PMID- 20206791
OWN - NLM
STAT- MEDLINE
DCOM- 20100528
LR  - 20231213
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 32
IP  - 2
DP  - 2010 Feb
TI  - Relative bioavailability of sapropterin from intact and dissolved sapropterin 
      dihydrochloride tablets and the effects of food: a randomized, open-label, 
      crossover study in healthy adults.
PG  - 338-46
LID - 10.1016/j.clinthera.2010.02.012 [doi]
AB  - BACKGROUND: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder 
      characterized by hyperphenylalaninemia in association with neurocognitive and 
      neuromotor impairment. Sapropterin dihydrochloride (hereafter referred to as 
      sapropterin) administered orally as dissolved tablets is approved by the US Food 
      and Drug Administration for hyperphenylalaninemia in patients with 
      tetrahydrobiopterin responsive PKU. OBJECTIVES: This study compared the relative 
      oral bioavailability of sapropterin when administered as intact and dissolved 
      tablets. It also assessed the effect of food on the oral bioavailability of 
      sapropterin administered as intact tablets. METHODS: This was a randomized, 
      open-label, 3-treatment, 6-sequence, 3-period crossover study in healthy male and 
      female subjects. Subjects were randomized to receive single oral 10-mg/kg doses 
      of sapropterin administered as dissolved tablets after a fast; as intact tablets 
      after a fast; and as intact tablets with a high-calorie, high-fat meal. The 3 
      dosing periods were separated by a washout period of at least 7 days. In each 
      dosing period, blood samples were obtained within 40 minutes before and at 0.5, 
      1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, and 24 hours after dosing. A 
      follow-up assessment was performed 5 to 7 days after the last dosing period. The 
      relative bioavailability of sapropterin from the 3 dosing regimens was assessed 
      based on C(max), AUC(0-t), and AUC(0-infinity), estimated from calculated plasma 
      tetrahydrobiopterin concentrations using a noncompartmental model. Safety 
      assessments included physical examinations, clinical laboratory tests, and ECGs 
      at the beginning and end of the study. Vital signs were monitored periodically 
      during each treatment period. RESULTS: The study enrolled 32 healthy subjects (16 
      men, 16 women) with a mean (SD) age of 29.2 (9.0) years, height of 172.7 (10.0) 
      cm, weight of 73.0 (13.9) kg, and body mass index ranging from 18 to 30 kg/m(2). 
      Twenty-three were white, 5 African American, 2 Asian/Pacific Islander, 1 
      Hispanic, and 1 Native American. The estimated geometric mean ratio of AUC(0-t) 
      for intact compared with dissolved tablets under fasting conditions was 141.24% 
      (90% CI, 122.05-163.43), and the geometric mean ratio of AUC(0-t) for intact 
      tablets under fed compared with fasting conditions was 143.46% (90% CI, 
      124.22-165.69). Nine subjects (28.1%) reported a total of 20 treatment-emergent 
      adverse events (AEs). The most frequently reported AEs were gastrointestinal 
      disorders (6 subjects [18.8%]) and central nervous system disorders (4 [12.5%]). 
      Eight AEs considered possibly or probably related to sapropterin were reported by 
      4 subjects (12.5%); these were of mild severity and gastrointestinal in nature. 
      No severe or serious AEs or discontinuations due to AEs occurred during the 
      study. CONCLUSIONS: Administration of sapropterin as intact tablets and with a 
      high-calorie, high-fat meal was associated with increased drug exposure. Oral 
      administration of sapropterin 10 mg/kg as intact tablets with or without food was 
      generally well tolerated.
CI  - Copyright 2010. Published by EM Inc USA.
FAU - Musson, Donald G
AU  - Musson DG
AD  - BioMarin Pharmaceutical Inc., Novato, California, USA. dmusson@bmm.com
FAU - Kramer, William G
AU  - Kramer WG
FAU - Foehr, Erik D
AU  - Foehr ED
FAU - Bieberdorf, Frederick A
AU  - Bieberdorf FA
FAU - Hornfeldt, Carl S
AU  - Hornfeldt CS
FAU - Kim, Sun Sook
AU  - Kim SS
FAU - Dorenbaum, Alex
AU  - Dorenbaum A
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Dietary Fats)
RN  - 0 (Tablets)
RN  - 0 (Biopterins)
RN  - EGX657432I (sapropterin)
SB  - IM
MH  - Administration, Oral
MH  - Adolescent
MH  - Adult
MH  - Area Under Curve
MH  - Biological Availability
MH  - Biopterins/administration & dosage/*analogs & derivatives/blood/pharmacokinetics
MH  - Cross-Over Studies
MH  - Dietary Fats/*administration & dosage
MH  - Energy Intake
MH  - Fasting
MH  - Female
MH  - *Food-Drug Interactions
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Models, Biological
MH  - Postprandial Period
MH  - Solubility
MH  - Tablets
MH  - Young Adult
EDAT- 2010/03/09 06:00
MHDA- 2010/05/29 06:00
CRDT- 2010/03/09 06:00
PHST- 2010/01/08 00:00 [accepted]
PHST- 2010/03/09 06:00 [entrez]
PHST- 2010/03/09 06:00 [pubmed]
PHST- 2010/05/29 06:00 [medline]
AID - S0149-2918(10)00063-9 [pii]
AID - 10.1016/j.clinthera.2010.02.012 [doi]
PST - ppublish
SO  - Clin Ther. 2010 Feb;32(2):338-46. doi: 10.1016/j.clinthera.2010.02.012.