Chemical formula: C₂₇H₂₆ClF₃N₆O₃ Molecular mass: 546.94 g/mol
Both the prodrug (telotristat ethyl) and its active metabolite (telotristat) are inhibitors of L-tryptophan hydroxylases (TPH1 and TPH2, the rate limiting steps in serotonin biosynthesis). Serotonin plays a critical role in regulating several major physiological processes, including secretion, motility, inflammation, and sensation of the gastrointestinal tract, and is over-secreted in patients with carcinoid syndrome. Through inhibition of peripheral TPH1, telotristat reduces the production of serotonin, thus alleviating symptoms associated with carcinoid syndrome.
In Phase 1 studies, dosing with telotristat ethyl in healthy subjects (dose range: 100 mg once daily to 500 mg tid) produced statistically significant reductions from baseline in whole blood serotonin and 24-hour urinary 5-hydroxyindoleacetic acid (u5-HIAA) compared with placebo. In patients with carcinoid syndrome, telotristat resulted in reductions in u5-HIAA. Statistically significant reductions in u5-HIAA were seen for telotristat ethyl 250 mg tid compared with placebo in both Phase 3 studies.
The pharmacokinetics of telotristat ethyl and its active metabolite have been characterised in healthy volunteers and patients with carcinoid syndrome.
After oral administration to healthy volunteers, telotristat ethyl was rapidly absorbed, and almost completely converted to its active metabolite. Peak plasma levels of telotristat ethyl were achieved in 0.53 to 2.00 hours and those of the active metabolite in 1.50 to 3.00 hours after oral administration. Following administration of a single 500 mg dose of telotristat ethyl (twice the recommended dosage) under fasted conditions in healthy subjects, the mean Cmax and AUC0-inf were 4.4 ng/mL and 6.23 ng•hr/mL, respectively for telotristat ethyl. The mean Cmax and AUC0-inf were 610 ng/mL and 2320 ng•hr/mL, respectively for telotristat.
In patients with carcinoid syndrome on long-acting SSA therapy, there was also a rapid conversion of telotristat ethyl to its active metabolite. A high variability (% CV range of 18% to 99%) in telotristat ethyl and its active metabolite parameters was observed within the overall PK. The mean PK parameters for telotristat ethyl and the active metabolite appeared unchanged between week 24 and week 48, suggesting the achievement of steady-state conditions at or prior to week 24.
In a food effect study administration of telotristat ethyl 500 mg with a high-fat meal resulted in higher exposure to the parent compound (Cmax, AUC0-tlast, and AUC0-∞ being 112%, 272%, and 264% higher, respectively compared with the fasted state) and its active metabolite (Cmax, AUC0-tlast, and AUC0-∞, 47%, 32%, and 33% higher, respectively compared with the fasted state).
Both telotristat ethyl and its active metabolite are >99% bound to human plasma proteins.
After oral administration, telotristat ethyl undergoes hydrolysis via carboxylesterases to its active and major metabolite. The only metabolite of telotristat (active metabolite) representing consistently >10% of total plasma drug-related material was its oxidative decarboxylated deaminated metabolite, LP-951757. Systemic exposure to LP-951757 was about 35% of the systemic exposure to telotristat (active metabolite) in the mass balance study. LP-951757 was pharmacologically inactive at TPH1 in vitro.
CYP2B6:
In vitro telotristat (active metabolite) caused a concentration dependent increase in CYP2B6 mRNA levels (>2-fold increase and >20% of the positive control, with a maximum observed effect similar to the positive control), suggesting possible CYP2B6 induction.
CYP3A4:
Telotristat ethyl and its active metabolite were not shown to be inducers of CYP3A4 at systemically relevant concentrations, based on in vitro findings. The potential of telotristat ethyl as an inducer of CYP3A4 was not assessed at concentrations expectable at the intestinal level, due to its low solubility in vitro.
In vitro, telotristat ethyl inhibited CYP3A4, suggesting a potential interaction with CYP3A4 substrates.
In an in vivo clinical drug-drug interaction (DDI) study with midazolam (a sensitive CYP3A4 substrate), following administration of multiple doses of telotristat ethyl, the systemic exposure to concomitant midazolam was significantly decreased. When 3 mg midazolam was coadministered orally after 5-day treatment with telotristat ethyl 500 mg tid (twice the recommended dose), the mean Cmax, and AUC0-inf for midazolam were decreased by 25%, and 48%, respectively, compared with administration of midazolam alone. The mean Cmax, and AUC0-inf for the active metabolite, 1'-hydroxymidazolam, were also decreased by 34%, and 48%, respectively.
Other CYPs:
Based on in vitro findings, no clinically-relevant interaction is expected with other cytochromes P450.
In vitro loperamide (CES2 inhibitor) had a moderate effect on the metabolism of telotristat ethyl, reducing the formation of telotristat by <30%. In vitro, telotristat ethyl inhibited CES2 with an IC50 approximately of 6.4 μM.
P-glycoprotein (P-gp) and Multi-drug Resistance associated Protein 2 (MRP-2):
In vitro telotristat ethyl inhibited P-gp, but its active metabolite did not at the clinically relevant concentrations.
Telotristat ethyl inhibited MRP2-mediated transport (98% inhibition).
In a specific clinical DDI study, the Cmax and AUC of fexofenadine (a P-gp and MRP-2 substrate) increased by 16% when a single 180 mg dose of fexofenadine was co-administered orally with a dose of telotristat ethyl 500 mg administered tid (twice the recommended dose) for 5 days. Based on the small increase observed, clinically meaningful interactions with P-gp and MRP-2 substrates are unlikely.
Breast Cancer Resistance Protein (BCRP):
In vitro telotristat ethyl inhibited BCRP (IC50 = 20 μM), but its active metabolite telotristat did not show any significant inhibition of BCRP activity (IC50 >30 μM). The potential for in vivo drug interaction via inhibition of BCRP is considered low.
Other transporters:
Based on in vitro findings, no clinically-relevant interaction is expected with other transporters.
A study examining the effect of short-acting octreotide (3 doses of 200◦micrograms given 8◦hours apart) on the single dose pharmacokinetics of telotristat in normal healthy volunteers showed an 83% and 81% decrease in Cmax and AUC of telotristat ethyl and telotristat, respectively. Reduced exposures were not observed in a 12◦week double-blind, placebo-controlled, randomised, multicentre clinical trial in adult patients with carcinoid syndrome on long-acting SSA therapy.
Concomitant use of telotristat etiprate (the hippurate salt of telotristat ethyl) with acid-reducers (omeprazole and famotidine) showed that the AUC of telotristat ethyl was increased 2-3 fold, while the AUC of the active metabolite (telotristat) was not changed. Since telotristat ethyl is rapidly converted to its active metabolite, which is >25× more active than telotristat ethyl, no dose adjustments are required when using telotristat with acid reducers.
Following a single 500 mg oral dose of 14C-telotristat ethyl, approximately 93% of the dose was recovered. The majority was eliminated in the faeces.
Telotristat ethyl and telotristat have a low renal elimination following oral administration (less than 1% of the dose recovered from the urine). Following a single oral 250 mg dose of telotristat ethyl to heathy volunteers, urine concentrations of telotristat ethyl were close to or below the limit of quantification (<0.1 ng/mL). The renal clearance of telotristat was 0.126 L/h.
The apparent half-life of telotristat ethyl in normal healthy volunteers following a single 500 mg oral dose 14C-telotristat ethyl was approximately 0.6 hour and that of its active metabolite was 5 hours. Following administration of 500 mg tid, the apparent terminal half-life was approximately 11 hours.
In patients treated at 250 mg tid, a slight accumulation of telotristat levels was observed with a median accumulation ratio based on AUC0-4h of 1.55 [minimum, 0.25; maximum, 5.00; n=11; week 12], with a high inter-subject variability (CV = 72). In patients treated at 500 mg tid (twice the recommended dose), a median accumulation ratio based on AUC0-4h of 1.095 (minimum, 0.274; maximum, 11.46; n=16; week 24) was observed, with a high inter-subject variability (CV = 141.8). Based on the high inter-subject variability observed, accumulation in a subset of patients with CS cannot be excluded.
The influence of age on the pharmacokinetics of telotristat ethyl and its active metabolite has not been conclusively evaluated. No specific study has been performed in the elderly population.
A study was conducted to investigate the impact of renal impairment on the pharmacokinetics of a single dose of telotristat ethyl 250 mg. Eight subjects with severe to moderate renal impairment not requiring dialysis [eGFR ≤ 33 mL/min at screening and ≤40 mL/min at the day prior to dosing] and eight healthy to mildly impaired subjects [eGFR ≥88 mL/min at screening and ≥83 mL/min at the day prior to dosing] were included in this study.
In the subjects with severe to moderate renal impairment, an increase (1.3-fold) in peak exposure Cmax of telotristat ethyl and an increase (<1.52-fold) in plasma exposure (AUC) and Cmax of its active metabolite telotristat was observed compared to healthy to mildly impaired subjects.
Variability of the main plasma telotristat PK parameters was higher in subjects with severe to moderate renal impairment, with CV% ranging from 53.3% for Cmax to 77.3% for AUC as compared to 45.4% for Cmax and 39.7% for AUC in healthy to mildly impaired subjects, respectively.
Administration of a single dose of 250 mg was well tolerated in subjects with severe to moderate renal impairment.
Overall, severe to moderate renal impairment did not result in a clinically meaningful change in the PK profile or safety of telotristat ethyl and its metabolite telotristat. Therefore, dose adjustment does not appear necessary in patients with mild, moderate or severe renal impairment; who are not requiring dialysis. Given the high variability observed, it is recommended as a precautionary measure that patients with severe renal impairment will be monitored for signs of reduced tolerability.
The efficacy and safety in patients with end-stage renal disease who require dialysis (eGFR <15 mL/min/1.73 m² requiring dialysis) has not been established.
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.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeat dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
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 nonglandular 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.
The carcinogenic potential of telotristat etiprate was studied in transgenic mice (26 weeks) and rats (104 weeks). These studies confirmed that telotristat did not increase the incidence of tumors in both species and sexes, at doses corresponding to an exposure of approximately 10- to 15-fold and 2- to 4.5-fold the human exposure to the active metabolite at the MRHD in mice and rats, respectively.
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.
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