Sephience (sepiapterin)

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Sepiapterin and its active metabolite, tetrahydrobiopterin (BH4), are substrates and inhibitors of breast cancer resistance protein (BCRP) in vitro. Coadministration of sepiapterin with curcumin, a BCRP inhibitor, increased BH4exposure by approximately 20-24% after a single dose; coadministration with rosuvastatin, a BCRP substrate, did not affect rosuvastatin exposure.

Sepiapterin showed no apparent in vitro inhibition of cytochrome P-450 (CYP) enzymes including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and no induction of CYP1A2, CYP2B6, or CYP3A4. Although BH4 was not directly assessed as a CYP inhibitor or inducer, clinically relevant CYP-mediated drug interactions are not expected.

Sepiapterin is not a P-glycoprotein substrate; BH4 is a P-glycoprotein substrate and inhibitor in vitro. Clinically relevant P-glycoprotein-mediated interactions are not expected.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Sepiapterin/Dihydrofolate Reductase Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dihydrofolate reductase (DHFR) inhibitors (e.g., trimethoprim, methotrexate, trimetrexate, pemetrexed, pralatrexate) may decrease conversion of sepiapterin to its active metabolite, tetrahydrobiopterin (BH4).(1)

CLINICAL EFFECTS: Concurrent use of DHFR inhibitors and sepiapterin may result in decreased levels of BH4 (the active metabolite of sepiapterin) and reduced or loss of efficacy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The concurrent use of DHFR inhibitors and sepiapterin should be avoided. If concurrent use cannot be avoided, monitor blood phenylalanine levels.(1)

DISCUSSION: Sepiapterin is metabolized by dihydrofolate reductase (DHFR) to its pharmacologically active form, tetrahydrobiopterin (BH4). Inhibitors of DHFR may reduce the metabolism of sepiapterin to BH4.(1) DHFR inhibitors linked to this monograph include: methotrexate, pemetrexed, pralatrexate, raltitrexed, trimethoprim, and trimetrexate.

There are no moderate interactions for this drug.

*None

There are no contraindication contraindications for this drug.

• Hemorrhage

There are no moderate contraindications for this drug.

Most common adverse reactions with sepiapterin (>=2% and greater than placebo) were diarrhea, headache, abdominal pain, hypophenylalaninemia, feces discoloration, and oropharyngeal pain.

There are no severe adverse reactions for this drug.

Less Frequent

• Acute abdominal pain
• Diarrhea
• Discolored feces
• Headache disorder
• Hypophenylalaninemia
• Pain in oropharynx

Rare or Very Rare

• Hemorrhage

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Safety and effectiveness of sepiapterin have been established in pediatric patients >=1 month of age with PKU. Use is supported by one adequate and well-controlled trial in 63 pediatric patients 1 to <17 years of age and additional safety and efficacy data from an ongoing open-label trial in adult and pediatric patients.

Safety and effectiveness have not been established in pediatric patients <1 month of age.

Available pregnancy data are insufficient to evaluate the risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes with sepiapterin. Uncontrolled blood phenylalanine levels before and during pregnancy are associated with adverse pregnancy and fetal outcomes. In animal studies, oral sepiapterin given during organogenesis produced no adverse developmental effects at exposures up to 9 times the human exposure in pregnant rats and up to 6 times the human exposure in pregnant rabbits at the maximum recommended human dose.

Uncontrolled blood phenylalanine levels before and during pregnancy are associated with adverse pregnancy and fetal outcomes. To reduce the risk of hyperphenylalaninemia related fetal harm, maintain blood phenylalanine concentrations between 120-360 micromol/L during pregnancy and for 3 months before conception.

Data from the Maternal Phenylketonuria Collaborative Study showed that uncontrolled phenylalanine concentrations >600 micromol/L during pregnancy were associated with increased risks of major birth defects, including microcephaly and major cardiac malformations, intrauterine growth restriction, and future intellectual disability with low IQ.

Patients who may become pregnant require preconception counseling and close monitoring because elevated maternal phenylalanine is teratogenic to the fetal brain and heart.

There are no data on sepiapterin in human or animal milk, its effects on the breastfed infant, or its effects on milk production. Consider the benefits of breastfeeding, the mother's need for sepiapterin, and potential risks to the breastfed infant from sepiapterin or the underlying maternal condition.

No dosage adjustment recommendation is provided by the manufacturer for geriatric patients; studies did not include patients >=65 years of age.

Clinical studies did not include patients >=65 years of age to determine whether they respond differently from younger adults.