Pharmacokinetics of orally administered tetrahydrobiopterin in patients with phenylalanine hydroxylase deficiency

The oral loading test with tetrahydrobiopterin (BH4) is used to discriminate between variants of hyper-phenylalaninaemia and to detect BH4-responsive patients. The outcome of the loading test depends on the genotype, dosage of BH4, and BH4 pharmacokinetics. A total of 71 patients with hyperphenylaianinaemia (mild to classic) were challenged with BH4 (20 mg/kg) according to different protocols (1 x 20 mg or 2 x 20 mu) and blood BH4 concentrations were measured in dried blood spots at different time points (T-0, T-2, T-4, T-8, T-12, T-14, T-32 and T-48h). Maximal BH4 concentrations (median 22.69 nmol/g Hb) were measured 4 h after BH4 administration in 63 out of 7 1 patients. Eight patients presented with maximal BH4 concentrations similar to 44% higher at 8 h than at 4 h. After 24 h, BH4 blood concentrations dropped to 11% of maximal values. This profile was similar using different protocols. The following pharmacokinetic parameters were calculated for BH4 in blood: t(max) = 4h, AUC (T0-32) = 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 BH4 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 BH4 administration, while one was found to be a non-responder. Only 10/19 patients (53%) with Phe concentrations of 600-1200 mu mol/L responded to BH4 administration, and of the patients with the severe classical phenotype (blood Phe > 1200 mu mol/L) only 4 out of 17 patient responded. An additional 36 patients with mild hyperphenylalaninaemia (HPA) who underwent the combined loading test with Phe+BH4 were all responders. Slow responders and non-responders were found in all groups of HPA.