sepiapterin

Action and Spectrum

Sepiapterin serves as a biosynthetic precursor to tetrahydrobiopterin (BH₄), an essential cofactor required for the enzymatic activity of phenylalanine hydroxylase (PAH). It functions as a dual pharmacological chaperone, with both sepiapterin and its metabolite BH₄ exhibiting distinct binding affinities to various PAH isoforms, including those typically unresponsive to BH₄ alone in phenylketonuria (PKU).

This dual mechanism supports proper folding and stabilization of the dysfunctional PAH enzyme. By facilitating the accumulation of intracellular BH₄ and improving the structural stability of misfolded PAH, sepiapterin enhances enzymatic function, thereby promoting the breakdown of phenylalanine and leading to a reduction in elevated blood phenylalanine concentrations.

Drug Interaction

Adverse Reaction

Frequency defined:

Very Common (≥1/10):

Upper respiratory tract infection

Headache

Diarrhea

Abdominal pain

Common (≥1/100 to <1/10):

Discolored feces

Hypophenylalaninaemia

Black Box Warning

No black box warning found

Contraindication / Caution

Contraindication

Hypersensitivity to sepiapterin or excipients

Cautions

Renal or hepatic impairment (not studied)

Concomitant DHFR inhibitors or vasodilators

Fructose intolerance (contains isomalt)

Pregnancy / Lactation

Pregnancy consideration:

Data on the use of sepiapterin during pregnancy are limited.

Lactation:

It is unclear if sepiapterin or its metabolites pass into human milk, so potential risk to infants cannot be ruled out.

Pregnancy category:

Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester.

Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women.

Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women

Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits.

Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women.

Category N: There is no data available for the drug under this category.

Pharmacology

Pharmacology

In individuals with phenylketonuria (PKU), the body lacks proper function of an enzyme responsible for metabolizing phenylalanine, an amino acid derived from dietary protein. As a result, phenylalanine accumulates to harmful levels in the blood. Sepiapterin (Sephience) supports the activation of this deficient enzyme, enhancing its ability to break down phenylalanine. By improving enzymatic function, Sephience helps reduce elevated phenylalanine concentrations and supports better metabolic control in patients with PKU.

Pharmacodynamics

Sepiapterin is a precursor of tetrahydrobiopterin (BH₄), a key cofactor for phenylalanine hydroxylase (PAH). By increasing intracellular BH₄ levels, sepiapterin enhances PAH enzyme activity, promoting the breakdown of phenylalanine and reducing its accumulation in the blood—especially in patients with PKU.

Pharmacokinetics

Absorption

After oral administration, sepiapterin is rapidly absorbed, reaching peak plasma levels within 1 to 3 hours. These levels decrease quickly and generally become undetectable within 12 hours. In a study involving a 7-day regimen of 60 mg/kg/day taken with a high-fat, high-calorie meal, the peak plasma concentration (Cmax) reached about 2.80 ng/mL. There was no evidence of drug accumulation with repeated dosing. Sepiapterin is extensively converted in the body to its active form, tetrahydrobiopterin (BH₄), which has a half-life of approximately 5 hours. Increases in BH₄ plasma levels (Cmax and AUC₀–₂₄h) were dose-dependent but not strictly proportional beyond 20 mg/kg.

Food intake significantly enhances BH₄ absorption. A low-fat meal increased BH₄ exposure by approximately 1.6–1.7 times, whereas a high-fat, high-calorie meal resulted in a 2.2–2.8 fold rise in BH₄ Cmax and AUC compared to fasting. Sepiapterin may be administered with any meal, at the same time each day.

Distribution

Both sepiapterin and BH₄ exhibit low plasma protein binding. In vitro assessments showed sepiapterin binds to proteins at around 15%, while BH₄ binding ranged from 24% to 41%, depending on concentration. Upon repeated dosing, BH₄ was detected in cerebrospinal fluid, indicating central nervous system penetration.

Metabolism

Sepiapterin is converted to BH₄ through a unidirectional two-step process involving sepiapterin reductase (SR) or carbonyl reductase, followed by dihydrofolate reductase (DHFR). The resulting BH₄ participates in enzymatic reactions as a cofactor for PAH, tyrosine hydroxylase, and nitric oxide synthase, among others. BH₄ metabolism mimics the endogenous pathway, where intermediate metabolites like quinonoid dihydrobiopterin may be recycled via pterin-4α-carbinolamine dehydratase and dihydropteridine reductase. Following radiolabeled sepiapterin administration, extensive metabolic transformation was observed, involving pathways like oxidation, methylation, and deamination.

Eimination/Excretion

Sepiapterin undergoes extensive metabolism, and its breakdown products are primarily eliminated via the feces. The plasma concentration of the parent drug drops rapidly after reaching Cmax, and BH₄ follows a mono-exponential decay with a terminal half-life of around 5 hours. A radiolabeled study indicated that approximately 6.7% of the dose was recovered in urine and 26.2% in feces, with total recovery reaching nearly 33% over 10 days. Most excretion occurred within the first 48 hours. Renal clearance was calculated to be around 1.54 L/h (25.6 mL/min). In vitro data confirm that volatile metabolites may also form in the gut via microbiota activity.

Adminstartion

Sephience should be given once daily with a meal, based on mg/kg dosing. The oral powder, available in 250 mg or 1,000 mg sachets, should be mixed with water, apple juice, or soft foods like applesauce or jam before administration.

Patient Information Leaflet

Patient information leaflet

Generic Name: sepiapterin

Pronounced: se-pi-AP-ter-in

Why do we use sepiapterin?

Sepiapterin is indicated for the treatment of hyperphenylalaninaemia (HPA) in both adult and pediatric patients with phenylketonuria (PKU). PKU is a genetic disorder characterized by the inability to break down phenylalanine, an amino acid that can accumulate to toxic levels in the body if not properly metabolized. This treatment is particularly beneficial for patients with PAH variants that may not respond adequately to traditional BH₄ therapy.