Ataluren Pharmacokinetics in Healthy Japanese and Caucasian Subjects

Abstract

To evaluate the potential for ethnicity‐related differences in ataluren pharmacokinetics (PK) and safety, a phase 1 single‐dose study was conducted in 48 healthy (24 Japanese and 24 Caucasian subjects), nonsmoking male volunteers who were equally divided into 3 cohorts of oral doses at 5, 10, and 20 mg/kg. Blood samples were collected until 48 hours postdose. PK results demonstrated rapid absorption of ataluren, with peak plasma levels (C max ) being attained between 0.875 and 2.5 hours after dosing. The mean C max and area under the concentration‐time curve (AUC (0‐last) ) increased with each increasing dose level in both Japanese and Caucasian subjects. Although the C max was similar across all subjects at each dose regardless of ethnicity, Japanese subjects had a mean AUC (0‐last) approximately 14% to 34% lower than that of Caucasian subjects across the 3 dose levels. This difference was likely due to the higher variability of AUC values in Caucasian subjects and the relatively small study population. In conclusion, similar ataluren PK profiles were observed in healthy Japanese and Caucasian subjects following single oral administration of ataluren at all dose levels.

Safety issues and harmful pharmacological interactions of nutritional supplements in Duchenne muscular dystrophy: considerations for Standard of Care and emerging virus outbreaks

“…DMD patients treated with drugs or other phenol-based nutraceuticals metabolized by UGT may, therefore, incur in unwanted interactions with GTE [128]. For instance, UGT1A9 is also the major enzyme that metabolizes ataluren, a novel drug recently approved for DMD to promote ribosomal read-through for patients with premature stop codon mutations [31,129]. Its metabolism could be delayed or impaired by GTE, with potential toxic effects.…”

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

“…Nonsense suppression therapy used in non-hematologic genetic diseases such as DMD and CF. Ataluren (Translarna ® ) is an approved drug for the treatment of DMD and, importantly, several Phase II/III clinical studies reported very low toxicity of ataluren even in pediatric patients aged two and older [189][190][191][192][193][194]219].…”

Deciphering the molecular mechanism of stop codon readthrough

“…This molecule, which can rescue expression of genes carrying UGA, UAG, or UAA nonsense mutations, has a mode of action that remains to be clarified, but might either target the A site of the ribosome as do aminoglycosides or interact directly with the stop codon to promote readthrough (Roy et al ., 2016; Tutone et al ., 2019). Even though the efficacy of this molecule seems too low for clinical development aimed at treating, for example, cystic fibrosis or Duchenne muscular dystrophy (Kerem et al ., 2014; Haas et al ., 2015), it does illustrate the need to identify readthrough molecules that might enhance the treatment of nonsense‐mutation‐related genetic diseases (Kong et al ., 2019). Among other readthrough molecules, a dipeptide‐like hydrazide antibiotic negamycin, originally purified from Streptomyces purpeofuscus , appears more potent than aminoglycosides and less toxic, as do negamycin derivatives (Arakawa et al ., 2003; Taguchi et al ., 2014; Hamada et al ., 2019) (Table 2).…”