Severe mucitis after sublingual administration of tetrahydrobiopterin in a patient with tetrahydrobiopterin-responsive phenylketonuria

Abstract

Tetrahydrobiopterin (BH4) is the cofactor for phenylalanine hydroxylase (PAH) and is essential to treat different forms of hyperphenylalaninaemia, i.e. patients with defects in the biosynthesis of BH4, but also in the PAH gene [1, 4,5]. Responsiveness of mutant PAH to BH4 administration relies on a chemical chaperon effect of BH4 preventing PAH from protein misfolding and inactivation [6], but several other mechanisms may also be involved [2]. Recently, we reported that sublingual administration of BH4 tablets in a single control person resulted in 58%–67% higher plasma BH4 concentrations than the usual oral route [3]. Drawbacks included rapid decomposition of tablets, acidic taste, and increased salivation. Since sublingual application could reduce therapy costs, orange flavoured artificially sweetened BH4 pastilles were tested on four healthy volunteers and a child with mild phenylketonuria (PKU). BH4 (Schircks, Switzerland) was administered to four healthy male volunteers (age 28–57 years) on 2 subsequent days either as tablets (50 mg) or pastilles (100 mg, containing 5 mg aspartame and orange aroma) with a 1 week wash-out between the two trials. Blood was collected before, and 1, 2, 3, and 4 h after administration. An 8-year-old patient with mild PKU (genotype P281L/R261Q) who was already on regular BH4 therapy was treated with BH4 pastilles (sublingually, 12 mg/kg/day; bid) in addition to P-AM 2 formula for 2 weeks. Written consensus was obtained from the family. In the four healthy male volunteers, total biopterin values before and up to 4 h after oral and sublingual administration were compared (Fig. 1A). No statistically significant difference between oral and sublingual administration was observed. Pterin concentrations increased after both oral and sublingual administration, reflecting instability of BH4 in blood. The ratio of pterin to cumulated biopterin and pterin ranged between 22.8% and 33.5%. Summing biopterin and pterin instead of total biopterin did not alter the ratio between oral and sublingual administration (data not shown). Changing from standard therapy to sublingual administration in a child with mild PKU resulted in almost unchanged plasma phenylalanine concentrations (Fig. 1B). After 2 weeks of twice daily sublingual BH4 administration, the patient complained of a painful prickling sensation at the tip of the tongue. He nevertheless continued the treatment for a further 10 days, moving the tablets in his mouth from one side to the other, which resulted in severe mucitis. His condition normalised rapidly upon discontinuation of the sublingual form. No mucitis appeared in healthy volunteers. A clinical trial with sublingual BH4 in a patient with mild PKU failed despite pharmacological effectiveness on blood phenylalanine levels because of an adverse pastille-related side-effect. Formulation of buffered tablets approaching neutral pH and further investigations on BH4 metabolism and pharmacokinetics are needed.