Sapropterin-oil suspensions for the treatment of phenylketonuria and hyperphenylalaninemia

Abstract

The present disclosure relates to methods of treating phenylketonuria or hyperphenylalaninemia in a subject in need thereof by administering a sapropterin dihydrochloride suspension. The present disclosure also relates to dosage forms with a sapropterin dihydrochloride suspension.

Description

SAPROPTERIN DIHYDROCHLORIDE SUSPENSIONS AND METHODS OF TREATMENT USING THE SAME

[0001] This present disclosure relates to a sapropterin dihydrochloride suspension and methods of treatment using the sapropterin dihydrochloride suspension.BACKGROUND

[0002] Phenylketonuria (PKU) and hyperphenylalaninemia (HP A) are conditions affecting how the body breaks down the amino acid phenylalanine. Patients suffering from PKU and HPA cannot break down phenylalanine leading to elevated levels of the amino acid in the blood and brain. This can lead to brain damage. PKU is a sufficiently large concern with pediatric medicine that it is diagnosed very shortly after birth by a heel prick blood test.

[0003] Phenylketonuria (PKU) and hyperphenylalaninemia (HPA) are conditions caused by mutations in the phenylalanine hydroxylase gene, resulting in a nonfunctional enzyme of the hepatic enzyme phenylalanine-4-hydroxylase (PAH) [Erlandsen 2004], which causes the inability to break down phenylalanine and in turn leads to elevated concentrations of phenylalanine (Phe) in the blood and brain. Hyperphenylalaninemia (HPA) can also be caused by a deficiency of tetrahydrobiopterin (BH4), a cofactor of PAH (BH4 deficiency). Phe is an essential amino acid, which is not synthesized de novo and must be obtained by diet. PAH converts Phe to tyrosine, an important precursor for catecholamines and melamine. PKU is an inherited, autosomal recessive disease caused by mutations in the PAH gene.

[0004] Previously the main treatment option in PKU involved putting patients on a restricted, low-Phe diet. More recently, sapropterin, a synthetic dihydrochloride salt formulation of the biologically active 6R-diastereoisomer of BH4 [Blau 2010], is prescribed for the treatment of PKU and HPA to restore the activity of phenylalanine hydroxylase. Besides being a cofactor and co-substrate for PAH, tetrahydrobiopterin is also a cofactor for several enzymes such as tyrosine hydroxylase, tryptophan hydroxylase, glyceryl ether monooxygenase and nitric oxide synthase. It is involved in the synthesis of monoamine neurotransmitters, including noradrenaline (norepinephrine), dopamine and 5- hydroxytryptamine (serotonin), and free radical nitric oxide, and patients with BH4 deficiencies may display neurological symptoms arising from the impaired production of these neurotransmitters [Blau 2010],

[0005] The structure of sapropterin, Formula I, is shown below.

[0006] Sapropterin is currently prescribed as a tablet or powder. KUVAN® (formulated sapropterin) is available from Biomarin as 100 mg tablets, and 100 mg or 500 mg powder sachets for resuspension. In the case of the tablet (100 mg is equivalent to 77 mg of sapropterin) the formulation contains ascorbic acid, crospovidone, anhydrous calcium hydrogen phosphate, mannitol, riboflavin and sodium stearyl fumarate; ascorbic acid protects the active compound from oxidation [Blau 2010], Kuvan tablets can be swallowed whole or dissolved in water or apple juice [Kuvan 2016], The latter results in white insoluble particles remaining in suspension which are likely due to components of the tablet formulation, including crospovidone, sodium stearyl fumarate, and dibasic calcium phosphate, not dissolving.

[0007] Children should not be allowed to chew sapropterin tablets. Because of the acidic nature of the dihydrochloride salt, chewing sapropterin tablets may cause mouth or throat irritation. If crushed sapropterin tablets are administered in applesauce or formula and the mouth should be rinsed with water or other liquid to prevent oral irritation. [Striepeke 2009] Dosage may be adjusted within the range of 5 to 20 mg / kg per day according to response to therapy, which is monitored through the measurement of blood Phe [Kuvan 2015],

[0008] Both formulations (powder and tablet), were reasonably stable when suspended in various foods and water at 20 mg / mL (62 mM). Only 3-7% sapropterin degraded after one hour regardless of the pH of food [Jurecki 2009], The low rate of degradation, is likely due to at least three factors:• High concentration: resuspension at high concentrations reduces rates of oxidation• Ascorbic acid within the formulation acting as a temporary sacrificial substrate for oxidation• Food antioxidants: most of the foods will comprise endogenous antioxidants.

[0009] Although sapropterin demonstrates reasonable stability on short exposure to food and water, this is not the case for prolonged exposure. At ambient temperature, sapropterin is not stable in the presence of molecular oxygen. Autoxidation takes place via a radical chain reaction mechanism in which the initiation step proceeds via electron transfer from sapropterin to oxygen. Direct reaction between sapropterin and oxygen serves as an initiation reaction for the further, rapid reaction of the thus formed superoxide with sapropterin, establishing a chain reaction process involving reduction of molecular oxygen by an intermediary tetrahydrobiopterin radical.

[0010] Therefore, prolonged storage of sapropterin can lead to degradation via the oxidative process discussed above.

[0011] Sapropterin is freely soluble in water and has acidic behaviour: a 1 mM solution in water gives a pH of 3.0 and a 1 M solution gives a pH of 0.45.

[0012] The reaction between sapropterin and oxygen is greater in neutral and alkaline solutions. Due to oxidation, sapropterin solutions become yellow.

[0013] After 1 hour open at room temperature, a 0.1 mM solution of sapropterin in water degrades by about 25% whereas a 1 mM solution degrades only by 2%. After 3 hours, 0.1 mM solutions degrade by more than 60% and 1 mM solutions degrade only by 10%. pH is also a key determinant in rate of degradation: Sapropterin’ s half-life in 0.1 M phosphate buffer, pH 6.8, is ~16 minutes at room temperature and it is completely destroyed in 90 minutes. However, solutions in 0.1 N HC1 are stable for several weeks at -20 °C [Sigma Datasheet], Moisture is also a driver for oxidation with optimal stability being achieved in dry conditions [Jurecki 2009], Interestingly, the nature of the oxidation subproducts is dependent on the pH, temperature and composition of buffer in which sapropterin is dissolved [Davis 1988],

[0014] Stabilizers (e.g. DTE and ascorbic acid) can reduce oxidation when in solution. However, these compounds can only slow down rather than stop the degradation of Sapropterin [Fiege 2004],

[0015] Due to the oxidation of sapropterin in solution, it is not possible to prepare a liquid formulation of sapropterin. This presents significant difficulties for dosing children with sapropterin. As discussed above, at present a child must be dosed by crushing a tablet or using a sachet then mixing with a food item or a drink. Furthermore, a drink or food item containing a high concentration of sapropterin can require further considerations after dosing,such as the need to rinse a child’s mouth with water or another drink to remove any potential residue of sapropterin to avoid irritation that can be caused by residual sapropterin.

[0016] Furthermore, prior studies in healthy subjects have shown that administration of dissolved sapropterin tablets (KUVAN®) after a high-fat / high-calorie meal resulted in mean increases in Cmax of 84% and AUC of 87% (dissolved in water) relative to the Cmax and AUC resulting from the administration of dissolved sapropterin tablets (KUVAN®) taken by the same subjects under fasted conditions. Thus, in order to ensure sufficient exposure to the drug, the KUVAN® product label instructs patients to take the dosage form “with a meal,” despite the fact that extensive variability in exposure was observed across individuals in KUVAN®’s clinical trials.

[0017] Accordingly, there is a need for a new dosage form, and methods of administering the same, that provide increased sapropterin exposure than currently provided by KUVAN®. There is also a need for a new dosage form that does not need to be administered with food and / or water, and methods of administering the same, that provide new administration options and greater flexibility than currently provided by KUVAN®.BRIEF SUMMARY OF THE DISCLOSURE

[0018] The present disclosure is directed to storage stable sapropterin dihydrochloride suspensions and methods of treating phenylketonuria or hyperphenylalaninemia in a subject in need thereof using the same.

[0019] In some embodiments, the method comprises: orally administering to the subject without food, water, or without food and water, about 1 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL.

[0020] In some embodiments, the subject is orally administered about 5 mg / kg to about 20 mg / kg of of sapropterin dihydrochloride.

[0021] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered withoutwater to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0022] In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0023] In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0024] In some embodiments, the oil comprises about 50% to about 80% caprylic acid triglyceride and about 20% to about 50% capric acid triglyceride.

[0025] In some embodiments, the sapropterin dihydrochloride suspension further comprises a thickening agent. In some embodiments, the thickening agent is colloidal silica.

[0026] In some embodiments, the sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL. In some embodiments, the sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL

[0027] In some embodiments, the subject is orally administered about 10 mg / kg of sapropterin dihydrochloride.

[0028] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprisingsapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0029] In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0030] In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0031] In some embodiments, the oil comprises about 50% to about 80% caprylic acid triglyceride and about 20% to about 50% capric acid triglyceride.

[0032] In some embodiments, the sapropterin dihydrochloride suspension further comprises a thickening agent. In some embodiments, the thickening agent is colloidal silica.

[0033] In some embodiments, the sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL. In some embodiments, the sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL.

[0034] In some embodiments, the subject is orally administered about 10 mg / kg of sapropterin dihydrochloride.

[0035] The present disclosure also relates to a dosage form comprising a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0036] In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0037] In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0038] In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0039] In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0040] In some embodiments of the dosage form, the oil comprises about 50% to about 80% caprylic acid triglyceride and about 20% to about 50% capric acid triglyceride.

[0041] In some embodiments of the dosage form, the sapropterin dihydrochloride suspension further comprises a thickening agent. In some embodiments, the thickening agent is colloidal silica.

[0042] In some embodiments of the dosage form, the sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL In some embodiments of the dosage form, the sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL.

[0043] In some embodiments of the dosage form, the subject is orally administered about 10 mg / kg of sapropterin dihydrochloride.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Embodiments of the present disclosure are further described hereinafter with reference to the accompanying drawings, in which:

[0045] Figure 1 is an analysis of the mean uncorrected plasma concentration of sapropterin dihydrochloride over time on a linear scale for four administrations of sapropterin, as described in Example 2.

[0046] Figure 2 is an analysis of the mean corrected plasma concentration of sapropterin dihydrochloride over time on a linear scale for four administrations of sapropterin, as described in Example 2.DETAILED DESCRIPTIONDefinitions

[0047] As used herein, the term “about” refers to ±5% of the noted value, unless otherwise specified, and unless the upper bound of the range would exceed 100% of the composition, in which case the upper limit of the range is limited to 99.9%.

[0048] As used herein, the term “impurity” or “impurities” refer to a chemical that is not sapropterin but can be formed from the synthesis, preparation, processing, degradation or decomposition of sapropterin, including but not limited to degradation products of sapropterin, by-products and intermediates from chemical reactions, and contaminants. As used herein, the term “degradation product” or “degradation products” refer to those compounds that result from the degradation of sapropterin.

[0049] The present disclosure is directed to methods of treating phenylketonuria or hyperphenylalaninemia in a subject in need thereof. In some embodiments, the presentdisclosure is directed to methods of treating pediatric phenylketonuria or pediatric hyperphenylal aninemia.

[0050] In some embodiments, the method comprises: orally administering to the subject without food, water, or without food and water, about 1 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL. In some embodiments, the sapropterin dihydrochloride suspension is administered without water to the subject in a fasted state. In some embodiments, the sapropterin dihydrochloride suspension is administered with water to the subject in a fasted state (e.g., the administration of the suspension is followed by a glass of water so that the total volume of suspension and water is 240 mL ± 5 mL). In some embodiments, the sapropterin dihydrochloride suspension is administered without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension is administered with water to the subject in a fed state (e.g., the administration of the suspension is followed by a glass of water so that the total volume of suspension and water is 240 mL ± 5 mL). In some embodiments, the subject is orally administered about 5 mg / kg to about 20 mg / kg of of sapropterin dihydrochloride.

[0051] In some embodiments, the method comprises orally administering to the subject about 1 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of the sapropterin dihydrochloride suspension. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered withoutwater to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0052] In some embodiments, the method comprises orally administering to the subject about 1 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of the sapropterin dihydrochloride suspension. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%,about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0053] In some embodiments, the method comprises orally administering to the subject about 1 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 and a sapropterin Cmax that are each at least about 5% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of the sapropterin dihydrochloride suspension. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 and a sapropterin Cmax that are each at least about 10% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 and a sapropterin Cmax that are each at least about 15% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 and a a sapropterin Cmax that are each about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0054] In some embodiments, sapropterin dihydrochloride is suspended in the oil at a concentration of about 25 mg to about 250 mg per mL, about 25 mg to about 200 mg per mL, about 25 mg to about 150 mg per mL, about 25 mg to about 125 mg per mL, about 25 mg toabout 100 mg per mL, about 50 mg to about 250 mg per mL, about 50 mg to about 200 mg per mL, about 50 mg to about 125 mg per mL, about 50 mg to about 150 mg per mL, about 50 mg to about 100 mg per mL, about 75 mg to about 250 mg per mL, about 75 mg to about 200 mg per mL, about 75 mg to about 150 mg per mL, about 75 mg to about 125 mg per mL, about 75 mg to about 100 mg per mL, about 100 mg to about 250 mg per mL, about 100 mg to about 200 mg per mL, about 100 mg to about 150 mg per mL, or about 100 mg to about 125 mg per mL.

[0055] In some embodiments, the subject is orally administered about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 of the sapropterin dihydrochloride suspension.

[0056] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater thana sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0057] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0058] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fastedstate, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0059] In some embodiments, the method comprises orally administering to the subject about 10 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 5% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterindihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0060] In some embodiments, the method comprises orally administering to the subject about 15 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0061] In some embodiments, the method comprises orally administering to the subject about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 5% greater than a sapropterinAUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0062] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fastedstate, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0063] In some embodiments, the method comprises orally administering to the subject about 10 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resultingfrom orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0064] In some embodiments, the method comprises orally administering to the subject about 15 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0065] In some embodiments, the method comprises orally administering to the subject about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fastedstate, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0066] Without being bound to any particular theory, administering the sapropterin dihydrochloride suspension without water to a subject in a fasted state surprisingly increases sapropterin bioavailability compared to administering an equivalent amount of sapropterin dihydrochloride powder dissolved water to the same subject based on AUCt, AUCinf, and Cmax. Such results are surprising in that prior studies in healthy subjects have shown that administration of dissolved sapropterin tablets (KUVAN®) after a high-fat / high-calorie meal resulted in mean increases in Cmax of 84% and AUC of 87% (dissolved in water) relative to the Cmax and AUC resulting from the administration of dissolved sapropterin tablets (KUVAN®) taken by the same subjects under fasted conditions. Stated another way, the studies described in the present specification have surprisingly shown that administering the sapropterin dihydrochloride suspension described herein without water to a subject in need thereof in a fasted state resulted in increased exposure to sapropterin relative to the currentlymarketed sapropterin product (KUVAN®), a product that needs to be administered with food since administering it without food results in reduced exposure to sapropterin. Accordingly, the present dosage form provides the option (i) to administer less sapropterin to a subject in need thereof to achieve the same net clinical benefit as the currently approved and marketed drug (KUVAN®) or (ii) to administer the same quantity of sapropterin to a subject in need thereof to achieve better clinical benefit than the currently approved and marketed drug (KUVAN®). Because the present dosage form can be administered without the need for food and water, it offers new administration options and greater flexibility for subjects in need thereof (e.g., PKU patients) relative to the currently marketed sapropterin product (KUVAN®). This added flexibility can result in greater patient convenience and compliance as subjects in need thereof (e.g., PKU patients) can take the present dosage form at anytime, even while on the go. In addition, because the present dosage form can be administered without water, and / or because less total drug may be required, the present dosage form provides a more patient-friendly medication capable of being delieved with significantly reduced volume to subjects in need thereof (e.g., PKU patients) relative to the currently marketed sapropterin product (KUVAN®), which may require more total active agent be delivered and that the active agent be taken with water or juice.

[0067] In some embodiments, the method comprises orally administering to the subject about 1 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of the sapropterin dihydrochloride suspension. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orallyadministered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0068] In some embodiments, the method comprises orally administering to the subject about 1 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of the sapropterin dihydrochloride suspension. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension,when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0069] In some embodiments, the method comprises orally administering to the subject about 1 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to the subject in a fasted state, provides a sapropterin AUC0-24 and a sapropterin Cmax that are each at least about 5% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of the sapropterin dihydrochloride suspension. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 and a sapropterin Cmax that are each at least about 10% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 and a sapropterin Cmax that are each at least about 15% greater than a sapropterin AUCo-24 and a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 and a sapropterin Cmax that are each about 5% to about 50%, about 5% to about 40%, about 5% to about 30%,or about 5% to about 20% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0070] In some embodiments, sapropterin dihydrochloride is suspended in the oil at a concentration of about 25 mg to about 250 mg per mL, about 25 mg to about 200 mg per mL, about 25 mg to about 150 mg per mL, about 25 mg to about 125 mg per mL, about 25 mg to about 100 mg per mL, about 50 mg to about 250 mg per mL, about 50 mg to about 200 mg per mL, about 50 mg to about 125 mg per mL, about 50 mg to about 150 mg per mL, about 50 mg to about 100 mg per mL, about 75 mg to about 250 mg per mL, about 75 mg to about 200 mg per mL, about 75 mg to about 150 mg per mL, about 75 mg to about 125 mg per mL, about 75 mg to about 100 mg per mL, about 100 mg to about 250 mg per mL, about 100 mg to about 200 mg per mL, about 100 mg to about 150 mg per mL, or about 100 mg to about 125 mg per mL.

[0071] In some embodiments, the subject is orally administered about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 of the sapropterin dihydrochloride suspension.

[0072] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterinAUCo-24 that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0073] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloridesuspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0074] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0075] In some embodiments, the method comprises orally administering to the subject about 5 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterindihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0076] In some embodiments, the method comprises orally administering to the subject about 10 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterinAUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0077] In some embodiments, the method comprises orally administering to the subject about 10 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0078] In some embodiments, the method comprises orally administering to the subject about 15 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterinAUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0079] In some embodiments, the method comprises orally administering to the subject about 15 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering anequivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0080] In some embodiments, the method comprises orally administering to the subject about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUCo-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0081] In some embodiments, the method comprises orally administering to the subject about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, thesapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments, the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0082] Without being bound to any particular theory administering the sapropterin dihydrochloride suspension without water to a subject in a fasted state surprisingly increases sapropterin bioavailability compared to administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the same subject based on AUCt, AUCinf, and Cmax. Such results are surprising in that prior studies in healthy subjects have shown that administration of dissolved sapropterin tablets (KUVAN®) after a high- fat / high-calorie meal resulted in mean increases in Cmax of 84% and AUC of 87% (dissolved in water) relative to the Cmax and AUC resulting from the administration of dissolved sapropterin tablets (KUVAN®) taken by the same subjects under fasted conditions. Stated another way, the studies described in the present specification have surprisingly shown thatadministering the sapropterin dihydrochloride suspension described herein to a subject in need thereof in a fasted state had increased exposure to sapropterin relative to administering the sapropterin dihydrochloride suspension described herein to the same subject in need thereof in a fed state, which is the opposite result of the currently marketed sapropterin product (KUVAN®), a product that needs to be administered with food since administering it without food results in reduced exposure to sapropterin. The studies described in the present specification also have surprisingly shown that administering the sapropterin dihydrochloride suspension described herein to a subject in need thereof in a fasted state had increased exposure to sapropterin relative to administering the currently marketed sapropterin product (KUVAN®) with food to the same subject. Accordingly, the present dosage form provides the options (i) to administer less sapropterin to a subject in need thereof to achieve the same net clinical benefit as the currently approved and marketed drug (KUVAN®) or (ii) to administer the same quantity of sapropterin to a subject in need thereof to achieve better clinical benefit as the currently approved and marketed drug (KUVAN®).

[0083] The present disclosure also relates to a dosage form comprising a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 10% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24 that is at least about 15% greater than a sapropterin AUCo-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administeredwithout water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0084] In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0085] In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 and a sapropterin Cmax that are each at least about 5% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting fromorally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 and a sapropterin Cmax that are each at least about 10% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 and a sapropterin Cmax that are each at least about 15% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 and a sapropterin Cmax that are each about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 and a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0086] In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of thesapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0087] In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension,when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0088] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0089] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved inwater. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0090] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterindihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0091] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of thedosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0092] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0093] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0094] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to the subject in a fasted state, provides asapropterin AUC0-24 that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0095] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension withor without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 5 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0096] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0097] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0098] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, whenabout 10 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0099] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting fromorally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 10 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0100] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering to subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0101] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0102] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, whenabout 15 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0103] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting fromorally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 15 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0104] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0105] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder (or tablet) dissolved in water.

[0106] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, whenabout 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0107] In some embodiments of the dosage form, sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 25% greater than a sapropterin Cmax resulting fromorally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 30% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state. In some embodiments of the dosage form, the sapropterin dihydrochloride suspension, when about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is about 5% to about 50%, about 5% to about 40%, about 5% to about 30%, or about 5% to about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

[0108] In the embodiments of the methods and dosage form described herein, a “fasted state” can describe subjects that have fasted for at least 10 hours prior to administration of the sapropterin dihydrochloride suspension and at least 4 hours post-dose. In the embodiments of the methods and dosage form described herein, a “fed state” can describe subjects that have fasted overnight for at least 10 hours and consumed a high-fat, high-calorie breakfast starting 30 minutes prior to administration of the sapropterin dihydrochloride suspension. In the embodiments of the methods and dosage form described herein, the high-fat, high-calorie meal can derive approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively. High-fat means that fat was approximately 50 percent of the total caloric content of the meal and high-calorie means that the meal contained approximately 800 to 1,000 calories total.

[0109] In the embodiments of the methods and dosage form described herein, the sapropterin dihydrochloride can have a shelf life of 1 month. In some embodiments, the sapropterin dihydrochloride suspension can have a shelf life of 3 months. In some embodiments, the sapropterin dihydrochloride suspension can have a shelf life of 6 months. In some embodiments, the sapropterin dihydrochloride suspension can have a shelf life of 9 months. In some embodiments, the sapropterin dihydrochloride suspension can have a shelf life of 12 months. In some embodiments, the sapropterin dihydrochloride suspension can have a shelf life of 15 months. In some embodiments, the sapropterin dihydrochloride suspension can have a shelf life of 18 months. In some embodiments, the sapropterindihydrochloride suspension can have a shelf life of 21 months. In some embodiments, the suspension can have a shelf life of 24 months.

[0110] In some embodiments of the sapropterin dihydrochloride suspension, the sapropterin dihydrochloride can be in particulate form. In some embodiments, the particulate sapropterin can have a Dv90 from about 170 pm to about 400 pm, about 170 pm to about 350 pm, about 170 pm to about 300 pm, about 170 pm to about 250 pm, or about 170 pm to about 200 pm. In some embodiments, the particulate sapropterin can have a Dv90 from about 200 pm to about 400 pm, about 200 pm to about 350 pm, about 200 pm to about 300 pm, about 200 pm to about 280 pm, about 200 pm to about 260 pm, about 200 pm to about 250 pm, about 200 pm to about 240 pm, or about 200 pm to about 220 pm. In some embodiments, the particulate sapropterin suspension can have a Dv90 from about 220 pm to about 400 pm, about 220 pm to about 350 pm, about 220 pm to about 300 pm, about 220 pm to about 250 pm, or about 220 pm to about 240 pm. In some embodiments, the particulate sapropterin suspension can have a Dv90 from about 240 pm to about 400 pm, about 240 pm to about 350 pm, about 240 pm to about 300 pm, about 240 pm to about 280 pm, about 240 pm to about 260 pm, or about 240 pm to about 250 pm.[OHl] In some embodiments, the particulate sapropterin can have a Dv50 from about 70 pm to about 170 pm, about 70 pm to about 150 pm, about 70 pm to about 130 pm, about 70 pm to about 120 pm, about 70 pm to about 100 pm, or about 70 pm to about 80 pm. In some embodiments, the particulate sapropterin can have a Dv50 from about 80 pm to about 170 pm, about 80 pm to about 150 pm, about 80 pm to about 130 pm, about 80 pm to about 120 pm, about 80 pm to about 100 pm, or about 80 pm to about 90 pm. In some embodiments, the particulate sapropterin can have a Dv50 from about 100 pm to about 170 pm, about 100 pm to about 160 pm, about 100 pm to about 150 pm, about 100 pm to about 140 pm, about 100 pm to about 130 pm, about 100 pm to about 120 pm, or about 100 pm to about 110 pm. In some embodiments, the particulate sapropterin can have a Dv50 from about 110 pm to about 170 pm, about 110 pm to about 160 pm, about 110 pm to about 150 pm, about 110 pm to about 140 pm, about 110 pm to about 130 pm, or about 110 pm to about 120 pm. In some embodiments, the particulate sapropterin can have a Dv50 from about 120 pm to about 170 pm, about 120 pm to about 160 pm, about 120 pm to about 150 pm, about 120 pm to about 140 pm, or about 120 pm to about 130 pm. In some embodiments, the particulate sapropterin can have a Dv50 from about 130 pm to about 170 pm, about 130 pm to about 160 pm, about130 m to about 150 pm, or about 130 pm to about 140 pm. In some embodiments, the particulate sapropterin can have a Dv50 from about 140 pm to about 170 pm, about 140 pm to about 160 pm, or about 140 pm to about 150 pm. In some embodiments, the particulate sapropterin in the suspension can have a Dv50 from about 150 pm to about 170 pm, about 150 pm to about 160 pm, or about 160 pm to about 170 pm.

[0112] In some embodiments, the particulate sapropterin can have a DvlO from about 10 pm to about 60 pm, about 10 pm to about 50 pm, about 10 pm to about 40 pm, about 10 pm to about 30 pm, or about 10 pm to about 20 pm. In some embodiments, the particulate sapropterin can have a DvlO from about 20 pm to about 60 pm, about 20 pm to about 50 pm, about 20 pm to about 40 pm, or about 20 pm to about 30 pm. In some embodiments, the particulate sapropterin can have a DvlO from about 30 pm to about 60 pm, about 30 pm to about 50 pm, or about 30 pm to about 40 pm. In some embodiments, the particulate sapropterin can have a DvlO from about 40 pm to about 60 pm, about 40 pm to about 50 pm, or about 50 pm to about 60 pm.

[0113] In some embodiments, the sapropterin particles can have a particle size distribution as set out below in Table 1 :Table 1

[0114] In some embodiments, the sapropterin dihydrochloride suspension can further comprise a thickening agent. The thickening agent can be selected from any known thickening agent capable of reducing the rate of sedimentation of the particulate sapropterin. In some embodiments, the thickening agent can be a colloidal silica.

[0115] In some embodiments, the suspension can comprise from about 1 to about 10% w / v of the thickening agent. In some embodiments, the suspension can comprise from about 1 to about 8%, about 1 to about 6%, about 1 to about 5%, about 1 to about 4%, or about 1 to about 2% w / v of the thickening agent. In some embodiments, the suspension can comprise from about 2 to about 8%, about 2 to about 6%, about 2 to about 5%, about 2 to about 4%, or about 2 to about 3% w / v of the thickening agent. In some embodiments, the suspension can comprise from about 3 to about 8%, about 3 to about 6%, about 3 to about 5%, or about 2 to about 4% w / v of the thickening agent. In some embodiments, the suspension can comprise from about 4 to about 8%, about 4 to about 7%, about 4 to about 6%, or about 4 to about 5% w / v of the thickening agent. In some embodiments, the suspension can comprise from about 5 to about 8%, about 5 to about 7%, or about 5 to about 6% w / v of the thickening agent. In some embodiments, the suspension can comprise from about 6 to about 8%, about 6 to about 7%, or about 7 to about 8% w / v of the thickening agent. In some embodiments, the suspension can comprise about 5% w / v of the thickening agent.

[0116] In some embodiments, the suspension can comprise from about 1 to about 10% w / v of colloidal silica. In some embodiments, the suspension can comprise from about 1 to about 8%, about 1 to about 6%, about 1 to about 5%, about 1 to about 4%, or about 1 to about 2% w / v of colloidal silica. In some embodiments, the suspension can comprise from about 2 to about 8%, about 2 to about 6%, about 2 to about 5%, about 2 to about 4%, or about 2 to about 3% w / v of colloidal silica. In some embodiments, the suspension can comprise from about 3 to about 8%, about 3 to about 6%, about 3 to about 5%, or about 2 to about 4% w / vof colloidal silica. In some embodiments, the suspension can comprise from about 4 to about 8%, about 4 to about 7%, about 4 to about 6%, or about 4 to about 5% w / v of colloidal silica. In some embodiments, the suspension can comprise from about 5 to about 8%, about 5 to about 7%, or about 5 to about 6% w / v of colloidal silica. In some embodiments, the suspension can comprise from about 6 to about 8%, about 6 to about 7%, or about 7 to about 8% w / v of colloidal silica. In some embodiments, the suspension can comprise about 5% w / v of colloidal silica.

[0117] In some embodiments, the particulate sapropterin can be dispersed (e.g., suspended) in the pharmaceutically acceptable oil. In some embodiments, the particulate sapropterin can be uniformly dispersed throughout the oil. The foregoing notwithstanding, and in other embodiments, for example upon storage, it is possible that the sapropterin can settle to the bottom of a container in which the suspension is stored such that the particulate sapropterin is not uniformly dispersed in throughout the oil. It is desirable to maintain a dispersion for as long a period as possible. Therefore, in some embodiments, the oil can be selected to enable dispersing the particulate sapropterin homogeneously throughout the oil. The homogenous dispersion of sapropterin can be formed upon agitation of the suspension. For example, the agitation could be caused by shaking a container holding the suspension.

[0118] In some embodiments, the ability to disperse the particulate sapropterin can be controlled by the viscosity of the oil or the viscosity of the composition. As such, in some embodiments, the oil can have a viscosity from about 10 to about 500 mPa*s at about 20 °C, for example, from about 10 to about 100 mPa*s at about 20 °C or from about 20 to about 50 mPa*s at about 20 °C.

[0119] In some embodiments, the viscosity of the suspension can be attributed solely to the oil. In some embodiments, the viscosity of the suspension can be modified by an additional excipient.

[0120] In some embodiments, the suspension optionally comprises an oil miscible excipient. In some embodiments, the oil can be a mixture of an oil with the oil miscible excipient. For example, the oil miscible excipient can be an alcohol (such as ethanol), glycerol, polypropylene glycol, or polyethylene glycol. In some embodiments, the oil miscible excipient can be a viscosity reducing agent.

[0121] In some embodiments, the oil can comprise short chain mono glycerides, medium chain monoglycerides, long chain monoglycerides, short chain diglycerides, medium chaindiglycerides, long chain diglycerides, short chain triglycerides, medium chain triglycerides, long chain triglycerides, or combinations thereof. Short chain, medium chain, and long chain are terms recognized within the art and relate to the carbon chain length of the fatty acid component of the mono-, di- and tri-glyceride. A short chain glyceride can comprise a fatty acid portion with a carbon chain length from 2 to 5. A medium chain glyceride can have a fatty acid portion with a carbon chain length from 6 to 12. A long chain glyceride can have a fatty acid portion with a carbon chain length from 13 to 26.

[0122] In some embodiments, the fatty acid component of a glyceride can be saturated or unsaturated.

[0123] In some embodiments, the oil can comprise one or more fatty acids. In some embodiments, the fatty acid can be present alone or as a glyceride. In some embodiments, the fatty acid can be selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, steric acid, arachidic acid, behenic acid, lignoceric acid, cerotic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linolaidic acid, linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, or combinations thereof.

[0124] In some embodiments, the oil can comprise a fatty acid glyceride selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, steric acid, and combinations thereof.

[0125] In certain embodiments, the oil can comprise a medium chain triglyceride. In some embodiments, the oil can be a combination of medium chain triglycerides. In some embodiments, the oil can be a combination of C8 triglycerides and CIO triglycerides. In some embodiments, the oil can comprise from about 50% to about 80% caprylic acid triglyceride (C8) and from about 20% to about 50% capric acid triglyceride (CIO).

[0126] MIGLYOL® 812 is a medium chain triglyceride comprising caprylic acid and capric acid. In some embodiments, MIGLYOL® 812 can comprise from about 50% to about 80% caprylic acid triglyceride (C8) and from about 20% to about 50% capric acid triglyceride (CIO). In some embodiments, the suspension can comprise MIGLYOL® 812.

[0127] In some embodiments, the oil can comprise a fatty acid, fatty acid glyceride, a polyol, a polyethylene glycol, a polypropylene glycol, a mineral oil, a plant derived oil, a mono-glyceride, di-glyceride, tri-glyceride or combinations thereof.

[0128] In some embodiments, the oil can comprise olive oil, sunflower oil, rapeseed oil, rice bran oil, a combination of capric triglyceride and caprylic triglyceride, or combinations thereof.

[0129] Without wishing to be bound by any particular theory, it is believed that the use of a non-polar solvent as carrier, such as a combination of capric triglyceride and caprylic triglyceride, slows down the rates of autooxidation. Alterations to the polarity of the solvent are believed to affect the rates of reaction and that autooxidation involves electron-transfer steps, which are precluded by the use of a non-polar solvent as carrier, since such an ionictype process would predominantly be facilitated by polar solvents.

[0130] In some embodiments, the suspension can further comprise a flavoring. The flavoring can be any pharmaceutically acceptable flavoring. In some embodiments, the flavoring can be selected from the group consisting of tangerine, lemon, peppermint, strawberry, raspberry, and tutti frutti. In some embodiments, the flavoring can be selected from the group consisting of tangerine, lemon, peppermint, strawberry, raspberry, tutti frutti, wintergreen, sweet mint, spearmint, vanillin, cherry, butterscotch, chocolate, cinnamon, clove, orange, rose, spice, violet, herbal, fruit, grape, pineapple, vanilla, peach, kiwi, papaya, mango, coconut, apple, coffee, plum, watermelon, nuts, green tea, grapefruit, banana, butter, chamomile, and combinations thereof.

[0131] In some embodiments, the suspension can comprise from about 0.1 % to about 1% g / lOOmL of the flavoring. In some embodiments, the suspension can comprise from about 0.1 % to about 0.8%, about 0.1 % to about 0.7%, about 0.1 % to about 0.6%, about 0.1 % to about 0.5%, about 0.1 % to about 0.4%, about 0.1 % to about 0.3%, or about 0.1 % to about 0.2% g / lOOmL of the flavoring. In some embodiments, the suspension can comprise from about 0.2 % to about 0.8%, about 0.2 % to about 0.7%, about 0.2 % to about 0.6%, about 0.2 % to about 0.5%, about 0.2 % to about 0.4%, or about 0.2 % to about 0.3% g / lOOmL of the flavoring. In some embodiments, the suspension can comprise from about 0.3 % to about 0.8%, about 0.3 % to about 0.7%, about 0.3 % to about 0.6%, about 0.3 % to about 0.5%, or about 0.3 % to about 0.4% g / lOOmL of the flavoring. In some embodiments, the suspension can comprise from about 0.4 % to about 0.8%, about 0.4 % to about 0.7%, about 0.4 % to about 0.6%, or about 0.4 % to about 0.5% g / lOOmL of the flavoring. In some embodiments, the suspension can comprise from about 0.5 % to about 0.8%, about 0.5 % to about 0.7%, or about 0.5 % to about 0.6% g / lOOmL of the flavoring. In some embodiments, the suspensioncan comprise from about 0.6 % to about 0.8%, about 0.6 % to about 0.7%, or about 0.7 % to about 0.8% g / lOOmL of the flavoring. In some embodiments, the suspension can comprise about 0.25% g / lOOmL of the flavoring.

[0132] In some embodiments, the suspension can comprise from about 0.1 % to about 1% g / lOOmL of tutti frutti flavoring. In some embodiments, the suspension can comprise from about 0.1 % to about 0.8%, about 0.1 % to about 0.7%, about 0.1 % to about 0.6%, about 0.1 % to about 0.5%, about 0.1 % to about 0.4%, about 0.1 % to about 0.3%, or about 0.1 % to about 0.2% g / lOOmL of tutti frutti flavoring. In some embodiments, the suspension can comprise from about 0.2 % to about 0.8%, about 0.2 % to about 0.7%, about 0.2 % to about 0.6%, about 0.2 % to about 0.5%, about 0.2 % to about 0.4%, or about 0.2 % to about 0.3% g / lOOmL of tutti frutti flavoring. In some embodiments, the suspension can comprise from about 0.3 % to about 0.8%, about 0.3 % to about 0.7%, about 0.3 % to about 0.6%, about 0.3 % to about 0.5%, or about 0.3 % to about 0.4% g / lOOmL of tutti frutti flavoring. In some embodiments, the suspension can comprise from about 0.4 % to about 0.8%, about 0.4 % to about 0.7%, about 0.4 % to about 0.6%, or about 0.4 % to about 0.5% g / lOOmL of tutti frutti flavoring. In some embodiments, the suspension can comprise from about 0.5 % to about 0.8%, about 0.5 % to about 0.7%, or about 0.5 % to about 0.6% g / lOOmL of tutti frutti flavoring. In some embodiments, the suspension can comprise from about 0.6 % to about 0.8%, about 0.6 % to about 0.7%, or about 0.7 % to about 0.8% g / lOOmL of tutti frutti flavoring. In some embodiments, the suspension can comprise about 0.25% g / lOOmL of tutti frutti flavoring.

[0133] In some embodiments, the suspension can comprise a sweetening agent. The sweetening agent can be any pharmaceutically acceptable sweetening agent. In some embodiments, the sweetening agent can be sucrose (sugar), dextrose, maltose, dextrin, xylose, ribose, glucose, lactose, mannose, galactose, fructose (levulose), invert sugar, fructo oligo saccharide syrups, partially hydrolyzed starch, com syrup solids, a sugar alcohol such as sorbitol, mannitol, lactitol, maltitol, xylitol, and erythritol, an artificial sweeteners such as aspartame, soluble saccharin salts, i.e., sodium or calcium saccharin salts, the free acid form of saccharin, acesulfame potassium, and combinations thereof.

[0134] In some embodiments, the suspension can comprise from about 0.5 % to about 15% g / lOOmL of the sweetening agent. In some embodiments, the suspension can comprise from about 1% to about 15%, about 1% to about 12.5%, about 1% to about 10%, about 1% toabout 7.5%, about 1% to about 5%, or about 1% to about 2.5% g / lOOmL of the sweetening agent. In some embodiments, the suspension can comprise from about 2.5% to about 15%, bout 2.5% to about 12.5%, about 2.5% to about 10%, about 2.5% to about 7.5%, or about 2.5% to about 5% g / lOOmL of the sweetening agent. In some embodiments, the suspension can comprise from about 5% to about 15%, bout 5% to about 12.5%, about 5% to about 10%, or about 5% to about 7.5% g / lOOmL of the sweetening agent. In some embodiments, the suspension can comprise from about 7.5% to about 15%, bout 7.5% to about 12.5%, about 7.5% to about 10%, about 10% to about 15%, bout 10% to about 12.5%, or about 12.5% to about 15% g / lOOmL of the sweetening agent. In some embodiments, the suspension can comprise about 5% g / lOOmL of the sweetening agent. In some embodiments, the suspension can comprise about 10% g / lOOmL of the sweetening agent.

[0135] In some embodiments, the suspension can be free of undesirable excipients. Where undesirable excipients are defined as those excipients that are contraindicated for inclusion in oral suspensions. In some embodiments, the suspension can be free of excipients that are contraindicated for inclusion in pediatric oral suspensions. For example, and in some embodiments, the suspension does not include alkonium chlorides, benzoic acid and benzoates, benzyl alcohol, ethanol, cetrimonium bromide (CTAB), parabenzoates and their salts, or any combination of any of the foregoing.

[0136] In some embodiments, the suspension can comprise about 10 g / lOOmL sapropterin dihydrochloride, about 5 g / lOOmL colloidal silica, about 0.25 g / lOOmL of a flavoring, and 85.75 g / lOOmL of an oil that can comprise from about 50% to about 80% caprylic acid triglyceride and from about 20% to about 50% capric acid triglyceride. In some embodiments, the suspension can consist essentially of about 10 g / lOOmL sapropterin dihydrochloride, about 5 g / lOOmL colloidal silica, about 0.25 g / lOOmL of a flavoring, and 85.75 g / lOOmL of an oil that can comprise from about 50% to about 80% caprylic acid triglyceride and from about 20% to about 50% capric acid triglyceride. In some embodiments, the suspension can consist of about 10 g / lOOmL sapropterin dihydrochloride, about 5 g / lOOmL colloidal silica, about 0.25 g / lOOmL of a flavoring, and 85.75 g / lOOmL of an oil that can comprise from about 50% to about 80% caprylic acid triglyceride and from about 20% to about 50% capric acid triglyceride.

[0137] MIGLYOL® 812is a medium chain triglyceride comprising caprylic acid and capric acid. Specifically, MIGLYOL® 812comprises between 50 and 80% caprylic acid triglyceride and between 20 and 50% capric acid triglyceride.

[0138] As discussed above, the suspension avoids degradation of sapropterin when in a liquid medium. This is particularly advantageous as prior work with sapropterin has demonstrated that degradation is rapid and prohibits long term storage of sapropterin in a liquid medium.

[0139] As discussed above, the homogeneity of the suspension can be measured based on the amount of sapropterin within a given volume when a volume is extracted from the suspension, for example by an oral syringe or onto a dosing spoon. The homogeneity can be assessed following the content uniformity of dosage forms as set out in the European Pharmacopea. For example, the content uniformity can be assessed by assaying 10 units individually using an appropriate analytical method. The assay should be carries out on an amount of well-mixed material that is removed from an individual container in conditions of normal use. The results of the assay can be expressed as a delivered dose. An acceptance value can be calculated. The acceptance value can be calculated using the formula:|M — X| + ks where M is a reference valueX is the mean of individual contents expressed as a percentage of the label claim k is an acceptability content which is either 2.4 or 2.0 depending whether the number of samples is 10 or 30 respectively s is the sample deviation.

[0140] In embodiments of the present disclosure, the suspension provides a dose containing between 75 - 125% of average dose, optionally 80 - 120% or 85 - 115% of the average dose. The average dose can be the average of the 10 assayed samples discussed above. Alternatively, the average dose can be the intended dose.

[0141] Without wishing to be bound by a particular theory, it is believed that the suspensions disclosed herein can benefit from the exclusion of oxygen from the suspension. One way to achieve this is to optionally use a gas proof seal on the suspension’s container. While a gas-proof seal may be helpful, any container for a liquid suspension known within the art can be suitable for packaging the suspension of the present disclosure. By way of example, and in some embodiments, the container can be a type III amber Glass bottle fittedwith a TE / CR polypropylene closure with a tri wad seal (expanded polyethylene, EPE). In certain embodiments, the glass bottle can be a 30 ml bottle with a 28 mm closure. However, any size suitable in the field can be used.EXAMPLES

[0142] These examples are provided for the purpose of illustration only and the embodiments described herein should in no way be construed as being limited to these examples. Rather, the embodiments should be construed to encompass any and all variations which become evident as a result of the teaching provided herein.

[0143] The following abbreviations are used in these examples:

[0144] Example 1 : Sapropterin Dihydrochloride Suspension and Manufacturing

[0145] A homogeneous mixture was manufactured by first adding MIGLYOL® 812N and Tutti-Frutti flavoring to a mixing tank. Colloidal silicon dioxide was added and mixed under vacuum with a homogenizer. Particulate sapropterin dihydrochloride, with a particulate size distribution of Dv90 between 170 and 250 microns, was then added, and mixed under vacuum with a homogenizer. A nitrogen blanket was then applied until filled.

[0146] The homogeneous mixture was portioned out into a 30 mL portion by filling a 30 mL amber glass Type III bottle, closed with a polypropylene child-resistant tamper-evident screw cap integrated with polyethylene plug for a measuring device.

[0147] The 100 mg / mL suspension is shown belown in Table 1 for a quantity of 100 mL and a quantity of 30 mL.

[0148] Table 1

[0149] Example 2: A Pilot, Phase 1, Randomized, Open-Label, Single-Dose, Four-Way Crossover Study to Compare the Pharmacokinetics (PK) of Sapropterin Dihydrochloride 100 mg / mL Oral Suspection with 100 mg Sapropterin Dihydrochloride Powder for Oral Solution (Reference; KUVAN®) and to Evaluate the Effect of Food and the Effect of Water on the Bioavailability of Sapropterin Dihydrochloride 100 mg / mL Oral Suspension in Healthy Subjects.

[0150] Study Design and Methodology:

[0151] The study had the following periods:

[0152] Screening Period: up to 30 days prior to Treatment Period 1 and included the provision of privacy and volunteer consent forms and the assessment of inclusion / exclusion criteria.

[0153] Admission of Treatment Period 1 (Dav -1 or Dav 1 of Period 1): Written informed consent was provided to the subjects and eligible subjects were admitted to the clinical site and randomized to complete each treatment using a 4-sequence Williams design (e.g., ADBC, BACD, CBDA, and DCAB). Treatments A, B, C, and D described in detail below.

[0154] Admission of Treatment Periods 2, 3, and 4 (Day -1 of Periods 2, 3, and 4): The subjects were admitted to the clinical site to receive the remaining study medications.

[0155] Treatment Period: There were 4 treatment periods (Period 1, Period 2, Period 3, Period 4) wherein the subjects ingested the study medications (a single 10 mg / kg dose of sapropterin dihydrochloride on Day 1, under fasting or fed conditions, and with or without water) and confined until the completion of assessments on Day 2. There was a washout period of at least 7 days between doses.

[0156] End of study (EOS): Study procedures (physical examination, vital sign measurement, 12-lead ECG, blood and urine collection) were performed for all subjects who completed the study at the end of the last treatment period.

[0157] Early Termination (ET): End of Study procedures were performed for all subjects who early terminated from the study.

[0158] Number of Subjects and Study Population:

[0159] Sixteen subjects were enrolled and randomized to give 16 subjects per treatment. Subjects met all inclusion criteria and none of the exclusion criteria (below) before they participated in the study.

[0160] Inclusion Criteria:1. Male or female, light smoker (no more than 10 cigarettes daily) or non-smoker, > 18 and < 50 years of age, with body mass index (BMI) > 18.5 and < 30.0 kg / m2 and body weight > 50.0 kg for males and > 45.0 kg for females.2. Healthy as defined by: a. the absence of clinically significant illness and surgery within 30 days prior to dosing. b. the absence of clinically significant history of neurological, endocrine, cardiovascular, respiratory, hematological, immunological, psychiatric, gastrointestinal, renal, hepatic, and metabolic disease.3. Female subjects of non-childbearing potential must be: a. post-menopausal (no menstrual period at least 12 consecutive months without any other medical cause and FSH and LH values consistent with being menopausal); or b. surgically sterile (bilateral oophorectomy, bilateral salpingectomy, hysterectomy or tubal ligation) at least 3 months prior to dosing.4. Sexually active female subjects of childbearing potential must be willing to use an acceptable single- or double- contraceptive method for the timeframes specified below and throughout the study: a. females: from 21 days prior to first study treatment administration until 28 days after the last PK blood sample in the study; and b. males: from the day of first study treatment administration until 28 days after the last PK blood sample in the study.5. Willing to take off dentures or mouth piercing at the time of dosing.6. Able to understand the study procedures and provide signed informed consent to participate in the study.

[0161] Exclusion Critera:1. Any clinically significant abnormal finding at physical examination.2. Clinically significant abnormal laboratory test results (may be repeated up to two times) or positive serology test results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV)-l and HIV-2 antibodies at screening.3. Positive pregnancy test or lactating female subject.4. Positive urine drug screen.5. Known allergic reactions to sapropterin dihydrochloride or other related drugs, or to any excipient in the suspension.6. Clinically significant ECG abnormalities or vital signs abnormalities (systolic blood pressure lower than 90 or over 150 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or pulse rate less than 50 or over 100 bpm) at screening. ECG and vitals signs may be repeated up to two times, to determine if the values are significantly abnormal.7. Recreational use of soft drugs (such as marijuana) within 1 month or hard drugs (such as cocaine, phencyclidine [PCP], crack, opioid derivatives including heroin, and amphetamine derivatives) within 3 months prior to screening.8. History of alcohol addiction requiring treatment.9. History of abuse of medicinal product or drugs within the last 3 years.History or presence of alcoholism within the last 3 years. (>40 g ethanol / day or more than 10 units per week [1 unit =150 mL of wine, or 360 mL of beer, or 45 mL of 45% alcohol]). Use of the following medications for the timeframes specified: a. Depot injection or implant of any drug for 3 months prior to dosing; b. Prescription medications for 14 days prior to dosing; c. Any vaccine, including the COVID-19 vaccine, for 14 days prior to dosing; or d. Over-the-counter (OTC) medications and natural health products (including herbal remedies such as St. John’s wort, homeopathic and traditional medicines, probiotics, food supplements such as vitamins, minerals, amino acids, essential fatty acids, and protein supplements used in sports) for 7 days prior to dosing (with the exception of the occasional use of acetaminophen up to 2 g daily). Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days prior to dosing, administration of a biological product in the context of a clinical research study within 90 days prior to dosing, or concomitant participation in an investigational study involving no drug or device administration. Known predisposition to seizures. Donation of plasma within 7 days prior to dosing or donation or loss of 500 mL or more of whole blood within 8 weeks prior to dosing. Presence of orthodontic braces or orthodontic retention wires, or any physical findings in the mouth or tongue that would be likely to interfere with successful completion of the dosing procedure. Females who: a. Have discontinued or changed the use of implanted, intrauterine, intravaginal, or injected hormonal contraceptives within 6 months prior to study treatment administration. b. Have discontinued or changed the use of oral or patch hormonal contraceptives within 1 month prior to study treatment administration. Any reason which, in the opinion of the Investigator, would prevent the subject from participating in the study.

[0162] Treatment, Dose, and Mode of Administration:

[0163] The treatments were administered orally via a metered syringe. The dose for each subject was calculated by multiplying the subject’s weight measured on Day -1 of Period 1 by 10 mg / kg then rounding up to the next 100 mg dose. For example, the weight of a 70.5 kg subject would be multiplied by 10 mg / kg, resulting in 705 mg and after rounding up, this subject would be assigned a dose of 800 mg.

[0164] The treatments that were administered were:

[0165] Treatment A: 1 x 10 mg / kg dose of sapropterin dihydrochloride oral suspension 100 mg / mL administered without water under fasting conditions. Subjects immediately swallowed all of the contents of the syringe without a rinse of the syringe. Subjects fasted from at least 10 hours prior to the study treatment administration until at least 4 hours postdose;

[0166] Treatment B: 1 x 10 mg / kg dose of sapropterin dihyrdrochloride oral suspension 100 mg / mL administered without water under fed conditions. Subjects immediately swallowed all of the contents of the syringe without a rinse of the syringe. After an overnight fast of at least 10 hours, subjects consumed a high-fat, high-calorie breakfast starting 30 minutes prior to study treatment administration;

[0167] Teatment C: 1 x 10 mg / kg dose of sapropterin dihydrochloride oral suspension 100 mg / mL administered with a glass of water under fed conditions. Subjects immediately swallowed all of the contents of the syringe followed by a glass of water so that the total volume of suspension and water is 240 mL (± 5 mL). After an overnight fast of at least 10 hours, subjects consumed a high-fat, high-calorie breakfast starting 30 minutes prior to study treatment administration; and

[0168] Treatment D: 1 x 10 mg / kg dose of 100 mg sapropterin dihydrochloride powder for oral solution dissolved in 120 mL (± 3 mL) of water within 15 minutes before administration and administered under fed conditions. To ensure that the entire dose was consumed, the dosing cup was rinsed twice with an additional 60 mL (± 1 mL) of water each time (total volume of 120 mL (± 2 mL)). After an overnight fast of at least 10 hours, subjects consumed a high-fat, high-calorie breakfast starting 30 minutes prior to study treatment administration.

[0169] The high-fat, high-calorie meal derived approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively. High-fat means that fat wasapproximately 50 percent of the total caloric content of the meal and high-calorie means that the meal contained approximately 800 to 1,000 calories total.

[0170] Subjects fasted for at least 4 hours post-dose. Subjects abstained from: food or beverages containing grapefruit, Seville orange, starfruit, pomegranate, pineapple, or pomelo from 7 days prior to dosing and throughout the study; food or beverages containing xanthine derivatives or xanthine-related compounds (coffee, black / green tea, chocolate) or energy drinks from 48 hours prior to dosing until after the last PK blood sample collection of each period; food containing poppy seeds from 24 hours prior to admission of each period; and chewing gum was prohibited at all times during the confirment.

[0171] Water was restricted from one hour prior to study treatment administration until one hour post-dose (except the water administered with the study treatment in Treatment C and D). Access to water was otherwise freely available to subjects.

[0172] Endpoints:

[0173] Primary:• PK• Uncorrected and baseline-corrected sapropterin AUCo-t, AUCo-inf, and Cmax.

[0174] Secondary:• PK• Uncorrected and baseline-corrected sapropterin Tmax and Tiag.• Uncorrected and baseline-corrected sapropterin T1 / 2 ei, Residual area, Kei, Cl / F, and Vz / F.

[0175] Safety:• Adverse events (AEs), vital signs measurements (blood pressure, pulse rate, respiratory rate, and temperature), 12-lead electrocardiogram (ECG) recordings, physical examinations, and clinical laboratory test results, including hematology, biochemistry, and urinalysis.

[0176] Efficacy and Safety Procedures:

[0177] Blood samples for PK analysis were collected during each treatment period at the protocol-specified times of one hour and half prior to the dose, pre-dose, 0.333, 0.667, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 12, 16, and 24 hours post-dose.

[0178] Blood pressure, pulse rate, respiration rate, and temperature were measured at screening and EOS. Temperature was measured daily during confinement. Blood pressure and pulse rate were measured before dosing (0-hour) and at 4 and 6 hours post-dose of each period. 12-lead ECG will be measured at screening, before dosing (0-hour), at 4 and 6 hours post-dose of each period, and at EOS.

[0179] Statistical Analyses:

[0180] Due to 2 subject drop-outs and 3 significant protocol deviations, there was some missing data, and statistical analyses were performed with an N equivalent to either 13, 14, 15, or 16.

[0181] Pharmacokinetics Analysis:

[0182] Sapropterin is an endogenous compound and was analyzed both with and without baseline correction. Therefore, for baseline correction was performed by calculating the mean plasma pre-dose levels for each subject within each period of the study using the measured concentrations at the -1, -0.5, and the 0-hour time points. The mean of these pre-dose values was the baseline for that period for that subject. The baseline value was subtracted from all subsequent measured concentrations (including 0-hour) for the same subject within the same period. Negative baseline adjusted levels was set to zero before the PK analysis. No adjustment of the pre-dose or post-dose concentrations was performed for the baseline uncorrected data.

[0183] Statistical analysis was performed using the PROC MIXED procedure in SAS. An analysis of variance (ANOVA) was performed on log-transformed AUCo-t, AUCo-inf, and Cmax parameters at the alpha level of 0.05 on uncorreted data. ANCOVA (Analysis of CoVariance) was performed on log-transformed AUCo-t, AUCo-inf, and Cmax parameters at the alpha level of 0.05 for the baseline-corrected analysis, using the actual total dose included in the ANOVA statistical model as a covariate. The ratio of geometric means (A / D, B / D, C / D, B / C, A / C, and B / A) and 90% confidence interval (CI) for the ratio of geometric means, based on least-squares means from the ANOVA of the log-transformed data, was calculated for AUCo-t, AUCo-inf, and Cmax.

[0184] Safety and Tolerability Analysis:

[0185] Safety and tolerability of sapropterin dihydrochloride were evaluated through the assessment of AEs (i.e., seriousness, severity, relationship to the study treatment, outcome, duration, and management), vital signs, 12-lead ECGs, clinical laboratory tests, and physical examinations. Treatment-emergent adverse events (TEAEs) were tabulated by treatment. Safety and tolerability data were reported using descriptive statistics.

[0186] Results and Conclusions:

[0187] Figures 1 and 2 provide the uncorrected and corrected mean plasma concentrations, respectively, of Treatment A, Treatment B, Treatment C, and Treatment D over time.

[0188] Table 2 provides the AUCt, AUCinf, and Cmax of Treatment C and Treatment D based on an ANOVA analysis of the uncorrected plasma sapropterin levels.Table 2

[0189] Table 3 provides the AUCt, AUCinf, and Cmax of Treatment C and Treatment D based on an ANCOVA analysis of the corrected plasma sapropterin levels.Table 3

[0190] Table 4 provides the AUCt, AUCinf, and Cmax of Treatment B and Treatment D based on an ANOVA analysis of the uncorrected plasma sapropterin levels.Table 4

[0191] Table 5 provides the AUCt, AUCinf, and Cmax of Treatment B and Treatment D based on an ANCOVA analysis of the corrected plasma sapropterin levels.Table 5

[0192] Table 6 provides the AUCt, AUCinf, and Cmax of Treatment B and Treatment C based on an ANOVA analysis of the uncorrected plasma sapropterin levels.Table 6

[0193] Table 7 provides the AUCt, AUCinf, and Cmax of Treatment B and Treatment C based on an ANCOVA analysis of the corrected plasma sapropterin levels.Table 7

[0194] Table 8 provides the AUCt, AUCinf, and Cmax of Treatment B and Treatment A based on an ANOVA analysis of the uncorrected plasma sapropterin levels.Table 8

[0195] Table 9 provides the AUCt, AUCinf, and Cmax of Treatment B and Treatment A based on an ANCOVA analysis of the corrected plasma sapropterin levels.Table 9

[0196] Table 10 provides the AUCt, AUCinf, and Cmax of Treatment A and Treatment D based on an ANOVA analysis of the uncorrected plasma sapropterin levels.Table 10

[0197] Table 11 provides the AUCt, AUCinf, and Cmax of Treatment A and Treatment D based on an ANCOVA analysis of the corrected plasma sapropterin levels.Table 11

[0198] Table 12 provides data for plasma baseline-corrected sapropterin pharmacokinetic parameters (potency corrected).Table 12CoefficientGeometric Arithmetic Standard of VariationParameter Trt Mean Mean Deviation (%) Median Minimum Maximum NAUCt A 782.01 880.80 509.26 57.82 669.42 434.80 2075.16 16(hr*ng / mL) B 706.50 738.82 237.34 32.12 680.86 432.53 1273.15 16C 701.71 735.94 241.45 32.81 720.85 440.45 1254.77 14D 735.05 753.88 170.68 22.64 782.38 448.20 1111.90 14AUCinf A 792.32 889.71 506.98 56.98 679.66 441.91 2078.55 16(hr*ng / mL) B 734.83 767.02 239.64 31.24 704.57 434.08 1305.47 15C 704.17 738.87 248.46 33.63 713.23 470.04 1264.51 13D 745.32 764.16 170.77 22.35 786.60 453.46 1112.17 14Residual A 0.74 1.22 1.09 88.92 1.00 0.03 3.83 16Area(%) B 0.95 1.46 1.12 76.74 1.18 0.08 3.72 15C 1.12 1.70 1.56 91.57 1.24 0.07 5.94 13D 0.80 1.40 1.27 90.60 0.90 0.03 3.87 14CmMA 133.53 158.77 112.47 70.84 118.46 68.50 423.21 16(ng / mL) B 106.35 118.44 60.13 50.77 104.89 54.32 247.18 16C 100.89 113.03 55.95 49.50 104.46 44.38 230.34 14D 123.34 128.70 37.64 29.25 132.40 68.05 204.01 14Tmax A 3.44 3.81 1.37 35.90 4.25 0.63 5.66 16(hr) B 5.14 5.34 1.80 33.66 4.72 4.25 11.32 16C 5.45 5.67 1.94 34.26 4.75 4.25 11.32 14D 4.92 4.94 0.38 7.68 4.89 4.60 5.64 14Tiag A 0.31 0.02 0.08 400.00 0.00 0.00 0.31 16(hr) B 0.94 0.06 0.24 400.00 0.00 0.00 0.94 16Table 12CoefficientGeometric Arithmetic Standard of VariationParameter Trt Mean Mean Deviation (%) Median Minimum Maximum NC 0.94 0.07 0.25 374.17 0.00 0.00 0.94 14D 0.00 0.00 0.00 0.00 0.00 14TIM A 3.16 3.35 1.23 36.62 3.00 1.52 6.40 16(hr) B 2.97 3.07 0.84 27.27 3.02 1.87 4.72 15C 2.90 2.98 0.70 23.42 2.95 1.81 4.38 13D 3.32 3.45 1.06 30.58 3.13 1.83 6.16 14Kei A 0.1952 0.2068 0.0736 35.58 0.2071 0.0965 0.4058 16(1 / hr) B 0.2075 0.2145 0.0568 26.48 0.2040 0.1308 0.3303 15C 0.2125 0.2182 0.0536 24.55 0.2089 0.1407 0.3414 13D 0.2184 0.2272 0.0673 29.62 0.2314 0.1177 0.3970 14TLIN A 7.06 7.99 3.12 39.07 7.55 0.94 11.32 16(hr) B 7.39 7.83 2.76 35.19 7.55 4.72 11.35 15C 6.78 7.26 2.90 40.03 5.66 4.72 11.32 13D 7.79 8.44 3.46 41.03 6.13 5.11 12.29 14R2A 0.9271 0.9273 0.0189 2.04 0.9351 0.8777 0.9432 16B 0.9251 0.9253 0.0168 1.82 0.9355 0.8990 0.9432 15C 0.9130 0.9135 0.0304 3.32 0.9234 0.8264 0.9423 13D 0.9874 0.9881 0.0395 4.00 0.9990 0.8947 1.0220 14Ct A 1.29 1.57 0.89 56.42 1.53 0.20 3.19 16(ng / mL) B 1.74 2.36 1.58 66.85 2.44 0.26 5.05 16C 1.87 2.28 1.25 55.03 2.03 0.24 4.42 14D 1.25 1.83 1.51 82.33 1.23 0.11 4.94 14LQCT A 22.08 22.18 1.89 8.52 22.64 15.09 22.72 16(hr) B 22.66 22.66 0.03 0.15 22.64 22.64 22.77 16C 22.64 22.64 0.01 0.03 22.64 22.64 22.66 14D 24.55 24.55 0.02 0.09 24.54 24.54 24.61 14Cl / F A 824.3 908.5 368.7 40.59 1021.3 344.4 1436.7 16(L / hr) B 883.7 908.6 213.1 23.45 899.1 562.4 1230.2 15C 939.2 975.8 286.4 29.34 897.4 623.1 1514.7 13D 1026.6 1057.2 270.9 25.63 970.9 692.3 1550.9 14Vz / F A 3983.3 4810.6 2588.8 53.81 4752.0 800.8 9067.7 16(L) B 4017.9 4194.9 1235.9 29.46 4214.3 2476.3 6611.8 15C 4169.3 4563.2 2201.5 48.24 4148.9 2503.5 10152.9 13D 4805.6 5158.4 2031.2 39.38 4815.4 2178.8 10062.4 14TLIN = start time for linear regressionR2= coefficient of determination for regression analysis Ct = last measurable concentration value at LQCT. This value was used for the extrapolation to infinity.LQCT = time of the last quantifiable concentrationTreatment A (Test Product): Sapropterin dihydrochloride 100 mg / mL oral suspension, administered without water under fasting conditionsTreatment B (Test Product): Sapropterin dihydrochloride 100 mg / mL oral suspension, administered without water under fed conditionsTreatment C (Test Product): Sapropterin dihydrochloride 100 mg / mL oral suspension, administered with water under fed conditionsTreatment D (Reference Product): Kuvan® (sapropterin dihydrochloride) 100 mg powder for oral solution, dissolved in water and administered under fed conditions,

[0199] Table 13 provides data for the increased sapropterin exposure in Treatment A relative to Treatments B, C, and D.Table 13

[0200] As shown by the above data, Treatments B (1 x 10 mg / kg dose sapropterin dihyrdrochloride oral suspension 100 mg / mL administered without water under fed conditions) and C (1 x 10 mg / kg dose sapropterin dihydrochloride oral suspension 100 mg / mL administered with a glass of water under fed conditions) demonstrated similar sapropterin bioavailiabity compared to Treatment D (1 x 10 mg / kg dose of 100 mg sapropterin dihydrochloride powder for oral solution dissolved in 120 mL (± 3 mL) of water) based on AUCt, AUCinf, and Cmax.

[0201] Treatment A (1 x 10 mg / kg dose of sapropterin dihydrochloride oral suspension 100 mg / mL administered without water under fasting conditions) increased sapropterin bioavailiabity compared to Treatments B (1 x 10 mg / kg dose sapropterin dihyrdrochloride oral suspension 100 mg / mL administered without water under fed conditions) and C (1 x 10 mg / kg dose sapropterin dihydrochloride oral suspension 100 mg / mL administered with a glass of water under fed conditions) based on AUCt, AUCinf, and Cmax.

[0202] Treatment A (1 x 10 mg / kg dose of sapropterin dihydrochloride oral suspension 100 mg / mL administered without water under fasting conditions) increased sapropterin bioavailiabity compared to Treatment D (1 x 10 mg / kg dose of 100 mg sapropterin dihydrochloride powder for oral solution dissolved in 120 mL (± 3 mL) of water) based on AUCt, AUCinf, and Cmax.

Claims

WHAT IS CLAIMED IS:

1. A method of treating phenylketonuria or hyperphenylalaninemia in a subject in need thereof, the method comprising: orally administering to the subject about 5 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

2. The method of claim 1, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

3. The method of claim 1 or claim 2, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 15% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

4. The method of any one of claims 1-3, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 5% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

5. The method of any one of claims 1-4, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

6. The method of any one of claims 1-5, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

7. The method of any one of claims 1-6, wherein the oil comprises about 50% to about 80% caprylic acid triglyceride and about 20% to about 50% capric acid triglyceride8. The method of any one of claims 1-7, wherein the sapropterin dihydrochloride suspension further comprises a thickening agent.

9. The method of claim 8, wherein the thickening agent is colloidal silica.

10. The method of any one of claims 1-9, wherein the sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL.

11. The method of any one of claims 1-10, wherein the sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL.

12. The method of any one of claims 1-11, wherein the subject is orally administered about 10 mg / kg of sapropterin dihydrochloride.

13. A method of treatment for phenylketonuria or hyperphenylalaninemia in a subject in need thereof, comprising:orally administering to the subject about 5 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when orally administered without water to the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

14. The method of claim 13, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

15. The method of claim 13 or claim 14, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

16. The method of any one of claims 13-15, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

17. The method of any one of claims 13-16, wherein the sapropterin dihydrochloride suspension, when orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting fromorally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

18. The method of any one of claims 13-17, wherein the oil comprises about 50% to about 80% caprylic acid triglyceride and about 20% to about 50% capric acid triglyceride19. The method of any one of claims 13-18, wherein the sapropterin dihydrochloride suspension further comprises a thickening agent.

20. The method of claim 19, wherein the thickening agent is colloidal silica.

21. The method of any one of claims 13-20, wherein the sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL.

22. The method of any one of claims 13-21, wherein the sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL.

23. The method of any one of claims 13-22, wherein the subject is orally administered about 10 mg / kg of sapropterin dihydrochloride.

24. A dosage form comprising: a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUC0-24 that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

25. The dosage form of claim 24, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of sapropterin powder dissolved in water.

26. The dosage form of claim 24 or claim 25, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 15% greater than a sapropterin AUC0-24 resulting from administering an equivalent amount of sapropterin powder dissolved in water.

27. The dosage form of any one of claims 24-26, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

28. The dosage form of any one of claims 24-27, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

29. The dosage form of any one of claims 24-28, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering to the subject in a fed state an equivalent amount of sapropterin powder dissolved in water.

30. The dosage form of any one of claims 24-29, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without waterto the subject in a fasted state, provides a sapropterin AUCo-24that is at least about 5% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

31. The dosage form of any one of claims 24-30, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin AUCo-24that is at least about 10% greater than a sapropterin AUC0-24 resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

32. The dosage form of any one of claims 24-31, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 10% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

33. The dosage form of any one of claims 24-32, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 15% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

34. The dosage form of any one of claims 24-33, wherein the sapropterin dihydrochloride suspension, when about 5 mg / kg to about 20 mg / kg is orally administered without water to a subject in a fasted state, provides a sapropterin Cmax that is at least about 20% greater than a sapropterin Cmax resulting from orally administering an equivalent amount of the sapropterin dihydrochloride suspension with or without water to the subject in a fed state.

35. The dosage form of any one of claims 24-34, wherein the oil comprises about 50% to about 80% caprylic acid triglyceride and about 20% to about 50% capric acid triglyceride.

36. The dosage form of any one of claims 24-35, wherein the sapropterin dihydrochloride suspension further comprises a thickening agent.

37. The dosage form of any one of claims 24-36, wherein the thickening agent is colloidal silica.

38. The dosage form of any one of claims 24-37, wherein the sapropterin dihydrochloride is suspended in the oil at a concentration of about 50 mg to about 150 mg per mL.

39. The dosage form of any one of claims 24-38, wherein the sapropterin dihydrochloride is suspended in the oil at a concentration of about 100 mg per mL.

40. The dosage form of any one of claims 24-39, wherein the subject is orally administered about 10 mg / kg of sapropterin dihydrochloride.

41. A method of treatment for phenylketonuria or hyperphenylalaninemia in a subject in need thereof, comprising: orally administering to the subject without food, water, or without food and water, about 1 mg / kg to about 20 mg / kg of a sapropterin dihydrochloride suspension comprising sapropterin dihydrochloride and a pharmaceutically acceptable oil, wherein sapropterin dihydrochloride is suspended in the oil at a concentration of about 10 mg to about 250 mg per mL.

42. The method of claim 41, wherein the subject is orally administered about 5 mg / kg to about 20 mg / kg of of sapropterin dihydrochloride.

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