XPHOZAH 20 mg Tenapanor 20 mg Tablet, Film Coated, 60-count — NDC 73154-120-60 (Billing 73154-0120-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tenapanor is a locally acting inhibitor that targets the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the epithelium of the small intestine and colon. Inhibition of NHE3 by tenapanor results in reduced sodium absorption and decreased phosphate absorption by reducing phosphate permeability through the paracellular pathway.

12.2Pharmacodynamics Cardiac Electrophysiology At 3 times the mean maximum exposure of the major pharmacologically inactive metabolite of tenapanor (M1) at the recommended dosage, there were no clinically relevant effects on the QTc. Food Effect Administration of XPHOZAH 5 to 10 minutes before a meal increased the 24-hour stool phosphorus excretion compared to taking XPHOZAH in the fed or fasting condition [see Dosage and Administration (2.2) ] . In clinical trials, XPHOZAH was administered just prior to the first meal and just prior to dinner.

Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of XPHOZAH was studied in 20 subjects with normal or moderate hepatic impairment function (Child-Pugh B) after a single 100-mg dose. Compared to subjects with normal hepatic function, the geometric mean C max of the pharmacologically inactive metabolite M1, was approximately 27% to 35% lower in subjects with moderate hepatic impairment. Tenapanor exhibited minimal systemic bioavailability in subjects with both normal hepatic function and moderate hepatic impairment, with plasma concentrations below the limit of quantitation (less than 0.5 ng/mL) in the majority of samples.

12.3Pharmacokinetics 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 subjects following single and repeated oral administration of tenapanor 30 mg twice daily. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (C max ), and half-life (t 1/2 ) 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 C max of M1 is approximately 3 ng/mL after a single dose of XPHOZAH 30 mg and 14 ng/mL at steady state following repeated dosing of XPHOZAH 30 mg twice daily in healthy subjects.

Based on a cross-study comparison, the steady state plasma concentration of M1 in CKD patients on dialysis (eGFR less than 15 mL/min/1.73 m 2 ) was not notably different from those of healthy subjects given similar doses of XPHOZAH. Excretion Following administration of a single 15 mg radiolabeled 14 C- XPHOZAH dose to healthy subjects, approximately 70% of the radioactivity was excreted in feces through 120 hours post-dose (79% through 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. 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 XPHOZAH 50 mg was administered twice a day for 13 days in healthy subjects. No significant effect on PepT1 activity using cefadroxil as a substrate was observed when tenapanor 50 mg was administered twice a day for 12 days in healthy subjects.

No significant effect on P-gp and CYP2C9 activity using digoxin and warfarin as a substrate was observed when tenapanor 30 mg wa… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Tenapanor is a locally acting inhibitor that targets the sodium/hydrogen exchanger 3 (NHE3), an antiporter expressed on the apical surface of the epithelium of the small intestine and colon. Inhibition of NHE3 by tenapanor results in reduced sodium absorption and decreased phosphate absorption by reducing phosphate permeability through the paracellular pathway.

12.3Pharmacokinetics 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 subjects following single and repeated oral administration of tenapanor 30 mg twice daily. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (C max ), and half-life (t 1/2 ) 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 C max of M1 is approximately 3 ng/mL after a single dose of XPHOZAH 30 mg and 14 ng/mL at steady state following repeated dosing of XPHOZAH 30 mg twice daily in healthy subjects.

Based on a cross-study comparison, the steady state plasma concentration of M1 in CKD patients on dialysis (eGFR less than 15 mL/min/1.73 m 2 ) was not notably different from those of healthy subjects given similar doses of XPHOZAH. Excretion Following administration of a single 15 mg radiolabeled 14 C- XPHOZAH dose to healthy subjects, approximately 70% of the radioactivity was excreted in feces through 120 hours post-dose (79% through 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. 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 XPHOZAH 50 mg was administered twice a day for 13 days in healthy subjects. No significant effect on PepT1 activity using cefadroxil as a substrate was observed when tenapanor 50 mg was administered twice a day for 12 days in healthy subjects.

No significant effect on P-gp and CYP2C9 activity using digoxin and warfarin as a substrate was observed when tenapanor 30 mg was administered twice a day for 12 days in healthy subjects. Following co-administration of a single dose of XPHOZAH 50 mg with repeated doses of itraconazole 200 mg, a CYP3A4 inhibitor, the mean AUC and C max 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.

Following administration of a single 20 mg enalapril dose with tenapanor (30 mg BID) at steady state, the mean AUC and C max of enalapril was decreased by 64% and 69%, respectively, in healthy subjects. The mean AUC and C max of enalaprilat was decreased by 52% and 68%, respectively, in healthy subjects. Membrane Transporter Mediated Drug Interactions Tenapanor inhibited OATP2B1, but is not an inhibitor of P-gp, BCRP, OATP1B1, OATP1B3, and PEPT1.

M1 did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K. Tenapanor is not a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. M1 is a substrate of P-gp .

Interactions with Phosphate Binders In vitro studies indicated the potential for tenapanor to bind to sevelamer carbonate but did not suggest the potential to bind to calcium carbonate or calcium acetate. In a clinical study, there did not appear to be a pharmacodynamic interaction between sevelamer carbonate (800 mg TID) and tenapanor (14 mg BID).

12.2Pharmacodynamics Cardiac Electrophysiology At 3 times the mean maximum exposure of the major pharmacologically inactive metabolite of tenapanor (M1) at the recommended dosage, there were no clinically relevant effects on the QTc. Food Effect Administration of XPHOZAH 5 to 10 minutes before a meal increased the 24-hour stool phosphorus excretion compared to taking XPHOZAH in the fed or fasting condition [see Dosage and Administration (2.2) ] . In clinical trials, XPHOZAH was administered just prior to the first meal and just prior to dinner.

Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of XPHOZAH was studied in 20 subjects with normal or moderate hepatic impairment function (Child-Pugh B) after a single 100-mg dose. Compared to subjects with normal hepatic function, the geometric mean C max of the pharmacologically inactive metabolite M1, was approximately 27% to 35% lower in subjects with moderate hepatic impairment. Tenapanor exhibited minimal systemic bioavailability in subjects with both normal hepatic function and moderate hepatic impairment, with plasma concentrations below the limit of quantitation (less than 0.5 ng/mL) in the majority of samples.

14 CLINICAL STUDIES The ability of XPHOZAH to lower serum phosphorus in adults with CKD on dialysis was evaluated in 3 trials: TEN-02-201 [NCT02675998], TEN-02-301 [NCT03427125]), and TEN-02-202 [NCT03824587]). Across these trials, the mean age of XPHOZAH-treated patients was 56 (range 24 to 88 years), 61% were males, 44% were White, 49% were Black/African American, 3% were Asian, 3% were American Indian or Alaska Native, and 1% were other. Both monotherapy trials (TEN-02-201 and TEN-02-301) enrolled patients who, following a 3-week washout period, had an increase in serum phosphorus of at least 1.5 mg/dL (compared to pre-wash out value) and a serum phosphorus level of at least 6.0 mg/dL and not more than 10.0 mg/dL.

Study TEN-02-301 Study TEN-02-301 included a 26-week randomized, active-controlled open-label treatment period, followed by a 12-week, blinded placebo-controlled randomized withdrawal period. A total of 564 patients were randomized into the 26-week treatment period (423 to XPHOZAH and 141 to the control arm which was intended to provide controlled safety data). Among the 423 patients randomized to XPHOZAH, 255 patients (60%) completed the 26-week treatment period and were rerandomized 1:1 to remain on XPHOZAH (n=128) or receive placebo (n=127).

During the randomized withdrawal phase, the phosphorus concentration rose in the placebo group by 0.7 mg/dL (95% CI: (0.2, 1.1), p=0.002) relative to patients who remained on XPHOZAH. Study TEN-02-201 Study TEN-02-201 included an 8-week randomized, double-blind period that evaluated three dosing regimens of XPHOZAH (3 mg twice daily, 10 mg twice daily, or a titration regimen). This period was followed by a 4-week placebo-controlled randomized-withdrawal phase, during which patients were rerandomized 1:1 to their current XPHOZAH treatment or to placebo.

Of the 219 patients included in the trial, 164 patients (75%) completed the 8-week randomized treatment period and were rerandomized 1:1 to receive XPHOZAH (n=82) or placebo (n=82). During the randomized withdrawal phase, the phosphorus concentration rose in the placebo group by 0.7 mg/dL (95% CI: (0.3, 1.2), p=0.003) relative to patients who remained on XPHOZAH. Study TEN-02-202 Study TEN-02-202 was a randomized, parallel-group, double-blind, placebo-controlled study that evaluated the effect of XPHOZAH on the change in serum phosphorus when used as add-on therapy in patients on stable phosphate-binder therapy with serum phosphorus greater than or equal to 5.5 mg/dL.

A total of 236 patients were randomized to receive XPHOZAH (n=117) or placebo BID (n=119) for 4 weeks. During the 4-week period, the serum phosphorus decreased by 0.7 mg/dL (95% CI: (0.3, 1.0), p=0.0004) in the add-on XPHOZAH group as compared to the add-on placebo group.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis 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 7.5 times the recommended human dose, based on the body surface area) in male mice and 800 mg/kg/day (approximately 65 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 0.8 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 13.3 times the maximum recommended human dose, based on the body surface area). Mutagenesis 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. The M1 metabolite of tenapanor was not genotoxic in the Ames assay and in an in vitro micronucleus assay using L5178Y cells.

Impairment of Fertility Tenapanor had no effect on fertility or reproductive function in male rats at oral doses up to 10 mg/kg/day (approximately 1.6 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 4 times the recommended human dose, based on the body surface area).