Tetrahydrobiopterin (BH4) — Phenylketonuria (PKU) Treatment Pregnancy: Use in pregnancy under specialist oversight — PKU in pregnancy requires strict Phe control to prevent maternal PKU syndrome (cardiac defects, microcephaly, intellectual disability in offspring). Sapropterin may be used to help maintain target Phe levels during pregnancy; maternal-foetal medicine and metabolic specialist co-management required.

Sapropterin

Brand names: Kuvan

Adult dose

Dose: Adults: 10–20 mg/kg once daily with food

Route: Oral (soluble tablets dissolved in water or apple juice)

Frequency: Once daily with food

Max: 20 mg/kg/day

Phenylketonuria (PKU) with responsive BH4 deficiency or responsive phenylalanine hydroxylase (PAH) mutations. Response testing mandatory: give 20 mg/kg/day for 1 month; measure blood phenylalanine before and after. Responders (≥30% phenylalanine reduction) continue. Non-responders: stop — no benefit. Source: BNF 90; NICE TA780.

Paediatric dose

Dose: 10–20 mg/kg once daily with food (same dosing as adults — weight-based) mg/kg

Route: Oral (soluble tablets — dissolve in water or juice; administer within 20 minutes; infants via spoon or syringe)

Frequency: Once daily with main meal

Max: 20 mg/kg/day

Licensed from 4 years in EU/UK. Off-label use from birth reported in specialist centres. Response testing at 1 month — if blood phenylalanine falls by ≥30%, continue; otherwise stop. Allows dietary phenylalanine relaxation in responders. Source: BNF for Children 2024; NICE TA780.

Dose adjustments

Renal

No dose adjustment required.

Hepatic

No dose adjustment required.

Paediatric weight-based calculator

Patient weight (kg)

Clinical pearls

PKU pathophysiology: phenylalanine hydroxylase (PAH) converts phenylalanine to tyrosine using BH4 as cofactor. PAH mutations → phenylalanine accumulates → toxic to brain (intellectual disability, seizures, psychiatric symptoms). Dietary restriction of phenylalanine (Phe) is the mainstay but restrictive diet impairs quality of life. Sapropterin (synthetic BH4) restores residual PAH activity in responsive mutations.
Response testing is mandatory: only 25–50% of PKU patients respond to sapropterin. Response rate is genotype-dependent — mild/moderate hyperphenylalaninaemia mutations most likely to respond. Classic PKU with null mutations unlikely to respond. ALWAYS perform 1-month response test (blood phenylalanine measurement before and after) before committing to long-term therapy.
NICE TA780: recommended for PKU in adults and children ≥4 years with mild-moderate phenotype who are responsive to sapropterin (confirmed by response test). Allows relaxation of dietary Phe restriction — improves quality of life significantly. Amino acid supplements can often be reduced in responders.
Pegvaliase alternative (adults): pegvaliase (Palynziq) — PEGylated phenylalanine ammonia lyase — is an alternative for adults with PKU who are non-responsive to sapropterin (MHRA licensed 2019). Reduces blood Phe by different mechanism. Requires titration over months. Paediatric sapropterin is used first.
Blood Phe target: maintain blood phenylalanine 120–360 micromol/L in children and pregnant women. Higher targets allowed in adults (120–600 micromol/L). If blood Phe drops below 120 micromol/L — increase dietary Phe intake (avoid Phe deficiency — causes tremor, eczema, poor growth). Source: BNF for Children 2024; NICE TA780; MHRA SPC Kuvan; PKU Alliance UK Guidelines.

Contraindications

Non-responsive genotype (PAH mutations unlikely to respond to BH4 — null mutations typically non-responsive)
Leucovorin or methotrexate use (theoretical interactions via DHFR pathway)
Hypersensitivity to sapropterin

Side effects

Headache, rhinorrhoea, pharyngitis (most common — mild)
Diarrhoea, nausea (gastrointestinal)
Low phenylalanine (if dietary intake not increased to match improved enzyme function — monitor blood Phe levels and adjust diet upward)
Elevated creatine kinase (rare)

Interactions

PDE5 inhibitors (sildenafil, tadalafil): both increase cGMP via BH4/NO pathway — additive vasodilation risk — use with caution
Levodopa: rare convulsions reported with combination — monitor

Monitoring

Blood phenylalanine (dried blood spot) — weekly initially, then monthly when stable (target 120–360 micromol/L in children)
Dietary phenylalanine intake log (adjust upward if Phe falls below target)
Neurodevelopmental assessment (school performance, cognitive testing annually)
Dietary amino acid supplement intake (may be able to reduce Phe-free amino acid supplements)
Height and weight (nutritional monitoring)

Reference: BNF for Children 2024; BNF 90; NICE TA780; Levy et al. Lancet 2007; MHRA SPC Kuvan; PKU Alliance UK. Verify against your local formulary and the latest BNF before prescribing.

Curated clinical cross-links plus same-class fallbacks.

Calculators

Pathways