VELSIPITY™ Clinical Pharmacology

(etrasimod)

12 CLINICAL PHARMACOLOGY

  

12.1 Mechanism of Action

Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P1,4,5). Etrasimod has minimal activity on S1P3 (25-fold lower than Cmax at the recommended dose) and no activity on S1P2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood. The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines.

12.2 Pharmacodynamics

Reduction in Blood Lymphocyte Counts

VELSIPITY causes a reduction in peripheral blood lymphocyte count [see Warnings and Precautions (5.1)]. In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 109/L) and the lower lymphocyte counts were maintained during treatment with VELSIPITY.

Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing VELSIPITY 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks.

Reduction in Heart Rate and AV Conduction Delays

VELSIPITY may result in a transient decrease in heart rate and AV conduction upon treatment initiation [see Warnings and Precautions (5.2)]. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of VELSIPITY on Day 1.

Cardiac Electrophysiology

At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation.

Pulmonary Function

Reductions in absolute FEV1 were observed in subjects treated with VELSIPITY [see Warnings and Precautions (5.9)].

Drug Interaction Studies

No clinically significant differences in heart rate reduction were observed when etrasimod was used concomitantly with stable beta blocker treatment. The effect of concomitant use of etrasimod with a calcium channel blocker on heart rate reduction is unknown [see Drug Interactions (7)].

12.3 Pharmacokinetics

Etrasimod mean (SD) steady-state maximum plasma concentration (Cmax) was 113 (27.5) ng/mL and area under the time concentration curve at the dosing interval (AUCtau) was 2162 (488) ng*h/mL at the recommended dosage. Etrasimod Cmax and AUC are approximately dose proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose.

Absorption

The median (range) time to reach etrasimod Cmax (Tmax) is approximately 4 hours (range 2 to 8 hours) after oral administration.

Effect of Food

No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of VELSIPITY with a high-fat meal (800 to 1000 calories) [see Dosage and Administration (2.2)].

Distribution

The mean apparent volume of distribution of etrasimod is 66 (24) L. Etrasimod plasma protein binding is 97.9%.

Elimination

The mean plasma elimination half-life (t1/2) of etrasimod is approximately 30 hours with an apparent steady-state oral clearance of approximately 1 L/h after oral administration.

Metabolism

Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma.

Excretion

Approximately 82% of total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of etrasimod were observed based on age (>65 years), sex, body weight, race, ethnicity, disease (healthy subjects vs. subjects with ulcerative colitis), and severe renal impairment (eGFR ≤29 mL/min).

Patients with Hepatic Impairment

Etrasimod AUC increased by 13% in subjects with mild (Child-Pugh A), 29% in moderate (Child-Pugh B), and 57% in severe (Child-Pugh C) hepatic impairment, respectively, compared with subjects with normal liver function. No clinically significant difference in the unbound etrasimod AUC was observed [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Combined moderate CYP2C9 and CYP3A4 inhibitors: Concomitant use of etrasimod with steady-state fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod AUC by 84% [see Drug Interactions (7)].

Combined CYP3A4 (strong), CYP2C8 (moderate) and CYP2C9 (moderate) inducers: Concomitant use of etrasimod with rifampin (strong CYP3A4, moderate CYP2C8, and CYP2C9 inducer) decreased etrasimod AUC by 49% [see Drug Interactions (7)].

Oral Contraceptives: No clinically significant differences in the pharmacokinetics and pharmacodynamics of oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were observed when used concomitantly with etrasimod.

Other Drugs: Itraconazole (a P-gp and strong CYP3A inhibitor) increased etrasimod AUC by 32%. Gemfibrozil (an inhibitor of OATP1B1 and OAT3 and a strong inhibitor of CYP2C8) increased etrasimod AUC by 36%. These effects are unlikely to be clinically significant.

In Vitro Studies

Based on in vitro studies, etrasimod is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, nor an inducer of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.

Etrasimod is not an inhibitor of UGT1A3, UGT1A4, UGT1A9, UGT2B7, or UGT2B17 in vitro.

Etrasimod is not a substrate or an inhibitor of P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2-K transporters.

12.5 Pharmacogenomics

CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when VELSIPITY is used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4 [see Drug Interactions (7) and Use in Specific Populations (8.7)].

CYP2C9 intermediate metabolizers (e.g., *1/*2, *1/*3, *2/*2) may have decreased clearance of etrasimod when VELSIPITY is used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4; however, the effect on VELSIPITY exposure in CYP2C9 intermediate metabolizers with concomitant CYP2C8 or CYP3A4 inhibitors is not known.

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2 to 3% in White populations, 0.5 to 4% in Asian populations, and <1% in African-American populations. Other decreased or nonfunctional CYP2C9 alleles (e.g., *5, *6, *8, *11) are more prevalent in African-American populations.

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Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

  

12.1 Mechanism of Action

Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4, and 5 (S1P1,4,5). Etrasimod has minimal activity on S1P3 (25-fold lower than Cmax at the recommended dose) and no activity on S1P2. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood. The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines.

12.2 Pharmacodynamics

Reduction in Blood Lymphocyte Counts

VELSIPITY causes a reduction in peripheral blood lymphocyte count [see Warnings and Precautions (5.1)]. In UC-1 and UC-2, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 109/L) and the lower lymphocyte counts were maintained during treatment with VELSIPITY.

Dose-response relationship analysis indicates there is a dose-dependent reduction in blood lymphocyte counts. After discontinuing VELSIPITY 2 mg once daily, the median time for peripheral blood lymphocytes to return to the normal range was 2.6 weeks, with approximately 90% of subjects in the normal range within 4.7 weeks.

Reduction in Heart Rate and AV Conduction Delays

VELSIPITY may result in a transient decrease in heart rate and AV conduction upon treatment initiation [see Warnings and Precautions (5.2)]. In UC-1 and UC-2, the mean (SD) decrease in heart rate was 7.2 (8.98) bpm at 2 to 3 hours after the first dose of VELSIPITY on Day 1.

Cardiac Electrophysiology

At 2 times the maximum recommended dose, etrasimod does not cause clinically significant QTc interval prolongation.

Pulmonary Function

Reductions in absolute FEV1 were observed in subjects treated with VELSIPITY [see Warnings and Precautions (5.9)].

Drug Interaction Studies

No clinically significant differences in heart rate reduction were observed when etrasimod was used concomitantly with stable beta blocker treatment. The effect of concomitant use of etrasimod with a calcium channel blocker on heart rate reduction is unknown [see Drug Interactions (7)].

12.3 Pharmacokinetics

Etrasimod mean (SD) steady-state maximum plasma concentration (Cmax) was 113 (27.5) ng/mL and area under the time concentration curve at the dosing interval (AUCtau) was 2162 (488) ng*h/mL at the recommended dosage. Etrasimod Cmax and AUC are approximately dose proportional from 0.7 mg to 2 mg (0.35 times up to the recommended dosage). Etrasimod steady state is reached within 7 days with an accumulation of approximately 2- to 3-fold compared to the first dose.

Absorption

The median (range) time to reach etrasimod Cmax (Tmax) is approximately 4 hours (range 2 to 8 hours) after oral administration.

Effect of Food

No clinically significant differences in the pharmacokinetics of etrasimod were observed following administration of VELSIPITY with a high-fat meal (800 to 1000 calories) [see Dosage and Administration (2.2)].

Distribution

The mean apparent volume of distribution of etrasimod is 66 (24) L. Etrasimod plasma protein binding is 97.9%.

Elimination

The mean plasma elimination half-life (t1/2) of etrasimod is approximately 30 hours with an apparent steady-state oral clearance of approximately 1 L/h after oral administration.

Metabolism

Etrasimod is metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8, CYP2C9, and CYP3A4, with a minor contribution by CYP2C19 and CYP2J2. Etrasimod also undergoes conjugation primarily mediated by UGTs, with a minor contribution by sulfotransferases. Unchanged etrasimod is the main circulating component in plasma.

Excretion

Approximately 82% of total radioactive etrasimod dose was recovered in the feces and 5% in the urine within 336 hours. Approximately 11% of administered radioactive dose was excreted as unchanged etrasimod in feces and none was excreted unchanged in urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of etrasimod were observed based on age (>65 years), sex, body weight, race, ethnicity, disease (healthy subjects vs. subjects with ulcerative colitis), and severe renal impairment (eGFR ≤29 mL/min).

Patients with Hepatic Impairment

Etrasimod AUC increased by 13% in subjects with mild (Child-Pugh A), 29% in moderate (Child-Pugh B), and 57% in severe (Child-Pugh C) hepatic impairment, respectively, compared with subjects with normal liver function. No clinically significant difference in the unbound etrasimod AUC was observed [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Clinical Studies

Combined moderate CYP2C9 and CYP3A4 inhibitors: Concomitant use of etrasimod with steady-state fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) increased etrasimod AUC by 84% [see Drug Interactions (7)].

Combined CYP3A4 (strong), CYP2C8 (moderate) and CYP2C9 (moderate) inducers: Concomitant use of etrasimod with rifampin (strong CYP3A4, moderate CYP2C8, and CYP2C9 inducer) decreased etrasimod AUC by 49% [see Drug Interactions (7)].

Oral Contraceptives: No clinically significant differences in the pharmacokinetics and pharmacodynamics of oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were observed when used concomitantly with etrasimod.

Other Drugs: Itraconazole (a P-gp and strong CYP3A inhibitor) increased etrasimod AUC by 32%. Gemfibrozil (an inhibitor of OATP1B1 and OAT3 and a strong inhibitor of CYP2C8) increased etrasimod AUC by 36%. These effects are unlikely to be clinically significant.

In Vitro Studies

Based on in vitro studies, etrasimod is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, nor an inducer of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.

Etrasimod is not an inhibitor of UGT1A3, UGT1A4, UGT1A9, UGT2B7, or UGT2B17 in vitro.

Etrasimod is not a substrate or an inhibitor of P-gp, BCRP, BSEP, OATP1B1, OATP1B3, OAT1, OAT3, OCT1, OCT2, MATE1, and MATE2-K transporters.

12.5 Pharmacogenomics

CYP2C9 activity is decreased in individuals with genetic variants such as CYP2C9*2 and CYP2C9*3 alleles. The impact of CYP2C9 genetic variants on the pharmacokinetics of etrasimod has not been directly evaluated. CYP2C9 poor metabolizers (e.g., *2/*3, *3/*3) may have decreased clearance of etrasimod when VELSIPITY is used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4 [see Drug Interactions (7) and Use in Specific Populations (8.7)].

CYP2C9 intermediate metabolizers (e.g., *1/*2, *1/*3, *2/*2) may have decreased clearance of etrasimod when VELSIPITY is used concomitantly with moderate to strong inhibitors of CYP2C8 or CYP3A4; however, the effect on VELSIPITY exposure in CYP2C9 intermediate metabolizers with concomitant CYP2C8 or CYP3A4 inhibitors is not known.

The prevalence of the CYP2C9 poor metabolizer phenotype is approximately 2 to 3% in White populations, 0.5 to 4% in Asian populations, and <1% in African-American populations. Other decreased or nonfunctional CYP2C9 alleles (e.g., *5, *6, *8, *11) are more prevalent in African-American populations.

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