12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Cardiac Electrophysiology

At 3 times the mean maximum exposure of M1 at the recommended dosage, there were no clinically relevant effects on the QTc interval.

Food Effect

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.

12.3 Pharmacokinetics

Absorption

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.

Distribution

Plasma protein binding of tenapanor and its major metabolite, M1, is approximately 99% and 97%, respectively, in vitro.

Elimination

Metabolism

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.

Excretion

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.

Specific Populations

Patients with Hepatic Impairment

Following a single dose of tenapanor 100 mg in patients with moderate hepatic impairment (Child-Pugh B), plasma concentrations of tenapanor were mostly below the limit of quantitation (< 0.5 ng/mL) and the pharmacokinetic parameters for tenapanor could not be determined. The geometric mean AUC and Cmax of the major metabolite, M1, were approximately 33% and 27% lower, respectively, in patients with moderate hepatic impairment compared to those of healthy subjects. The decrease in M1 systemic exposure is not clinically relevant.

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 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. The decrease in M1 systemic exposure is not clinically relevant. Plasma concentrations of tenapanor were mostly below the limit of quantitation (less than 0.5 ng/mL) after co-administration of itraconazole.

No significant effect on CYP2C9 activity using warfarin as a substrate was observed when tenapanor 30 mg was administered twice a day (a dosage 0.6 times the recommended dosage) for 12 days in healthy subjects.

Membrane Transporter Mediated Drug Interactions

Tenapanor inhibited OATP2B1, but is not an inhibitor of P-gp, BCRP, OATP1B1, and OATP1B3. M1 did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, 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.

No significant effect on P-gp activity using digoxin as a substrate was observed when tenapanor 30 mg was administered twice a day (a dosage 0.6 times the recommended dosage) for 12 days in healthy subjects.

Following administration of a single 20 mg dose of enalapril (OATP2B1 substrate) with tenapanor 30 mg administered twice a day (a dosage 0.6 times the recommended dosage) at steady state in healthy subjects, the mean AUC and Cmax of enalapril was decreased by 64% and 69%, respectively. The mean AUC and Cmax of enalaprilat was decreased by 52% and 68%, respectively [see Drug Interactions (7.1)].