Source: FDA, National Drug Code (US) Revision Year: 2020
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 (2)]. 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 (t1/2) 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 subjects.
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.
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.
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 vitro.
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.
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 carcinogenic potential of tenapanor was assessed in a 6-month carcinogenicity study in Tg rasH2 mice and in a 2-year carcinogenicity study in rats.
Tenapanor was not tumorigenic at oral doses up to 100 mg/kg/day (approximately 4.5 times the recommended human dose, based on the body surface area) in male mice and 800 mg/kg/day (approximately 39 times the maximum recommended human dose, based on the body surface area) for female mice. Tenapanor was not tumorigenic in male and female rats at oral doses up to 5 mg/kg/day (approximately 0.5 times the recommended human dose, based on the body surface area). The major metabolite of tenapanor, M1, was not tumorigenic in Tg rasH2 mice at oral doses up to 165 mg/kg/day (approximately 8 times the maximum recommended human dose, based on the body surface area)
Tenapanor was not genotoxic in the in vitro bacterial reverse mutation (Ames) assays, an in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes or the in vivo micronucleus assays in mice and rats.
Tenapanor had no effect on fertility or reproductive function in male rats at oral doses up to 10 mg/kg/day (approximately 0.97 times the recommended human dose, based on the body surface area) and in female mice at oral doses up to 50 mg/kg/day (approximately 2.4 times the recommended human dose, based on the body surface area).
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:
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 as:
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:
| Trial 1 | |||
|---|---|---|---|
| IBSRELA N=293 | Placebo N=300 | Treatment Difference [95% CI*] | |
| Responder† | 37% | 24% | 13% [6%, 20%] |
| Components of Responder Endpoint: | |||
| CSBM Responder‡ | 47% | 33% | |
| Abdominal Pain Responder§ | 50% | 38% | |
| Trial 2 | |||
| Responder Rates | IBSRELA N=307 | Placebo N=299 | Treatment Difference [95% CI*] |
| Responder† | 27% | 19% | 8% [2%, 15%] |
| Components of Responder Endpoint: | |||
| CSBM Responder‡ | 34% | 29% | |
| Abdominal Pain Responder§ | 44% | 33% | |
* CI: Confidence Interval
† 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.
‡ 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.
§ 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.
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