Chemical formula: C₁₅H₉FN₂O₃ Molecular mass: 284.242 g/mol PubChem compound: 11219835
A nonsense mutation in DNA results in a premature stop codon within an mRNA. This premature stop codon in the mRNA causes disease by terminating translation before a full-length protein is generated. Ataluren enables ribosomal readthrough of mRNA containing such a premature stop codon, resulting in production of a full-length protein.
Nonclinical in vitro experiments in nonsense mutation cellular assays and fish larvae cultured in an ataluren solution have shown that ataluren enabled ribosomal readthrough with a bell-shaped (inverted-U shaped) concentration-response relationship. It is hypothesised that the in vivo dose response relationship may also be bell-shaped, but in vivo data were too limited to confirm this hypothesis in a mouse model for nmDMD and in humans.
Nonclinical in vitro studies suggest that continuous exposure to ataluren may be important for maximizing activity and that effects of the active substance on ribosomal read-through of premature stop codons reverse shortly after withdrawal of ataluren.
Administration of ataluren on a body weight-adjusted basis (mg/kg) resulted in similar steady-state exposures (AUC) among children and adolescents with nmDMD over a broad range of body weights. Although ataluren is practically insoluble in water, ataluren is readily absorbed after oral administration as a suspension.
Peak plasma levels of ataluren are attained approximately 1.5 hours after dosing in subjects who received medicinal product within 30 minutes of a meal. Based on the urinary recovery of radioactivity in a single-dose study of radiolabelled ataluren, the oral bioavailability of ataluren is estimated to be ≥55%. Ataluren plasma concentrations at steady state increase proportionally with increasing dose. Steady-state plasma concentrations are dose-proportional for ataluren doses between 10 and 50 mg/kg, and no accumulation is observed after repeated dosing.
In vitro, ataluren is 99.6% bound to human plasma proteins and the binding is independent of plasma concentration. Ataluren does not distribute into red blood cells.
Ataluren is metabolized by conjugation via uridine diphosphate glucuronosyltransferase (UGT) enzymes, predominantly UGT1A9 in liver, intestine and kidney.
In vivo, the only metabolite detected in plasma after oral administration of radio-labelled ataluren was the ataluren-O-1β-acyl glucuronide; exposure to this metabolite in humans was approximately 8% of the plasma AUC of ataluren.
Ataluren plasma half-life ranges from 2-6 hours and is unaffected either by dose or repeated administration. The elimination of ataluren is likely dependent on hepatic and renal glucuronidation of ataluren followed by renal and hepatic excretion of the resulting glucuronide metabolite.
After a single oral dose of radiolabelled ataluren, approximately half of the administered radioactive dose is recovered in the faeces and the remainder was recovered in the urine. In the urine, unchanged ataluren and the acyl glucuronide metabolite account for <1% and 49%, respectively, of the administered dose.
Steady-state plasma concentrations are dose-proportional for ataluren doses between 10 and 50 mg/kg, and no accumulation is observed after repeated dosing. Based on data in healthy volunteers, the relative bioavailability of ataluren is approximately 40% lower at steady-state than after the initial dose. The onset of reduction in relative bioavailability is estimated to occur approximately 60 hours after the first dose. The steady-state is established after approximately two weeks of thrice daily dosing.
Based on data from subjects ranging in age from 2 years to 57 years, there is no apparent effect of age on ataluren plasma exposure. Age-adjusted dosing is not required.
The pharmacokinetics of ataluren has been evaluated in study PTC124-GD-030 over a duration of 4 weeks. Ataluren plasma concentrations in patients from 2 to less than 5 years old were consistent with those seen in patients above the age of 5 years receiving the 10/10/20 mg/kg dose regimen.
Females were not studied in nmDMD clinical trials. However there were no apparent effects of gender on ataluren plasma exposure in other populations.
It is unlikely that the pharmacokinetics of ataluren are significantly affected by UGT1A9 polymorphisms in a Caucasian population. Due to the low number of other races included in the clinical studies, no conclusions can be drawn on the effect of UGT1A9 in other ethnic groups.
No dosage adjustment is required for patients with mild or moderate renal impairment. In a pharmacokinetic study in subjects with varying degrees of renal impairment, following a single dose administration, ataluren plasma exposure changed by -13%, 27%, and 61% for the mild, moderate and severe groups, respectively, and 46% for the end-stage renal disease group compared with the normal renal function group. In addition, a 3 to 8 fold increase in ataluren metabolite has been reported in patients with severe renal impairment (eGFR <30 ml/min). Following multiple dosing, the increase in ataluren and ataluren metabolite is anticipated to be higher in patients with severe renal impairment and end-stage renal disease when compared with patients with normal renal function at steady state. Patients with severe renal impairment (eGFR <30 ml/min) or end-stage renal disease should be treated with ataluren only if the anticipated clinical benefit outweighs the potential risk.
Based on a pharmacokinetic assessment conducted in groups with either mild, moderate or severe hepatic impairment versus a control group of healthy subjects, no dose adjustment is required for patients with any degree of hepatic impairment. No apparent differences of the total ataluren exposure in the control, mild, and severe hepatic impairment groups were observed. An approximately 40% decrease of mean total ataluren exposure in the moderate hepatic impairment group versus the control group was noted probably due to the small sample size and variability.
There were no apparent differences in either steady-state relative bioavailability or apparent clearance due to loss of ambulation. No dosing adjustment is needed for patients who are becoming non-ambulatory.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and genotoxicity.
A standard package of reproduction toxicity studies was available. No effects on male and female fertility were observed, but effects of early juvenile treatment on fertility during adulthood were not investigated. In rats and rabbits embryo-foetal toxicity (e.g. increased early resorptions, post-implantation loss, decreased viable foetuses) and signs of delayed development (increased skeletal variations) were found in the presence of maternal toxicity. Exposure at the no observed adverse effect level (NOAEL) was similar to (rabbit) or 4 times (rat) the systemic exposure in humans (40 mg/kg/day). Placental transfer was shown of radiolabelled ataluren in rats. At a single tested, relatively low, maternal dose of 30 mg/kg, the concentration of foetal radioactivity was ≤27% of the maternal concentration. In the rat pre/postnatal developmental toxicity study, at exposure about 5 times human exposure, significant maternal toxicity as well as effects on offspring body weight and development of ambulatory activity were observed. The maternal systemic exposure at the no observed effect level (NOEL) for neonatal toxicity was about 3 times human exposure. At a single, relatively low, maternal dose of 30 mg/kg radiolabelled ataluren, the highest measured concentration of radioactivity in rat milk was 37% of the maternal plasma concentration. Presence of radioactivity in pup plasma confirmed absorption from the milk by the pups.
Renal toxicity (nephrosis in the distal nephron) occurred in repeat oral dose studies in mice at systemic exposure equivalent to 0.3 times the steady state AUC in patients administered ataluren at respective morning, midday, and evening doses of 10-, 10-, 20-mg/kg and higher.
In a 26-week transgenic mouse model for carcinogenicity, no evidence of carcinogenicity was found. In a 2-year rat carcinogenicity study, one case of hibernoma was found. In addition, at exposure much higher than in patients an increase of (rare) urinary bladder tumours was found. Significance of the urinary bladder tumours for humans is considered unlikely.
One out of two 26-week rat repeat dose studies, initiated in 4-5 weeks old rats, showed a dose related increase of the incidence of malignant hibernoma, a rare tumour in rats. In addition, one case of malignant hibernoma was found at the highest dose in a 2-year rat carcinogenicity study. Background incidence of this tumour type in rats as well as humans is very low and the mechanism causing these tumours in the rat studies (including its relation to ataluren treatment) is unknown. The significance for humans is not known.
A 1-year study in 10-12 weeks old dogs demonstrated findings in the adrenal gland (focal inflammation and degeneration in the glucocorticoid-producing regions of the cortex) and a mild compromise of cortisol production after exogenous stimulation with adrenocorticotropic hormone. These findings were seen in dogs at systemic exposure equivalent to 0.8 times the steady state AUC in patients administered ataluren at respective morning, midday, and evening doses of 40 mg/kg/day and higher. In a rat distribution study a high adrenal concentration of ataluren was observed.
In addition to the above mentioned effects, several other less adverse effects were found in the repeat dose studies; in particular decreased body weight gain, food intake and increased liver weight without a histological correlate and of unclear clinical significance. Also rat and dog studies showed changes in plasma lipid (cholesterol and triglycerides) suggestive of changes in fat metabolism.
No adverse findings, including in the adrenal gland, were observed in a 3-month study in neonatal dogs (1-week old) followed by a 3-month recovery period up to steady state systemic exposures equivalent to the steady state AUC in patients. In preliminary studies in neonatal dogs (1-week old), initial systemic exposures equivalent to 5-10 times the steady state AUC in patients were not tolerated in some animals.
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