12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Telotristat, the active metabolite of telotristat ethyl, is an inhibitor of tryptophan hydroxylase, which mediates the rate limiting step in serotonin biosynthesis. The in vitro inhibitory potency of telotristat towards tryptophan hydroxylase is 29 times higher than that of telotristat ethyl. Serotonin plays a role in mediating secretion, motility, inflammation, and sensation of the gastrointestinal tract, and is over-produced in patients with carcinoid syndrome. Through inhibition of tryptophan hydroxylase, telotristat and telotristat ethyl reduce the production of peripheral serotonin, and the frequency of carcinoid syndrome diarrhea.

12.2 Pharmacodynamics

In healthy subjects, telotristat ethyl 500 mg three times daily (twice the recommended dosage) for 14 days decreased whole blood serotonin and 24-hour urinary 5-hydroxyindolacetic acid (u5-HIAA) from baseline. A decrease in 24-hour u5-HIAA was observed as early as after 5 days of treatment.

In patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea, 24-hour u5-HIAA decreased from baseline following 6 and 12 weeks of treatment with Xermelo 250 mg three times a day, whereas placebo did not decrease u5-HIAA.

Cardiac Electrophysiology

At a dose 6 times the recommended dose of 250 mg, Xermelo does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption

After a single oral dose of telotristat ethyl to healthy subjects, telotristat ethyl was absorbed and metabolized to its active metabolite, telotristat. Peak plasma concentrations of telotristat ethyl were achieved within 0.5 to 2 hours, and those of telotristat within 1 to 3 hours. Plasma concentrations thereafter declined in a biphasic manner. 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. Peak plasma concentrations and AUC of telotristat ethyl and telotristat appeared to be dose proportional following administration of a single dose of telotristat ethyl in the range of 100 mg (0.4 times the lowest recommended dose to 1000 mg [4 times the highest recommended dose]) under fasted conditions.

Following multiple-dose administration of telotristat ethyl 500 mg three times daily, there was negligible accumulation at steady state for both telotristat ethyl and telotristat.

In patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea treated with SSA therapy, the median Tmax for telotristat ethyl and telotristat was approximately 1 and 2 hours, respectively. Following administration of 500 mg telotristat ethyl three times daily, with meals in patients, the mean Cmax and AUC0-6hr were approximately 7 ng/mL and 22 ng•hr/mL, respectively, for telotristat ethyl. The mean Cmax and AUC0-6hr were approximately 900 ng/mL and 3000 ng•hr/mL, respectively for telotristat. The pharmacokinetic parameters for both telotristat ethyl and telotristat were highly variable with about 55% coefficient of variation.

Food Effect

Administration of a single 500 mg dose of Xermelo (twice the recommended dose) with food resulted in higher exposure to both telotristat ethyl and telotristat. The systemic exposure to telotristat ethyl, was significantly increased following administration with a high-fat meal, with Cmax, and AUC0-inf being 112%, and 264% higher, respectively compared to the fasted state. Following administration of a single 500 mg dose of telotristat ethyl under fed conditions in healthy subjects, the mean Cmax and AUC0-inf were 10.5 ng/mL and 21.6 ng•hr/mL, respectively for telotristat ethyl. The Cmax and AUC0-inf values for telotristat were also increased by 47% and 33%, respectively, with a high-fat meal compared to the fasted state. The mean Cmax and AUC0-inf were 908 ng/mL and 2980 ng•hr/mL, respectively for telotristat under fed conditions [see Dosage and Administration (2)].

Distribution

Both telotristat ethyl and telotristat are greater than 99% bound to human plasma proteins.

In vitro data suggests that telotristat is a substrate of P-glycoprotein.

Elimination

Following a single 500 mg oral dose of telotristat ethyl in healthy subjects, the apparent half-life was approximately 0.6 hours for telotristat ethyl and 5 hours for telotristat. The apparent total clearance at steady state (CL/Fss) following oral dosing with telotristat ethyl 500 mg three times daily for 14 days (twice the recommended dosage) in healthy subjects was 2.7 and 152 L/hr for telotristat ethyl and telotristat, respectively.

Metabolism

After oral administration, telotristat ethyl undergoes hydrolysis via carboxylesterases to telotristat, its active metabolite. Telotristat is further metabolized. Among the metabolites of telotristat, the systemic exposure to an acid metabolite of oxidative deaminated decarboxylated telotristat was about 35% of that of telotristat. In vitro data suggest that telotristat ethyl and telotristat are not substrates for CYP enzymes.

Excretion

Following a single 500 mg oral dose of 14C-telotristat ethyl, 93.2% of the dose was recovered over 240 hours: 92.8% was recovered in the feces, with less than 0.4% being recovered in the urine.

Specific Populations

Age and Sex

Population pharmacokinetic analysis indicated that age (18 to 83 years) and sex do not affect the pharmacokinetics of telotristat.

Renal Impairment

Exposure to telotristat ethyl and its active metabolite, telotristat, was similar in patients with severe renal impairment or end-stage renal disease without dialysis (eGFR < 30 mL/min/1.73 m2) compared with subjects with normal renal function following a single oral dose of Xermelo [see Use in Specific Populations (8.6)]. Xermelo was not studied in patients with end-stage renal disease who require dialysis (eGFR < 15 mL/min/1.73 m2).

Hepatic Impairment

Following a single dose of Xermelo 500 mg, systemic exposure (AUC0-last) to telotristat ethyl was 2.3- and 3.2-fold higher in subjects with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, than in subjects with normal hepatic function. In subjects with severe (Child-Pugh C) hepatic impairment, following a single Xermelo 250 mg dose, systemic exposure (AUC0-last), was 4-fold higher than in subjects with normal hepatic function. In these same studies, AUC0-last for telotristat (active metabolite) was 2.4-, 3.5-, and 5-fold higher in subjects with mild, moderate, and severe hepatic impairment, respectively [see Use in Specific Populations (8.7)].

In patients with metastatic neuroendocrine tumors and carcinoid syndrome diarrhea, population pharmacokinetic analysis indicated that mild hepatic impairment (defined as total bilirubin greater than 1 to 1.5 times the upper limit of normal [ULN] or AST greater than the ULN) did not affect the pharmacokinetics of telotristat.

Drug Interaction Studies

Effect of Telotristat Ethyl on Other Drugs

In vitro studies

Based on in vitro studies, the potential for telotristat ethyl, telotristat, and the acid metabolite of telotristat to inhibit major CYP enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5) and to induce CYP1A2 is low at the recommended dosage of Xermelo.

Based on in vitro studies, potential induction of CYP2B6 in vivo by Xermelo cannot be ruled out [see Drug Interactions (7.2)].

In vitro telotristat ethyl, but not telotristat, inhibited breast cancer resistance protein (BCRP) at the clinically relevant concentrations. However, in vivo drug interaction potential via inhibition of BCRP is low based on in vitro studies and in vivo findings.

Based on in vitro studies, in vivo drug interaction potential via inhibition of organic cation transporter 1 (OCT1), OCT2, organic anion transporter 1 (OAT1), OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, or bile salt export pump (BSEP) transporters by telotristat ethyl and telotristat is low at the recommended dosage.

Based on in vitro study results, the potential for the acid metabolite of telotristat to inhibit P-gp, BCRP, OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, BSEP, and MRP2 transporters is low at the recommended dosage.

Midazolam (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 co-administered orally after 5 day treatment with telotristat ethyl 500 mg three times daily (twice the recommended dosage), the mean Cmax, and AUC0-inf for midazolam were decreased by 25%, and 48%, respectively, compared to administration of midazolam alone. The mean Cmax, and AUC0-inf for the active metabolite, 1'-hydroxymidazolam, were also decreased by 34%, and 48%, respectively. The reduction in the systemic exposure to both midazolam and its active metabolite suggests that the glucuronidation of 1'-hydroxymidazolam may have been increased by telotristat ethyl [see Drug Interactions (7.1)].

Fexofenadine (sensitive P-gp substrate)

In vitro telotristat ethyl, but not telotristat, inhibited P-glycoprotein (P-gp). In healthy volunteers, the Cmax and AUC of fexofenadine increased by 16% when a single 180 mg dose of fexofenadine was co-administered orally with the final dose of telotristat ethyl 500 mg administered three times daily (twice the recommended dosage) for 5 days. Clinically meaningful interactions with P-gp substrates are unlikely.

Effect of Other Drugs on Telotristat Ethyl

Short-Acting Octreotide

The mean Cmax and AUC0-last of telotristat ethyl were decreased by 86% and 81%, respectively, following administration of a single 500 mg dose of Xermelo (twice the recommended dose), co-administered with short-acting octreotide 200 mcg injected subcutaneously in healthy subjects. The mean Cmax and AUC0-last of telotristat were decreased by 79% and 68%, respectively.

Gastric Acid Reducers (Proton Pump Inhibitor and H2-Receptor Antagonist)

Omeprazole: The Cmax and AUCinf of telotristat ethyl were increased by 68% and 185%, respectively, when a single 250 mg dose of Xermelo was coadministered with a 40 mg dose of omeprazole once daily compared to administration of Xermelo alone. No significant change (<9%) in AUC and Cmax of the active metabolite, telotristat, was observed following coadministration of Xermelo with omeprazole compared to administration of Xermelo alone. These changes in exposure of telotristat ethyl and telotristat are not considered to be clinically meaningful.

Famotidine: The Cmax and AUCinf of telotristat ethyl were increased by 22% and 111%, respectively, when a single 250 mg dose of Xermelo was coadministered with a 40 mg dose of famotidine twice daily. No significant change (<5%) in AUC and Cmax to the active metabolite, telotristat, was observed following coadministration of Xermelo with famotidine compared to administration of Xermelo alone. These changes in exposure are not considered to be clinically meaningful.