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A prospective population pharmacokinetic analysis of sapropterin dihydrochloride in infants and young children with phenylketonuria.

Qi Y, Mould DR, Zhou H, Merilainen M, Musson DG - Clin Pharmacokinet (2015)

Bottom Line: Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance.Body weight was the only covariate significantly affecting sapropterin pharmacokinetics.The effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate.

View Article: PubMed Central - PubMed

Affiliation: BioMarin Pharmaceutical Inc., 105 Digital Dr., 94949, Novato, CA, USA, yqi@bmrn.com.

ABSTRACT

Background and objectives: Untreated phenylketonuria (PKU), a hereditary metabolic disorder caused by a genetic mutation in phenylalanine hydroxylase (PAH), is characterized by elevated blood phenylalanine (Phe) and severe neurologic disease. Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance. The objective of this study was to determine the appropriate dose of sapropterin in pediatric patients (0-6 years). The study design used D-optimization and was prospectively powered to achieve precise estimates of clearance and volume of distribution.

Methods: Oral sapropterin (5 or 20 mg/kg) was administered once daily. Sapropterin plasma concentrations were measured by a validated method. Population pharmacokinetic analysis was performed with NONMEM(®) version 7.2 on pooled data from 156 pediatric and adult PKU patients in two phase III clinical studies.

Results: The best pharmacokinetic model was a one-compartment model with an absorption lag, first-order input, and linear elimination, with a factor describing endogenous BH4 levels. Body weight was the only covariate significantly affecting sapropterin pharmacokinetics. Based on recommended dosing, exposure across age groups was comparable. The absorption rate and terminal half-life suggest flip-flop pharmacokinetic behavior where absorption is rate limiting.

Conclusion: The effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate. The doses selected for pediatric patients provided similar exposure as in adults. Given the slow absorption and elimination half-life, once-daily dosing is justified.

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Related in: MedlinePlus

Comparison of tetrahydrobiopterin exposure by age groups. Whiskers represent 10th and 90th percentile, boxes represent 25th and 75th percentile, center lines represent median, and solid dots represent outliers. AUC area under the concentration–time curve
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Fig4: Comparison of tetrahydrobiopterin exposure by age groups. Whiskers represent 10th and 90th percentile, boxes represent 25th and 75th percentile, center lines represent median, and solid dots represent outliers. AUC area under the concentration–time curve

Mentions: In simulated concentration–time profiles following 20 mg/kg dosing for a range of weights, concentrations remain above the endogenous level for the dose interval (Electronic Supplementary Material Fig. 4S). Overall, BH4 exposure (area under the concentration–time curve at steady state; AUCss) based on administered dose and individual clearance estimates was comparable across all age groups, although there is a slight visual trend towards higher exposure (AUCss) as the age decreases (Fig. 4). However, the number of patients in the youngest age group is small, so this trend should be considered with caution. Maximum (peak) drug concentration (Cmax) could not be determined as the shrinkage on Vc/F was high and there were no terms for inter-individual variability on ka, making parameters used to calculate Cmax unlikely to reflect individual values. No other covariates were identified.Fig. 4


A prospective population pharmacokinetic analysis of sapropterin dihydrochloride in infants and young children with phenylketonuria.

Qi Y, Mould DR, Zhou H, Merilainen M, Musson DG - Clin Pharmacokinet (2015)

Comparison of tetrahydrobiopterin exposure by age groups. Whiskers represent 10th and 90th percentile, boxes represent 25th and 75th percentile, center lines represent median, and solid dots represent outliers. AUC area under the concentration–time curve
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4306193&req=5

Fig4: Comparison of tetrahydrobiopterin exposure by age groups. Whiskers represent 10th and 90th percentile, boxes represent 25th and 75th percentile, center lines represent median, and solid dots represent outliers. AUC area under the concentration–time curve
Mentions: In simulated concentration–time profiles following 20 mg/kg dosing for a range of weights, concentrations remain above the endogenous level for the dose interval (Electronic Supplementary Material Fig. 4S). Overall, BH4 exposure (area under the concentration–time curve at steady state; AUCss) based on administered dose and individual clearance estimates was comparable across all age groups, although there is a slight visual trend towards higher exposure (AUCss) as the age decreases (Fig. 4). However, the number of patients in the youngest age group is small, so this trend should be considered with caution. Maximum (peak) drug concentration (Cmax) could not be determined as the shrinkage on Vc/F was high and there were no terms for inter-individual variability on ka, making parameters used to calculate Cmax unlikely to reflect individual values. No other covariates were identified.Fig. 4

Bottom Line: Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance.Body weight was the only covariate significantly affecting sapropterin pharmacokinetics.The effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate.

View Article: PubMed Central - PubMed

Affiliation: BioMarin Pharmaceutical Inc., 105 Digital Dr., 94949, Novato, CA, USA, yqi@bmrn.com.

ABSTRACT

Background and objectives: Untreated phenylketonuria (PKU), a hereditary metabolic disorder caused by a genetic mutation in phenylalanine hydroxylase (PAH), is characterized by elevated blood phenylalanine (Phe) and severe neurologic disease. Sapropterin dihydrochloride, a synthetic preparation of naturally occurring PAH cofactor tetrahydrobiopterin (BH4), activates residual PAH in a subset of patients, resulting in decreased blood Phe and increased Phe tolerance. The objective of this study was to determine the appropriate dose of sapropterin in pediatric patients (0-6 years). The study design used D-optimization and was prospectively powered to achieve precise estimates of clearance and volume of distribution.

Methods: Oral sapropterin (5 or 20 mg/kg) was administered once daily. Sapropterin plasma concentrations were measured by a validated method. Population pharmacokinetic analysis was performed with NONMEM(®) version 7.2 on pooled data from 156 pediatric and adult PKU patients in two phase III clinical studies.

Results: The best pharmacokinetic model was a one-compartment model with an absorption lag, first-order input, and linear elimination, with a factor describing endogenous BH4 levels. Body weight was the only covariate significantly affecting sapropterin pharmacokinetics. Based on recommended dosing, exposure across age groups was comparable. The absorption rate and terminal half-life suggest flip-flop pharmacokinetic behavior where absorption is rate limiting.

Conclusion: The effect of weight on sapropterin pharmacokinetics was significant and exposure was comparable across age groups; thus, weight-based dosing is appropriate. The doses selected for pediatric patients provided similar exposure as in adults. Given the slow absorption and elimination half-life, once-daily dosing is justified.

Show MeSH
Related in: MedlinePlus