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KUVAN (sapropterin dihydrochloride) tablets(十)
2015-08-13 10:31:57 来源: 作者: 【 】 浏览:7557次 评论:0
f Kuvan on the QTc interval

A thorough QTc study was performed in 56 healthy adults.  This randomized, placebo and active controlled crossover study was conducted to determine if a single supra-therapeutic (100 mg/kg) dose of Kuvan or a single therapeutic dose (20 mg/kg) of Kuvan had an effect on cardiac repolarization. In this study, Kuvan was administered after dissolving tablets in water under fed condition. This study demonstrated a dose-dependent shortening of the QT interval. The maximum placebo-subtracted mean change from baseline of the QTc interval was -3.69 and -8.32 ms (lower bound of 90% CI: -5.3 and -10.6 ms) at 20 and 100 mg/kg, respectively.  


12.3 PharmacokineticsStudies in healthy volunteers have shown comparable absorption of sapropterin 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, 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 study in healthy adults with 10 mg/kg of Kuvan demonstrated the absorption via intact tablet administration was 40% greater than via dissolved tablet administration under fasted conditions based on AUC0-t. The administration of intact tablets under fed conditions resulted in an approximately 43% increase in the extent of absorption compared to fasted conditions based on AUC0-t.

Population pharmacokinetic analysis of sapropterin including patients from 1 month to 49 years of age showed that body weight is the only covariate substantially affecting clearance or distribution volume (see Table 4). Pharmacokinetics in patients >49 years of age have not been studied.

Table 4.  Apparent Plasma Clearance by Age

Parameter
 0 to <1 yr*

(N=10)
 1 to <6 yr*

(N=57)
 6 to <12 yr†

(N=23)
 12 to <18 yr†

(N=24)
 ≥18 yr†

(N=42)
 
CL/F (L/hr/kg)

Mean ± SD

(Median)
 81.5 ± 92.4
(53.6)
 50.7 ± 20.1
(48.4)
 51.7 ± 21.9
(47.4)
 39.2 ± 9.3
(38.3)
 37.9 ± 20.2
(31.8)
 
*eva luated at 20 mg/kg per day dose

†eva luated at 5, 10, or 20 mg/kg per day doses

Metabolism

Sapropterin is a synthetic form of tetrahydrobiopterin (BH4) and is expected to be metabolized and recycled by the same endogenous enzymes. In vivo endogenous BH4 is converted to quinoid dihydrobiopterin and is metabolized to dihydrobiopterin and biopterin. The enzymes dihydrofolate reductase and dihydropteridine reductase are responsible for the metabolism and recycling of BH4.

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13.  NONCLINICAL TOXICOLOGY


13.1  Carcinogenesis, Mutagenesis, Impairment of FertilityA 2-year carcinogenicity study was conducted in F-344 rats, and a 78-week carcinogenicity study was conducted in CD-1 mice. In the 104-week oral carcinogenicity study in rats, sapro

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