inically 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.
Short-acting octreotide
A study examining the effect of short-acting octreotide (3 doses of 200 micrograms given 8 hours apart) on the single dose pharmacokinetics of Xermelo in normal healthy volunteers showed an 83% and 81% decrease in Cmax and AUC of telotristat ethyl and telotristat, respectively (see section 4.5). 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.
Elimination
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, with less than 1% in the urine.
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.
Linearity/non-linearity
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.
Special populations
Elderly
The influence of age on the pharmacokinetics of telotristat ethyl and its active metabolite has not been conclusively eva luated. No specific study has been performed in the elderly population.
Renal impairment
The influence of renal impairment on the pharmacokinetics of telotristat ethyl and its active metabolite has not been conclusively eva luated. No specific study has been performed in patients with renal impairment.
Renal impairment is not expected to affect clearance of the parent compound or its active metabolite because telotristat ethyl has low renal elimination following oral administration (less than 1% of the dose recovered from the urine).
Patients with mild and moderate renal impairment should be treated with caution.
The use of telotristat is not recommended in patients with severe renal impairment based on the limited data available.
Telotristat was n |
