From the Guidelines
Kuvan (sapropterin dihydrochloride) should be administered orally once daily at a dose of 20 mg/kg/day to treat phenylketonuria (PKU), with treatment response evaluated after 1 month by measuring blood phenylalanine levels and a decrease of at least 30% indicating responsiveness. The treatment of PKU with Kuvan involves a trial of sapropterin therapy to assess responsiveness, except for patients with two null mutations in trans 1. The dose of 20 mg/kg/day is the most commonly used dose for initiation and maintenance, and it is recommended to take the medication with food to enhance absorption. Key points to consider when treating PKU with Kuvan include:
- Treatment response is typically greater in individuals with mild or moderate PKU than in those with classical PKU 1
- Individuals who respond to sapropterin treatment are often able to increase natural protein (phenylalanine) intake, relax adherence to a low-phenylalanine diet, and reduce consumption of medical foods 1
- Regular blood monitoring is essential to ensure optimal phenylalanine levels and adjust treatment as needed 1
- Common side effects include headache, runny nose, diarrhea, vomiting, and abdominal pain, and micronutrient levels, including amino acids, may vary in response to sapropterin treatment 1. It is also important to note that even with Kuvan treatment, most patients still need to follow a phenylalanine-restricted diet, though some may be able to increase their dietary phenylalanine intake 1. Overall, the use of Kuvan in the treatment of PKU has been shown to improve quality of life, increase dietary phenylalanine tolerance, and reduce blood phenylalanine levels in responsive patients 1.
From the FDA Drug Label
2 DOSAGE AND ADMINISTRATION
1 Recommendations Prior to Sapropterin Dihydrochloride Tablets Treatment Treatment with sapropterin dihydrochloride tablets should be directed by physicians knowledgeable in the management of PKU. All patients with PKU who are being treated with sapropterin dihydrochloride tablets should also be treated with a Phe-restricted diet, including dietary protein and Phe restriction.
2 Recommended Dosage and Administration The recommended starting dosage of sapropterin dihydrochloride tablets is: Pediatric Patients 1 month to 6 years:10 mg/kg (actual body weight) administered orally once daily. Patients 7 years and older:10 to 20 mg/kg (actual body weight) administered orally once daily Administer sapropterin dihydrochloride tablets with a meal, preferably at the same time each day
The treatment for Kuvan (sapropterin dihydrochloride) is:
- Sapropterin dihydrochloride tablets administered orally once daily
- Starting dosage:
- Pediatric patients 1 month to 6 years: 10 mg/kg (actual body weight)
- Patients 7 years and older: 10 to 20 mg/kg (actual body weight)
- Administration: with a meal, preferably at the same time each day
- Concomitant treatment: a Phe-restricted diet, including dietary protein and Phe restriction, should also be used in all patients with PKU 2
From the Research
Treatment Overview
- Kuvan (sapropterin dihydrochloride) is a synthetic formulation of the active 6R-isomer of tetrahydrobiopterin, used to treat hyperphenylalaninaemia in patients with tetrahydrobiopterin-responsive phenylketonuria (PKU) 3.
- The treatment is approved in the EU for patients ≥4 years of age with tetrahydrobiopterin-responsive PKU and in adults and children with tetrahydrobiopterin deficiency who have been shown to be responsive to such treatment 3.
- In the US, it is approved to reduce blood phenylalanine levels in patients with hyperphenylalaninaemia due to tetrahydrobiopterin-responsive PKU 3.
Mechanism of Action
- The mechanism of action of sapropterin in lowering blood phenylalanine levels in patients with PKU has not been fully elucidated, but appears to be related to its effect in augmenting and stabilizing mutant phenylalanine hydroxylases, resulting in increased clearance of phenylalanine from the body 3.
- In tetrahydrobiopterin deficiency, its mechanism of action is presumed to be secondary to replacement of endogenous tetrahydrobiopterin 3.
Pharmacokinetics
- Orally-administered sapropterin is absorbed into the bloodstream, reaching maximum concentrations in 3-4 hours 3.
- It has a mean elimination half-life of approximately 4 hours in healthy adults and 6.7 hours in patients with tetrahydrobiopterin-responsive PKU 3.
- Total body weight is the only significant covariate identified, and its inclusion on both the apparent clearance and central volume of distribution substantially improved the model's ability to describe the data 4.
Efficacy and Tolerability
- Sapropterin effectively lowers blood phenylalanine levels in a proportion of patients with PKU 3.
- Approximately 20% of patients responded to sapropterin 10 mg/kg/day in an 8-day screening study 3.
- Sapropterin was well tolerated in patients with PKU, although longer-term tolerability data are required 3.
- Common adverse events included headache, rhinorrhoea, pharyngolaryngeal pain, nasal congestion, cough, diarrhoea, vomiting, abdominal pain, and hypophenylalaninaemia 3.
Clinical Trials
- A randomized, double-blind, placebo-controlled trial showed that sapropterin recipients experienced a significant 28% decrease from baseline in mean blood phenylalanine level, while there was no significant change in placebo recipients 3.
- An extension of this trial showed significantly greater reductions in blood phenylalanine levels with sapropterin dosages of 10 and 20 mg/kg/day than with sapropterin 5 mg/kg/day 3.
- A clinical trial in children aged 4-12 years with tetrahydrobiopterin-responsive PKU showed that patients treated with sapropterin 20 mg/kg/day had reduced blood phenylalanine levels after 3 weeks of treatment 5.