Phenylketonuria (PKU) Medication

Updated: Nov 23, 2020
  • Author: Eric T Rush, MD, FAAP; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Medication Summary

Treatment of phenylketonuria (PKU) is primarily diet-based; however, some patients may benefit from the administration of large neutral amino acids (additional studies are needed). Drugs approved in the United States include an enzyme cofactor (sapropterin) and enzyme substitute (pegvaliase). The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Large neutral amino acids (NeoPhe-PreKunil, PhenylAde, PreKunil)

Some evidence suggests that consumption of high doses of other large neutral amino acids can increase competition with phenylalanine for crossing the blood-brain barrier into the brain, thus decreasing phenylalanine levels in the brain.

Adults and older teenagers refusing dietary restrictions can be prescribed a preparation of high-dose large neutral amino acids (LNAAs). This therapy may decrease entry of phenylalanine into the CNS. However, it does not protect a developing fetus from the teratogenic effects of phenylalanine.

It should be kept in mind that LNAAs contain high doses of tyrosine and tryptophan. Too much tyrosine can cause headaches, which limits the numbers of tabs that can be consumed. Furthermore, by competitive inhibition, they also counteract uptake of Phe across the blood-brain barrier, thus reducing its impairing effect on neurotransmitter production.

LNAAs may be ideal for young adults, for poorly compliant patients, and for late-diagnosed patients in whom compliance is low and in whom drinking formula can be a burden for the patient and caretakers.

The tablets must be combined with a certain amount of natural protein in order for the diet to contain sufficient protein. PreKunil does not contain lysine, an essential amino acid, and lysine deficiency has been reported. Individuals taking PreKunil continue to require nutritional assessment because teens and adults who are "off diet" often fail to consume sufficient protein to meet essential amino acid and vitamin/mineral requirements.


Enzyme Cofactors

Class Summary

Clinical trials have shown that a subset of children with classic PKU respond to tetrahydrobiopterin (BH4) therapy, depending on their PAH gene mutation. Synthetic BH4 (sapropterin) is a cofactor for the enzyme phenylalanine hydroxylase (PAH).

Sapropterin (Kuvan)

Sapropterin is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates phenylalanine (Phe) through an oxidative reaction to form tyrosine. PAH activity is absent or deficient in patients with PKU. Treatment with BH4 can activate residual PAH, improve normal oxidative metabolism of Phe, and decrease Phe levels in some patients. It is to be used in conjunction with a Phe-restricted diet.


Enzymes, Metabolic

Class Summary

PEGylated phenylalanine ammonia lyase (PAL) that substitutes for the deficient phenylalanine hydroxylase (PAH) enzyme activity in patients with PKU and reduces blood phenylalanine concentrations.

Pegvaliase (Palynziq, pegvaliase-pqpz)

PEGylated phenylalanine ammonia lyase (PAL) enzyme that converts phenylalanine (Phe) to ammonia and trans-cinnamic acid. It is indicated to reduce blood Phe concentrations in adults with PKU who have uncontrolled blood Phe concentrations >600 μmol/L on existing management.