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Mechanism of Action
Kuvan (saproterin dihydrochloride tablets) is a synthetic form of BH4, the cofactor for the enzyme phenylalanine hydroxylase (PAH). PAH hydroxylates Phe through an oxidative reaction to form tyrosine. In patients with PKU, PAH activity is absent or deficient. Treatment with BH4 can activate residual PAH enzyme, improve the normal oxidative metabolism of Phe, and decrease Phe levels in some patients.
In PKU patients who are responsive to BH4 treatment, blood Phe levels decrease within 24 hours after a single administration of sapropterin dihydrochloride, although maximal effect on Phe level may take up to a month, depending on the patient. A single daily dose of Kuvan (saproterin dihydrochloride tablets) is adequate to maintain stable blood Phe levels over a 24-hour period. Twelve patients with blood Phe levels ranging from 516 to 986 µmol/L (mean 747 ± 153 µmol/L) were assessed with 24-hour blood Phe level monitoring following a daily morning dose of 10 mg/kg/day. The blood Phe level remained stable during a 24-hour observation period. No substantial increases in blood Phe levels were observed following food intake throughout the 24-hour period.
Doses above 20 mg/kg/day have not been evaluated in clinical studies.
Studies in healthy volunteers have shown comparable absorption of sapropterin dihydrochloride when tablets are dissolved in water or orange juice and taken under fasted conditions. Administration of dissolved tablets after a high-fat/high-calorie meal resulted in mean increases in Cmax of 84% and AUC of 87% (dissolved in water). However, there was extensive variability in individual subject values for Cmax and AUC across the different modes of administration and meal conditions. In the clinical trials of Kuvan (saproterin dihydrochloride tablets) , drug was administered in the morning as a dissolved tablet without regard to meals. The mean elimination half-life in PKU patients was approximately 6.7 hours (range 3.9 to 17 hr), comparable with values seen in healthy subjects (range 3.0 to 5.3 hr).
A population pharmacokinetic analysis of sapropterin that included patients between 9 and 49 years of age showed no effect of age on sapropterin dihydrochloride pharmacokinetics. Pharmacokinetics in patients < 9 years and > 49 years of age have not been studied.
Clinical Studies in PKU
The efficacy and safety of Kuvan (saproterin dihydrochloride tablets) were evaluated in 4 clinical studies in patients with PKU.
Study 1 was a multicenter, open-label, uncontrolled clinical trial of 489 patients with PKU, ages 8 to 48 years (mean 22 years), who had baseline blood Phe levels ≥ 450 µmol/L and who were not on Phe-restricted diets. All patients received treatment with Kuvan (saproterin dihydrochloride tablets) 10 mg/kg/day for 8 days. For the purposes of this study, response to Kuvan (saproterin dihydrochloride tablets) treatment was defined as a ≥ 30% decrease in blood Phe from baseline. At Day 8, 96 patients (20%) were identified as responders.
Study 2 was a multicenter, double-blind, placebo-controlled study of 88 patients with PKU who responded to Kuvan (saproterin dihydrochloride tablets) in Study 1. After a washout period from Study 1, patients were randomized equally to either Kuvan (saproterin dihydrochloride tablets) 10 mg/kg/day (N=41) or placebo (N=47) for 6 weeks. Efficacy was assessed by the mean change in blood Phe level from baseline to Week 6 in the Kuvan (saproterin dihydrochloride tablets) -treated group as compared to the mean change in the placebo group.
The results showed that at baseline, the mean (±SD) blood Phe level was 843 (±300) µmol/L in the Kuvan (saproterin dihydrochloride tablets) -treated group and 888 (±323) µmol/L in the placebo group. At Week 6, the Kuvan (saproterin dihydrochloride tablets) -treated group had a mean (±SD) blood Phe level of 607 (±377) µmol/L, and the placebo group had a mean blood Phe level of 891 (±348) µmol/L. At Week 6, the Kuvan (saproterin dihydrochloride tablets) - and placebo-treated groups had mean changes in blood Phe level of -239 and 6 µmol/L, respectively (mean percent changes of -29% (±32) and 3% (±33), respectively). The difference between the groups was statistically significant (p < 0.001) (Table 2).
Table 2: Blood Phe Results in Study 2
|Baseline Blood Phe Level1 (µmol/L)|
|Mean (±SD)||843 (±300)||888 (±323)|
|Percentiles (25th, 75th)||620, 990||618, 1141|
|Week 6 Blood Phe Level (µmol/L)|
|Mean (±SD)||607 (±377)||891 (±348)|
|Percentiles (25th, 75th)||307, 812||619, 1143|
|Mean Change in Blood Phe From Baseline to Week 6 (µmol/L)|
|Adjusted Mean (±SE)2||-239 (±38)||6 (±36)|
|Percentiles (25th, 75th)||-397, -92||-96, 93|
|Mean Percent Change in Blood Phe From Baseline to Week 6|
|Mean (±SD)||- 29 (±32)||3 (±33)|
|Percentiles (25th, 75th)||-61, -11||-13, 12|
| 1The mean baseline (BL) levels
shown in this table represent the mean of 3 pretreatment levels (Wk -2,
Wk -1, and Wk 0). Treatment with Kuvan (saproterin dihydrochloride tablets) or placebo started at Wk 0.
2p-value < 0.001, adjusted mean and standard error from an ANCOVA model with change in blood Phe level from baseline to Week 6 as the response variable, and both treatment group and baseline blood Phe level as covariates.
Change in blood Phe was noted in the Kuvan (saproterin dihydrochloride tablets) -treated group at Week 1 and was sustained through Week 6 (Figure 1).
Figure 1: Mean Blood Phenylalanine (Phe) Level Over Time1
Study 3 was a multicenter, open-label, extension study in which 80 patients who responded to Kuvan (saproterin dihydrochloride tablets) treatment in Study 1 and completed Study 2 underwent 6 weeks of forced dose-titration with 3 different doses of Kuvan (saproterin dihydrochloride tablets) . Treatments consisted of 3 consecutive 2-week courses of Kuvan (saproterin dihydrochloride tablets) at doses of 5, then 20, and then 10 mg/kg/day. Blood Phe level was monitored after 2 weeks of treatment at each dose level. At baseline, mean (±SD) blood Phe was 844 (±398) µmol/L. At the end of treatment with 5, 10, and 20 mg/kg/day, mean (±SD) blood Phe levels were 744 (±384) µmol/L, 640 (±382) µmol/L, and 581 (±399) µmol/L, respectively (Table 3).
Table 3: Blood Phe Results From Forced Dose-Titration in Study 3
| Kuvan Dose Level
| No. of
| Mean (±SD) Blood
Phe Level (µmol/L)
| Mean Changes (±SD) in
Blood Phe Level From
Week 0 (µmol/L)
|5||80||744 (±384)||-100 (±295)|
|10||80||640 (±382)||-204 (±303)|
|20||80||581 (±399)||-263 (±318)|
Study 4 was a multicenter study of 90 children with PKU, ages 4 to 12 years, who were on Phe-restricted diets and who had blood Phe levels ≤ 480 µmol/L at screening. All patients were treated with open-label Kuvan (saproterin dihydrochloride tablets) 20 mg/kg/day for 8 days. Response to Kuvan (saproterin dihydrochloride tablets) was defined as a ≥ 30% decrease in blood Phe from baseline at Day 8. At Day 8, 50 patients (56%) had a ≥ 30% decrease in blood Phe.
Last reviewed on RxList: 1/3/2008
This monograph has been modified to include the generic and brand name in many instances.
Additional Kuvan Information
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