Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, Various alimentary tract and metabolism products, ATC code: A16AX15

Mechanism of action
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.

Pharmacodynamic effects
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 (refer to Table 3 for TELESTAR and information provided for TELECAST). Statistically significant reductions in u5-HIAA were seen for telotristat ethyl 250 mg tid compared with placebo in both phase 3 studies.

Clinical efficacy and safety
The efficacy and safety of telotristat for the treatment of carcinoid syndrome in patients with metastatic neuroendocrine tumours who were receiving SSA therapy was established in a 12-week double-blind, placebo-controlled, randomised, multicentre phase 3 trial in adult patients, which included a 36-week extension during which all patients were treated with open-label telotristat (TELESTAR study).


A total of 135 patients were evaluated for efficacy. The mean age was 64 years (range 37 to 88 years), 52% were male and 90% were white. All patients had well-differentiated metastatic neuroendocrine tumours and carcinoid syndrome. They were on SSA therapy and had ≥4 daily BM.

The study included a 12-week double-blind treatment (DBT) period, in which patients initially received placebo (n=45), telotristat ethyl 250 mg (n=45) or a higher dose (telotristat ethyl 500 mg; n=45) tid. During the study, patients were allowed to use rescue medicinal product (short-acting SSA therapy) and anti-diarrhoeals for symptomatic relief but were required to be on stable-dose long-acting SSA therapy for the duration of the DBT period. Xermelo was taken within 15 minutes before, or within 1 hour after food.

Table 2: BM response (TELESTAR study)
Telotristat ethyl
Parameter                 Placebo
250 mg tid
Number of patients                 45                         45
BMs/day at baseline
Baseline mean (SD)              5.2 (1.35)                6.1 (2.07)

Primary endpoint:        Number of patients                 45                         45 change from baseline
Change averaged in BMs/day averaged over 12 weeks: mean            ˗0.6 (0.83)                ˗1.4 (1.37) over 12 weeks
(SD)
Least square mean
---                     -0.6 difference
ANCOVAa                  97.5% CL for
---                   -1.16, -0.06 difference p value                            ---                       0.01
Percentage of           Number of patients                 45                        45 patients with durable responseb               Responder, n (%)                9 (20.0)                 20 (44.4)c BM = bowel movement; CL=confidence limit; tid=three times daily; SD=standard deviation.
a. Analysis of covariance including treatment group and urinary 5-HIAA stratification at randomisation as fixed effects, and the baseline number of BM as a fixed covariate.
b. Defined as the proportion of responders with ≥30% reduction in daily number of BMs for ≥50% of time over the DBT period.
c. p=0.01

When the full effect of telotristat is observed (during the last 6 weeks of the DBT period) the proportion of responders with at least 30% BM reduction was 51% (23/45) in the 250 mg group versus 22% (10/45) in the placebo group (post-hoc analysis).

In the 12-week DBT period of the study, average weekly reductions in BM frequency on telotristat were observed as early as 3 weeks, with the greatest reductions occurring during the last 6 weeks of the DBT period, compared with placebo (refer to Figure 1).


Figure 1 – Mean change from baseline in BMs by study week during the DBT period, intent-to- treat, population p
0.00

Mean Change from Baseline (and 95% CL)
-0.25 in Bowel Movements (counts/day)       -0.50
-0.75
-1.00
-1.25
-1.50
-1.75
-2.00
-2.25
-2.50   Placebo     Telotristat Ethyl 250mg

0      1     2      3      4     5        6        7    8   9   10     11    12 Study week
Note: This figure plots the arithmetic mean and 95% confidence limits (CL) (based on normal approximation) of the change from Baseline in the number of daily bowel movements (counts/day) averaged at each week.


The proportions of patients reporting reductions from baseline in daily BM frequency (averaged over 12 weeks) were:
-     Patients with a mean reduction of at least 1 BM per day: 66.7% (telotristat ethyl 250 mg) and 31.1% (placebo);
-     Patients with a mean reduction of at least 1.5 BM per day: 46.7% (telotristat ethyl 250 mg) and 20.0% (placebo);
-     Patients with a mean reduction of at least 2 BM per day: 33.3% (telotristat ethyl 250 mg) and 4.4% (placebo).

Table 3: u5-HIAA excretion at baseline and week 12 (TELESTAR study)
Telotristat ethyl
Parameter                          Placebo
250 mg tid u5-HIAA excretion                                            Number of patients                          44                      42 (mg/24 hours) at baseline                                                     Baseline meana (SD)                 81.0 (161.01)                92.6 (114.90) Number of patients                          28                          32 Percent change from
Percent change at week baseline in u5-HIAA                                                                               14.4 (57.80)                -42.3 (41.96) 12: Mean (SD) excretion (mg/24 hours) at week 12        Estimate of treatment                                     -53.4 c b             --- difference (95% CL)                                  (-69.32, -38.79) CL=confidence limit; tid=three times daily; SD=standard deviation; u5-HIAA = urinary 5-hydroxyindoleacetic acid.
a. Baseline data based on all patients with data at baseline.
b. Statistical tests used a blocked 2-sample Wilcoxon Rank Sum statistic (van Elteren test) stratified by the u5-HIAA stratification at randomisation. CLs were based on the Hodges- Lehmann estimator of the median paired difference.
c.   p<0.001

There was no significant difference between treatment groups for the endpoints of flushing and abdominal pain.

A post-hoc analysis showed that the average number of daily short-acting SSA injections used for rescue therapy over the 12-week DBT period was 0.3 and 0.7 in the telotristat ethyl 250 mg and placebo groups, respectively.

A pre-specified patient exit interview substudy was conducted to assess relevance and clinical meaningfulness of symptom improvements in 35 patients. Questions were asked to blinded participants to further characterise the degree of change experienced during the trial. There were 12 patients who were “very satisfied”, and all of them were on telotristat. The proportions of patients who were “very satisfied” were 0/9 (0%) on placebo, 5/9 (56%) on telotristat ethyl 250 mg tid and 7/15 (47%) on a higher dose of telotristat ethyl.

Overall, 18 patients (13.2%) prematurely discontinued from the study during the DBT period, 7 patients in the placebo group, 3 in the telotristat ethyl 250 mg group and 8 in the higher dose group.
At the conclusion of the 12-week DBT period, 115 patients (85.2%) entered the 36-week open-label extension period, where all patients were titrated to receive a higher dose of telotristat ethyl (500 mg) tid.

In a phase 3 study of similar design (TELECAST), a total of 76 patients were evaluated for efficacy.
The mean age was 63 years (range 35 to 84 years), 55% were male and 97% were white.
All patients had well-differentiated metastatic neuroendocrine tumour with carcinoid syndrome. Most patients (92.1%) had fewer than 4 BM per day and all except 9 were treated by SSA therapy.

The primary endpoint was the percent change from baseline in u5-HIAA at week 12. The mean u5-HIAA excretion at baseline was 69.1 mg/24 hours in the 250 mg group (n=17) and 84.8 mg/24 hours in the placebo group (n=22). The percent change from baseline in u5-HIAA excretion at week 12 was +97.7% in the placebo group versus -33.2% in the 250 mg group.

The mean number of daily BM at baseline was 2.2 and 2.5 respectively in the placebo (n=25) and 250 mg group (n=25). The change from baseline in daily BM averaged over 12 weeks was +0.1 and
-0.5 in the placebo and 250 mg groups respectively. Telotristat ethyl 250 mg showed that stool consistency, as measured by Bristol Stool Form Scale, was improved compared with placebo. There were 40% patients (10/25) with durable response (as defined in Table 2) in the telotristat ethyl 250 mg group, versus 0% in the placebo group (0/26) (p=0.001).

The long-term safety and tolerability of telotristat was evaluated in a nonpivotal (nonrandomised), phase 3, multicentre, open-label, long-term extension study. Patients having participated in any Xermelo phase 2 or phase 3 carcinoid syndrome study were eligible to enter the study at the same dose level and regimen as identified in their original study, for at least 84 weeks of treatment. No new significant safety signals were identified.
The secondary objective of this study was to evaluate changes in patients’ quality of life (QOL) through week 84. QOL was generally stable over the course of the study.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of telotristat ethyl and its active metabolite have been characterised in healthy volunteers and patients with carcinoid syndrome.

Absorption
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 dose) 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.
Food effect
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).

Distribution
Both telotristat ethyl and its active metabolite are > 99% bound to human plasma proteins.

Biotransformation
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.

Interactions
Cytochromes
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 (see section 4.5).

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 engages in an allosteric interaction with CYP3A4 resulting at the same time in a reduced conversion of midazolam to 1’-OH-MDZ, and increased conversion to 4-OH-MDZ.

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 (see section 4.5). 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.

Carboxylesterases
The IC50 of the inhibition of loperamide on the metabolism of telotristat ethyl by CES2 was 5.2 µM (see section 4.5).
In vitro, telotristat ethyl inhibited CES2 with an IC50 approximately of 0.56 μM.

Transporters

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.

Short-acting octreotide
A study examining the effect of short-acting octreotide (3 doses of 200◦micrograms injected subcutaneously given 8◦hours apart) on the single dose pharmacokinetics of telotristat ethyl 500 mg in normal healthy volunteers showed an 83% and 81% decrease in geometric mean Cmax and AUC0-tlast of telotristat ethyl (see section 4.5). Reduced exposures were not observed in a 12◦week double-blind, placebo-controlled, randomised, multicentre clinical study in adult patients with carcinoid syndrome on long-acting SSA therapy.
Pharmacokinetic/pharmacodynamic relationship(s)

Acid reducers
Concomitant use of telotristat etiprate (Xermelo, 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 Xermelo with acid reducers.

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.

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.

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 evaluated. No specific study has been performed in the elderly population.

Renal impairment
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.

Hepatic impairment
A hepatic impairment study was conducted in subjects with mild and moderate hepatic impairment and in healthy subjects. At a single dose of 500 mg, exposures to the parent compound and its active metabolite (based on AUC0-last) 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. A reduction in dose may be necessary in patients with mild or moderate hepatic impairment (respectively Child Pugh score A and B) based on tolerability (see section 4.2).

A further hepatic impairment study was conducted in subjects with severe hepatic impairment and in healthy subjects. At a single dose of 250 mg, exposure to the parent compound (AUCt and Cmax) was increased 317.0% and 529.5%, respectively, and to the active metabolite (AUCt, AUCinf, and Cmax) 497%, 500%, and 217%, respectively, for subjects with severe hepatic impairment compared to subjects with normal hepatic function. In addition, the half-life of the active metabolite was increased, i.e. the mean half life was 16.0 hours in subjects with severe hepatic impairment compared to 5.47 hours in healthy subjects. Based on these findings, the use of telotristat etiprate is not recommended in patients with severe hepatic impairment (Child Pugh score C) (see section 4.2).