Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients < 4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064173%3A_____%2F17%3AN0000082" target="_blank" >RIV/00064173:_____/17:N0000082 - isvavai.cz</a>

Result on the web

<a href="http://dx.doi.org/10.1186/s13023-017-0600-x" target="_blank" >http://dx.doi.org/10.1186/s13023-017-0600-x</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s13023-017-0600-x" target="_blank" >10.1186/s13023-017-0600-x</a>

Result language

angličtina

Original language name

Efficacy, safety and population pharmacokinetics of sapropterin in PKU patients < 4 years: results from the SPARK open-label, multicentre, randomized phase IIIb trial

Original language description

Background: Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients >= 4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan r) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children < 4 years. Results: In total, 109 male or female children < 4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1: 1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with >= 1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using nonlinear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. Conclusions: The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children < 4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients < 4 years with BH4-responsive phenylketonuria.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30202 - Endocrinology and metabolism (including diabetes, hormones)

Project

—

Continuities

N - Vyzkumna aktivita podporovana z neverejnych zdroju

Publication year

2017

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Orphanet Journal of Rare Diseases

ISSN

1750-1172

e-ISSN

1750-1172

Volume of the periodical

12

Issue of the periodical within the volume

March

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

Article 47

UT code for WoS article

000397661900002

EID of the result in the Scopus database

2-s2.0-85014844316