No QTcF Prolongation with Sepiapterin: Results From a Thorough QT Study in Healthy Subjects at Therapeutic and Supratherapeutic Doses.
Sepiapterin and its major metabolite 6R‐L‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH4) bind to distinct variants of phenylalanine hydroxylase (PAH), which converts excess phenylalanine to tyrosine, thereby stabilizing, enhancing, and prolonging PAH activity. Sepiapterin was recently approved in Europe...
| Publicado en: | Journal of Clinical Pharmacology Vol. 66; no. 1; pp. 1 - 13 |
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| Autores principales: | , , , , , , , |
| Formato: | research tables/charts randomized controlled trial Journal Article |
| Publicado: |
Wiley-Blackwell
Jan2026
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=191106137&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 191106137 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00912700 5WH jtl: Journal of Clinical Pharmacology issn: 00912700 maglogo: Y pubinfo: dt: Jan2026 vid: 66 iid: 1 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 191106137 191106137 191106137 10.1002/jcph.70149 191106137 ppf: 1 ppct: 12 formats: tig: atl: No QTcF Prolongation with Sepiapterin: Results From a Thorough QT Study in Healthy Subjects at Therapeutic and Supratherapeutic Doses. aug: au: Gao, Lan Xue, Hongqi Darpo, Borje Ingalls, Kimberly Kaushik, Diksha Smith, Neil Kong, Ronald Golden, Lee affil: PTC Therapeutics, Inc., Warren NJ,, USA sug: subj: Heterocyclic Compounds Administration and Dosage Heterocyclic Compounds Adverse Effects Long QT Syndrome Risk Factors Cardiovascular Risk Factors Evaluation Risk Assessment Dose-Response Relationship, Drug Heterocyclic Compounds Pharmacokinetics Metabolites Evaluation Human Randomized Controlled Trials Comparative Studies Random Assignment Placebos Administration and Dosage Male Female Adult Middle Age Funding Source Quinolines Administration and Dosage Heart Conduction System Drug Effects Heart Rate Drug Effects Heterocyclic Compounds Blood Administration, Oral Crossover Design United States Electrocardiography Patient Safety Chromatography, High Pressure Liquid Descriptive Statistics Confidence Intervals Data Analysis Software Regression Electrocardiography, Ambulatory Dietary Fats Meals Solubility Adult: 19-44 years Middle Aged: 45-64 years Male Female ab: Sepiapterin and its major metabolite 6R‐L‐erythro‐5,6,7,8‐tetrahydrobiopterin (BH4) bind to distinct variants of phenylalanine hydroxylase (PAH), which converts excess phenylalanine to tyrosine, thereby stabilizing, enhancing, and prolonging PAH activity. Sepiapterin was recently approved in Europe and the USA for the treatment of hyperphenylalaninemia patients with phenylketonuria, an inherent metabolic disease caused by PAH deficiency. A thorough QT study of sepiapterin in healthy volunteers at therapeutic (60 mg/kg) and supratherapeutic (120 mg/kg) doses was conducted to assess potential cardiovascular risks. Thirty‐two participants were randomized into one of 12 sequences and received single doses of sepiapterin (60 or 120 mg/kg), moxifloxacin 400 mg, or placebo in separate periods. Sepiapterin had no effect on heart rate or cardiac conduction (PR/QRS interval). Saturable sepiapterin absorption was observed, which resulted in less than dose‐proportional increase of sepiapterin and BH4 and limited the maximum plasma concentrations clinically achievable. Using concentration‐QT analysis, the placebo‐corrected change from baseline in QT interval corrected using Fridericia's formula (ΔΔQTcF) was −2.11 (90% CI: −3.44, −0.79) ms at geometric mean baseline‐corrected BH4 Cmax (728 ng/mL) and −1.9 (−3.25, −0.56) ms at sepiapterin Cmax (2.08 ng/mL) at the supratherapeutic dose of 120 mg/kg. An effect on ΔΔQTcF exceeding 10 ms was excluded within the observed concentration range of baseline‐corrected BH4 up to 1088 ng/mL and sepiapterin up to 5.77 ng/mL. The consistency of results from this study and the previous concentration‐QTc analysis based on pooled data from multiple clinical studies demonstrated the reliability of using concentration‐QTc for assessing cardiovascular risks in early clinical development. pubtype: Academic Journal doctype: research tables/charts randomized controlled trial Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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