12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Avacopan is a complement 5a receptor (C5aR) antagonist that inhibits the interaction between C5aR and the anaphylatoxin C5a. Avacopan blocks C5a-mediated neutrophil activation and migration. The precise mechanism by which avacopan exerts a therapeutic effect in patients with ANCA-associated vasculitis has not been definitively established.

12.2 Pharmacodynamics

Avacopan blocks the C5a-induced upregulation of CD11b (integrin alpha M) on neutrophils taken from humans dosed with avacopan. The clinical significance of the pharmacodynamic effect is unclear.

Cardiac Electrophysiology

At the approved recommended dose, TAVNEOS does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Based on population pharmacokinetic analysis, the mean steady state plasma exposure estimates of avacopan are 3466 ± 1921 ng∙h/mL for the 12-hour area under the plasma drug concentration over time curve (AUC0-12hr) and 349 ± 169 ng/mL for the maximum plasma concentration (Cmax) in patients with ANCA-associated vasculitis receiving 30 mg avacopan twice daily. Steady state plasma levels of avacopan are reached by 13 weeks and the accumulation is approximately 4-fold.

Absorption

Co-administration of 30 mg in capsule formulation with a high-fat, high-calorie meal increases AUC and Cmax of avacopan by approximately 72% and 8%, respectively, and delays tmax by approximately 4 hours (from 2.0 hours to 6.0 hours).

Distribution

The plasma protein binding (e.g., to albumin and α1-acid glycoprotein) of avacopan and metabolite M1 is greater than 99.9%. The apparent volume of distribution of avacopan is estimated to be 345 L.

Elimination

Based on population pharmacokinetic analysis, the estimated total apparent body clearance (CL/F) of avacopan is 16.3 L/h. Following a single dose of 30 mg avacopan with food, the mean elimination half-lives of avacopan and M1 are 97.6 hours and 55.6 hours, respectively, in healthy subjects.

Metabolism

CYP3A4 is the major enzyme responsible for the clearance of avacopan and for the formation and clearance of the major circulating metabolite M1, a mono-hydroxylated product of avacopan. M1 was present at ~12% of the total drug-related materials in plasma and has approximately the same activity as avacopan on the C5aR.

Excretion

The main route of clearance of avacopan is metabolism followed by biliary excretion of the metabolites into feces. Following oral administration of radiolabelled avacopan, about 77% and 10% of the radioactivity was recovered in feces and urine, respectively, and 7% and <0.1% of the radioactive dose was recovered as unchanged avacopan in feces and urine, respectively.

Specific Populations

No clinically significant differences in plasma exposure of avacopan and metabolite M1 were observed based on race (White, Asian, Black), gender (female 31%), age (18 to 83 years), body weight (40.3-174 kg), and renal function (eGFR 14-170 mL/min/1.73 m2 at baseline).

Patients with Hepatic Impairment

Mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on avacopan and M1 plasma exposure. In subjects with mild or moderate hepatic impairment, avacopan AUC increased by 12% and 12%, respectively, Cmax decreased by 13% and 17%, respectively, compared to subjects with normal liver function. In subjects with mild or moderate hepatic impairment, M1 AUC increased by 11% and 18%, respectively, Cmax decreased by 5% and 16%, respectively, compared to subjects with normal liver function.

TAVNEOS has not been studied in subjects with severe hepatic impairment (Child-Pugh Class C).

Drug Interaction Studies

Effects of Other Drugs on TAVNEOS

Avacopan is primarily metabolized by CYP3A4. In vitro studies indicate that avacopan is not a substrate of BCRP and P-gp efflux, and OATP1B1 and OATP1B3 uptake transporters. M1 is a substrate of P-gp but is not a substrate of BCRP efflux, and OATP1B1 and OATP1B3 uptake transporters. Summary of results from a clinical study which evaluated the effect of co-administered drugs on avacopan and M1 plasma exposures is shown in Table 2.

Table 2. Changes in Pharmacokinetics of Avacopan and M1 in the Presence of Co-administered Drugs
Co-administered Drug	Regimen of Co-administered Drug	Ratio (90% CI)*
Co-administered Drug	Regimen of Co-administered Drug		Cmax	AUC
CI: Confidence interval
* Ratios for Cmax and AUC comparing co-administration of the medication with avacopan vs. administration of avacopan alone.
Strong CYP3A4 inhibitor: itraconazole	200 mg once daily for 4 days	Avacopan	1.87 (1.70, 2.06)	2.19 (2.00, 2.41)
Strong CYP3A4 inhibitor: itraconazole	200 mg once daily for 4 days	M1	1.03 (0.95, 1.11)	1.19 (1.11, 1.28)
Strong CYP3A4 inducer: rifampin	600 mg once daily for 11 days	Avacopan	0.21 (0.18, 0.25)	0.07 (0.06, 0.10)
Strong CYP3A4 inducer: rifampin	600 mg once daily for 11 days	M1	0.27 (0.23, 0.31)	0.07 (0.06, 0.09)

Proton-pump inhibitors such as omeprazole are not expected to have a clinically relevant effect on avacopan plasma exposure.

Effect of TAVNEOS on Other Drug Substances

In vitro studies indicate that avacopan does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, and does not induce CYP1A2 and CYP2B6, but shows induction and time-dependent inhibition of CYP3A4. In vitro studies indicate that M1 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C19, and CYP2D6, and has a low potential to induce CYP3A4, CYP1A2 and CYP2B6, but may inhibit CYP2C9 and CYP3A4.

In vitro studies indicate that avacopan and M1 do not inhibit the transporters P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, and MATE2K at clinically relevant concentrations.

Summary of results from clinical studies which evaluated the effect of avacopan on other drugs is shown in Table 3.

Table 3. Change in Pharmacokinetics of Co-administered Drugs in the Presence of Avacopan
Co-administered Drug	Regimen of Avacopan	Ratio (90% CI)*
Co-administered Drug	Regimen of Avacopan	Cmax	AUC
CI: Confidence interval
* Ratios for Cmax and AUC comparing co-administration of the medication with avacopan vs. administration of medication alone. † Avacopan doses were taken with food. Avacopan systemic exposure represents the therapeutic exposure at steady state with 30 mg twice daily under fed conditions. ‡ Avacopan doses were taken under fasted conditions. No food was allowed for at least 2 hours post dose for the morning doses. Avacopan systemic exposure was below the therapeutic exposure at steady state with 30 mg twice daily under fed conditions.
Sensitive CYP3A4 substrate: simvastatin	60 mg twice daily for 7 days (fed)†	3.20 (2.49, 4.10)	3.53 (3.23, 3.85)
Sensitive CYP3A4 substrate: midazolam	30 mg twice daily for 11 days (fasted)‡	1.55 (1.41, 1.69)	1.81 (1.65, 1.98)
Sensitive CYP2C9 substrate: celecoxib	30 mg twice daily for 11 days (fasted)‡	1.64 (1.34, 2.00)	1.15 (1.03, 1.28)