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.