ot studied in end-stage renal disease patients requiring dialysis.
Hepatic impairment
In a hepatic impairment study conducted at a single dose of 500 mg, exposures to the parent compound and its active metabolite (based on AUC0-tlast) were higher in patients with mild hepatic impairment (2.3- and 2.4-fold, respectively) and in patients with moderate hepatic impairment (3.2- and 3.5-fold, respectively) compared with healthy subjects. Administration of a single dose of 500 mg was well tolerated. The use of telotristat is not recommended in patients with severe hepatic impairment as no data are available.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenicity potential, and reproductive toxicity. A two-year carcinogenicity study is ongoing.
In rats, decrease in brain serotonin (5-HT) was observed at doses≥1,000 mg/kg/day of telotristat etiprate per os. Brain 5-HIAA levels were unchanged at all doses of telotristat ethyl examined. This is approximately 14 times the human exposure (AUC total) at the maximum recommended human dose (MRHD) of 750 mg/day for the active metabolite LP-778902.
In a 26-week repeat-dose toxicity study in rats, a No-Observed Adverse Effect Level (NOAEL) of 50 mg/kg/day was determined. This is approximately 0.4 times the human exposure (AUC total) at MRHD of 750 mg/day for the active metabolite LP-778902. At doses of 200 and 500 mg/kg/day degeneration/necrosis in the non-glandular and/or glandular portions of the stomach and/or increased protein droplets in the glandular portions were observed. The microscopic changes in the gastrointestinal tract reversed with a 4-week recovery period. Relevance of these gastrointestinal findings to humans is unknown.
In dogs, decreases in brain 5-HT and 5-HIAA levels were observed at dose of 200 mg/kg/day and 30 mg/kg/day of telotristat etiprate per os, respectively. This is approximately 21 times the human exposure (AUC total) at MRHD of 750 mg/day for the active metabolite LP-778902. No decrease in brain 5-HT and 5-HIAA levels were observed after intravenous application of active metabolite. The clinical significance of the decrease in brain 5-HIAA with or without a concomitant decrease in brain 5-HT is unknown.
In a 39-week repeat-dose toxicity study in dogs, NOAEL of 300 mg/kg/day was determined. Clinical signs were limited to increase in frequency of liquid faeces at all doses. This is approximately 20 times the human exposure (AUC total) at MRHD of 750 mg/day for the active metabolite LP-778902.
In rats, there were no adverse effects on male and female fertility. Prenatal development in rats and rabbits was affected by increased prenatal lethality (increased early and late resorptions), while no adverse effects were noted on postnatal development in rats. The NOAEL for parental / maternal / prenatal and postnatal toxicity is 500 mg/kg/day in rats corresponding to 3 to 4 times the estimated human exposure (AUC0-24) of the active metabolite LP-778902 at the MRHD. In rabbits the NOAEL for maternal and prenatal toxicity is 125 mg/kg/d corresponding to 1.5 to 4 times the estimated human exposure (AUC0-24) of the active metabolite LP-778902 at the MRHD.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Lactose anhydrous
Hydroxypropylcellulose
Croscarmellose sodium
Magnesium stearate
Silica, colloidal anydrous
Fim-coating |
