive patients. The outcome of the loading test depends on the genotype, dosage of BH(4), and BH(4) pharmacokinetics. A total of 71 patients with hyperphenylalaninaemia (mild to classic) were challenged with BH(4) (20 mg/kg) according to different protocols (1 x 20 mg or 2 x 20 mg) and blood BH(4) concentrations were measured in dried blood spots at different time points (T(0), T(2), T(4), T(8), T(12), T(24), T(32) and T(48 h)). Maximal BH(4) concentrations (median 22.69 nmol/g Hb) were measured 4 h after BH(4) administration in 63 out of 71 patients. Eight patients presented with maximal BH(4) concentrations approximately 44% higher at 8 h than at 4 h. After 24 h, BH(4) blood concentrations dropped to 11% of maximal values. This profile was similar using different protocols. The following pharmacokinetic parameters were calculated for BH(4) in blood: t (max) = 4 h, AUC (T(0-32)) = 370 nmol x h/g Hb, and t (1/2) for absorption (1.1 h), distribution (2.5 h), and elimination (46.0 h) phases. Maximal BH(4) blood concentrations were not significantly lower in non-responders and there was no correlation between blood concentrations and responsiveness. Of mild PKU patients, 97% responded to BH(4) administration, while one was found to be a non-responder. Only 10/19 patients (53%) with Phe concentrations of 600-1200 mumol/L responded to BH(4) administration, and of the patients with the severe classical phenotype (blood Phe> 1200 mumol/L) only 4 out of 17 patient responded. An additional 36 patients with mild hyperphenylalaninaemia (HPA) who underwent the combined loading test with Phe+BH(4) were all responders. Slow responders and non-responders were found in all groups of HPA.

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

“…This variability did not show any association with age or phenotype group. Although the levels of B + P were highly variable between patients, the time course of BH 4 kinetics was almost identical in all patients with a maximum B + P level 4 hours after BH 4 loading confirming the findings of Fiege and colleagues in healthy individuals (Fiege et al 2004) and Zurflü h and colleagues in HPA patients (Zurflü h et al 2006).…”

“…Maximum B + P levels did not show a significant association with decrease in Phe level in any of the phenotypic groups, as documented by Zurflü h and colleagues in 71 patients (Zurflü h et al 2006).…”

Classifying tetrahydrobiopterin responsiveness in the hyperphenylalaninaemias

“…30% at 8 h (Bernegger andBlau 2002, Fiori et al 2005) and 15 h (Muntau et al 2002), or 50% at 24 h . The subdivision of the response into Ffast_, Fmoderate_, Fslow_, and Fnone_ has resulted in more elaborated classification schemes which try to reproduce the various time courses of blood Phe Zurflü h et al 2006). They pose the problem that either the response remains Fundefined_ by definition in some combinations of test results (Zurflü h et al 2006) or that patients, within the same test, are Fresponsive_ as well as Funresponsive_ .…”

“…The subdivision of the response into Ffast_, Fmoderate_, Fslow_, and Fnone_ has resulted in more elaborated classification schemes which try to reproduce the various time courses of blood Phe Zurflü h et al 2006). They pose the problem that either the response remains Fundefined_ by definition in some combinations of test results (Zurflü h et al 2006) or that patients, within the same test, are Fresponsive_ as well as Funresponsive_ . By the scheme of Bernegger and Blau (2002), loading tests with S > 3.75 (see above) are considered significantly positive.…”

Effects and clinical significance of tetrahydrobiopterin supplementation in phenylalanine hydroxylase‐deficient hyperphenylalaninaemia

“…In most studies patients are classified as BH 4 responsive when blood Phe concentrations after oral BH 4 drop by at least 30% from baseline within 8-24 h. More sophisticated classification schemes define patients showing a blood Phe decrease of <30% 8 h after BH 4 challenge but >20% after 24 h as slowresponders (Zurflü h et al 2006). Leuzzi and colleagues postulate BH 4 responsiveness when the decline of Phe concentrations with BH 4 exceeds variability of blood Phe levels without BH 4 (Leuzzi et al 2006).…”