Mechanism Of Action
Tenapanor is a locally acting
inhibitor of the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on
the apical surface of the small intestine and colon primarily responsible for
the absorption of dietary sodium. In vitro and animal studies indicate its
major metabolite, M1, is not active against NHE3. By inhibiting NHE3 on the
apical surface of the enterocytes, tenapanor reduces absorption of sodium from
the small intestine and colon, resulting in an increase in water secretion into
the intestinal lumen, which accelerates intestinal transit time and results in
a softer stool consistency.
Tenapanor has also been shown
to reduce abdominal pain by decreasing visceral hypersensitivity and by
decreasing intestinal permeability in animal models. In rat model of colonic
hypersensitivity, tenapanor reduced visceral hyperalgesia and normalized
colonic sensory neuronal excitability.
At 3 times the mean maximum
exposure of M1 at the recommended dosage, there were no clinically relevant
effects on the QTc interval.
Administration of IBSRELA 5 to
10 minutes before a meal increased the 24-hour stool sodium excretion compared
to taking IBSRELA in the fed or fasting condition [see DOSAGE AND
ADMINISTRATION]. In clinical trials, IBSRELA was administered immediately
prior to the first meal of the day and immediately prior to dinner.
Tenapanor is minimally absorbed following repeated twice
daily oral administration. Plasma concentrations of tenapanor were below the
limit of quantitation (less than 0.5 ng/mL) in the majority of samples from
healthy subjects following single and repeated oral administration of IBSRELA
50 mg twice daily. Therefore, standard pharmacokinetic parameters such as area
under the curve (AUC), maximum concentration (Cmax), and half-life (t½) could
not be determined.
Plasma protein binding of tenapanor and its major
metabolite, M1, is approximately 99% and 97%, respectively, in vitro.
Tenapanor is metabolized primarily by CYP3A4/5 and low
levels of its major metabolite, M1, are detected in plasma. The Cmax of M1 is
approximately 13 ng/mL after single dose of IBSRELA 50 mg and 15 ng/mL at
steady state following repeated dosing of IBSRELA 50 mg twice daily in healthy
Following administration of a single 15 mg radiolabeled 14C-tenapanor
dose to healthy subjects, approximately 70% of the radioactivity was excreted
in feces within 120 hours post-dose and 79% within 240 hours post-dose, mostly
as the parent drug accounting for 65% of dose within 144 hours post-dose.
Approximately 9% of the administered dose was recovered in urine, primarily as
metabolites. M1 is excreted in urine unchanged accounting for 1.5% of dose
within 144 hours post-dose.
Patients With Renal Impairment
Based on a cross-study comparison, plasma concentrations
of M1 in end-stage renal disease patients on hemodialysis (eGFR less than 15
mL/min/1.73m²) was not notably different from those of healthy subjects given
comparable doses of IBSRELA.
Drug Interaction Studies
CYP Metabolism Mediated Drug Interactions
Tenapanor and M1 did not inhibit CYP1A2, CYP2B6, CYP2C8,
CYP2C9, CYP2C19, and CYP2D6 in vitro.
Tenapanor and M1 did not induce CYP1A2 and CYP2B6 in
No significant inhibition or induction of CYP3A4 enzyme
using midazolam as a substrate was observed when IBSRELA 50 mg was administered
twice a day for 13 days in healthy subjects.
Following co-administration of a single dose of IBSRELA
50 mg with repeated doses of itraconazole 200 mg, a CYP3A4 inhibitor, the mean
AUC and Cmax of M1 was decreased 50% in healthy subjects. Plasma concentrations
of tenapanor were mostly below the limit of quantitation (less than 0.5 ng/mL)
after co-administration of itraconazole.
Membrane Transporter Mediated Drug Interactions
Tenapanor and M1 did not inhibit P-gp, BCRP, OATP1B1, and
OATP1B3. M1 did not inhibit OAT1, OAT3, OCT2, MATE1, and MATE2-K.
M1 is a substrate of P-gp. Tenapanor is not a substrate
of P-gp, BCRP, OATP1B1, and OATP1B3. M1 is not a substrate of BCRP, OAT1, OAT3,
OCT2, MATE1 and MATE2-K.
No significant effect on PepT1 activity using cefadroxil
as a substrate was observed when IBSRELA 50 mg was administered twice a day for
12 days in healthy subjects.
The efficacy of IBSRELA for the treatment of IBS-C was
established in two double-blind, placebo-controlled, randomized, multicenter
trials in adult patients: Trial 1 (TEN-01-302; NCT02686138) and Trial 2
(TEN-01-301; NCT02621892). The intent-to-treat (ITT) analysis population
included 620 patients in Trial 1 and 606 patients in Trial 2 with mean age of
46 years (range 18 to 75 years), 80% females, 64% White and 31% Black/African
American. In these clinical trials, IBSRELA was administered immediately prior
to breakfast or the first meal of the day and immediately prior to dinner.
To enter the trials, all patients met Rome III criteria
for IBS-C and were required to meet the following clinical criteria during the
2-week baseline run-in period:
- a mean abdominal pain score of at least 3 on a
0-to-10-point numeric rating scale where a score of 0 indicates no pain and 10
indicates very severe pain
- less than 3 complete spontaneous bowel movements (CSBMs)
per week, where a CSBM is defined as a spontaneous bowel movement (SBM) that is
associated with a sense of complete evacuation (an SBM is a bowel movement
occurring in the absence of laxative use)
- less than or equal to 5 SBMs per week
The trial designs were identical through the first 12
weeks of treatment, and thereafter differed in that Trial 1 continued for an
additional 14 weeks of treatment (26 weeks double-blind treatment), whereas
Trial 2 included a 4-week randomized withdrawal (RW) period.
Efficacy of IBSRELA was assessed using responder analyses
based on daily diary entries.
In both trials, the primary endpoint was the proportion
of responders, where a responder was defined as a patient achieving both the
stool frequency and abdominal pain intensity responder criteria in the same
week for at least 6 of the first 12 weeks of treatment. The stool frequency
(CSBM) and abdominal pain responder criteria assessed each week were defined
- CSBM responder: a patient who experienced an increase of
at least 1 CSBM in weekly average from baseline.
- Abdominal pain responder: a patient who experienced at
least a 30% reduction in the weekly average of abdominal pain score compared
The responder rates for the primary endpoint and
components of the primary endpoint (CSBM and abdominal pain), which were
pre-specified key secondary endpoints, are shown in Table 2.
Table 2: Efficacy Responder Rates in
Placebo-Controlled Trials (Trial 1 and Trial 2) in Adults with IBS-C: Responder
for at least 6 of the First 12 Weeks of Treatment
|Treatment Difference [95% CIa]
|Components of Responder Endpoint:
|Abdominal Pain Responderd
|Treatment Difference [95% CIa]
|Components of Responder Endpoint:
|Abdominal Pain Responded
|a CI: Confidence Interval
b A responder for these trials was defined as a patient who met both
the abdominal pain and CSBM weekly responder criteria for at least 6 of the
first 12 weeks.
c A CSBM responder was defined as a patient who achieved an increase
in at least 1 CSBM per week, from baseline, for a least 6 of at least 12 weeks.
d An abdominal pain responder was defined as a patient who met the
criteria of at least 30% reduction from baseline in weekly average of the worst
daily abdominal pain, for at least 6 of the first 12 weeks.
In Trials 1 and 2, the proportion of responders for 9 out
of the first 12 weeks, including at least 3 of the last 4 weeks, was greater in
IBSRELA-treated patients compared to placebo-treated patients. In addition, in
Trial 1, the proportion of responders for 13 out of 26 weeks was greater in
IBSRELA-treated patients compared to placebo-treated patients.
In both trials, improvements
from baseline in average weekly CSBMs and abdominal pain were observed by Week
1, with improvement maintained through the end of treatment.
In IBSRELA-treated patients
re-randomized to placebo in Trial 2, CSBM frequency and abdominal pain severity
worsened on average over the 4-week period but remained improved compared to
baseline. Patients who continued on IBSRELA maintained their response to
therapy on average over the additional 4 weeks. Patients on placebo who were
re-randomized to IBSRELA had an average increase in CSBM frequency and a
decrease in abdominal pain.