Sapropterin

Indication

Sapropterin [1, 2] is indicated for the treatment of hyperphenylalaninaemia (HPA) in patients with phenylketonuria (PKU) and/or tetrahydrobiopterin (BH4) deficiency who have been shown to be responsive to such treatment.

Mechanism

PKU patients, who are deficient in phenylalanine hydroxylase (PAH), and patients with BH4 deficiency, are unable to convert phenylalanine from the diet. PAH hydroxylates phenylalanine through an oxidative reaction with tetrahydrobiopterin (BH4) as co-factor to form tyrosine. Deficiency for either PAH or BH4 can result in high blood phenylalanine concentrations, which are toxic to the brain and can lead to neurological and behavioural disorders such as lower intelligence, decreased mental concentration, slowed reaction time, depression and phobias. Dietary restrictions in order to minimize phenylalanine intake are difficult to maintain and often cause other deficiencies.

Sapropterin dihydrochloride is a synthetic form of cofactor BH4. Excess of cofactor activates residual PAH enzyme, improving phenylalanine metabolism and decreasing phenylalanine concentrations in the blood of PKU patients. In patients with BH4 deficiency, sapropterin provides an effective alternative to BH4. PKU patients treated with sapropterin must continue their restricted phenylalanine diet and undergo regular clinical assessment (monitoring of blood phenylalanine and tyrosine concentrations, nutrient intake and psychomotor development).

Adverse effects

Hypophenylalaninaemia is a direct adverse effect of sapropterin therapy. This condition requires dose adjustment or increased dietary phenylalanine intake. Common adverse events among sapropterin-treated subjects in the clinical trials included headache, rhinorrhoea, pharyngolaryngeal pain, vomiting, diarrhoea, nasal congestion, cough and contusion.

In prescribing this product, it is important to stress that the product does not work in all patients with PKU or BH4 deficiency but only in those who have shown a definite effect of sapropterin.

Mechanism of action of sapropterin in phenylalanine deficiency.

Normal: the enzyme phenylalanine hydroxylase (PAH) converts phenylalanine from dietary intake into tyrosine which is the precursor of many neurotransmitters (e.g. dopamine). Tetrahydrobiopterin (BH4) is cofactor in this conversion with dihydrobiopterin (BH2) as product.

PAH or BH4 deficiency: in PAH or BH4 deficiency, phenylalanine is hardly converted into tyrosine. This results in decreased tyrosine concentrations and subsequent decreased concentrations of neurotransmitters. Phenylalanine then accumulates and is partially converted by another enzyme into phenylketone.

Sapropterin therapy: sapropterin is a synthetic form of cofactor BH4 and is able to partially restore PAH activity or supply BH4, thereby decreasing the amounts of phenylalanine and phenylketone and increasing tyrosine (and dopamine) production.