Chemical formula: C₉H₁₅N₅O₃ Molecular mass: 241.247 g/mol PubChem compound: 44257
Hyperphenylalaninaemia (HPA) is diagnosed as an abnormal elevation in blood phenylalanine levels and is usually caused by autosomal recessive mutations in the genes encoding for phenylalanine hydroxylase enzyme (in the case of phenylketonuria, PKU) or for the enzymes involved in 6R-tetrahydrobiopterin (6R-BH4) biosynthesis or regeneration (in the case of BH4 deficiency). BH4 deficiency is a group of disorders arising from mutations or deletions in the genes encoding for one of the five enzymes involved in the biosynthesis or recycling of BH4. In both cases, phenylalanine cannot be effectively transformed into the amino acid tyrosine, leading to increased phenylalanine levels in the blood.
Sapropterin is a synthetic version of the naturally occurring 6R-BH4, which is a cofactor of the hydroxylases for phenylalanine, tyrosine and tryptophan.
The rationale for administration of sapropterin in patients with BH4-responsive PKU is to enhance the activity of the defective phenylalanine hydroxylase and thereby increase or restore the oxidative metabolism of phenylalanine sufficient to reduce or maintain blood phenylalanine levels, prevent or decrease further phenylalanine accumulation, and increase tolerance to phenylalanine intake in the diet. The rationale for administration of sapropterin in patients with BH4 Deficiency is to replace the deficient levels of BH4, thereby restoring the activity of phenylalanine hydroxylase.
Sapropterin is absorbed after oral administration of the dissolved tablet, and the maximum blood concentration (Cmax) is achieved 3 to 4 hours after dosing in the fasted state. The rate and extent of absorption of sapropterin is influenced by food. The absorption of sapropterin is higher after a high-fat, high-calorie meal as compared to fasting, resulting, in average, in 40-85% higher maximum blood concentrations achieved 4 to 5 hours after administration.
Absolute bioavailability or bioavailability for humans after oral administration is not known.
In non-clinical studies, sapropterin was primarily distributed to the kidneys, adrenal glands, and liver as assessed by levels of total and reduced biopterin concentrations. In rats, following intravenous radiolabeled sapropterin administration, radioactivity was found to distribute in foetuses. Excretion of total biopterin in milk was demonstrated in rats by intravenous route. No increase in total biopterin concentrations in either foetuses or milk was observed in rats after oral administration of 10 mg/kg sapropterin dihydrochloride.
Sapropterin dihydrochloride is primarily metabolised in the liver to dihydrobiopterin and biopterin. Since sapropterin dihydrochloride is a synthetic version of the naturally occurring 6R-BH4, it can be reasonably anticipated to undergo the same metabolism, including 6R-BH4 regeneration.
Following intravenous administration in rats, sapropterin dihydrochloride is mainly excreted in the urine. Following oral administration it is mainly eliminated through faeces while a small proportion is excreted in urine.
Population pharmacokinetic analysis of sapropterin including patients from birth to 49 years of age showed that body weight is the only covariate substantially affecting clearance or volume of distribution.
In vitro, sapropterin did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5, nor induce CYP1A2, 2B6, or 3A4/5.
Based on an in vitro study, there is potential for sapropterin dihydrochloride to inhibit p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in the gut at the therapeutic doses. A higher intestinal concentration of sapropterin is needed to inhibit BCRP than P-gp, as inhibitory potency in intestine for BCRP (IC50=267 μM) is lower than P-gp (IC50=158 μM).
In healthy subjects, administration of a single dose of sapropterin at the maximum therapeutic dose of 20 mg/kg had no effect on the pharmacokinetics of a single dose of digoxin (P-gp substrate) administered concomitantly. Based on the in vitro and in vivo results, co-administration of sapropterin is unlikely to increase systemic exposure to drugs that are substrates for BCRP.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology (CNS, respiratory, cardiovascular, genitourinary), and toxicity to reproduction.
An increased incidence of altered renal microscopic morphology (collecting tubule basophilia) was observed in rats following chronic oral administration of sapropterin dihydrochloride at exposures at or slightly above the maximal recommended human dose.
Sapropterin was found to be weakly mutagenic in bacterial cells and an increase in chromosome aberrations was detected in Chinese hamster lung and ovary cells. However, sapropterin has not been shown to be genotoxic in the in vitro test with human lymphocytes as well as in in vivo micronucleus mouse tests.
No tumorigenic activity was observed in an oral carcinogenicity study in mice at doses of up to 250 mg/kg/day (12.5 to 50 times the human therapeutic dose range).
Emesis has been observed in both the safety pharmacology and the repeated-dose toxicity studies. Emesis is considered to be related to the pH of the solution containing sapropterin.
No clear evidence of teratogenic activity was found in rats and in rabbits at doses of approximately 3 and 10 times the maximum recommended human dose, based on body surface area.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
