Chemical formula: C₃₃H₃₅F₄N₃O₂ Molecular mass: 581.656 g/mol PubChem compound: 49841217
Avacopan is a selective antagonist of the human complement 5a receptor (C5aR1 or CD88) and competitively inhibits the interaction between C5aR1 and the anaphylatoxin C5a.
The specific and selective blockade of C5aR1 by avacopan reduces the pro-inflammatory effects of C5a, which include neutrophil activation, migration, and adherence to sites of small blood vessel inflammation, vascular endothelial cell retraction and permeability.
Avacopan blocks the C5a-induced upregulation of CD11b (integrin alpha M) on neutrophils taken from humans dosed with avacopan. CD11b facilitates neutrophil adherence to vascular endothelial surfaces, one of the steps in the vasculitis disease process.
When administered without food, avacopan peak plasma concentration (Cmax) occurs at a median time (tmax) of approximately 2 hours. Avacopan has shown an approximate dose-proportional increase in systemic exposure in the dose range of 10 to 30 mg.
Co-administration of 30 mg in capsule formulation with a high-fat, high-calorie meal increases the plasma exposure (AUC) of avacopan by approximately 72% and delays tmax by approximately 3 hours; however, the Cmax is not affected.
The reversible 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 is high (Vz/F 3,000-11,000 L), indicating broad tissue distribution of the active substance.
Avacopan is eliminated mainly through phase I metabolism. Following oral administration of radiolabelled avacopan, the bulk of the active substance-related materials was recovered in faeces in the form of phase I metabolites. One major circulating metabolite (M1), a mono-hydroxylated product of avacopan, was present at ~12% of the total active substance-related materials in plasma. This metabolite constitutes 30 to 50% of the parent exposure and has approximately the same activity as avacopan on C5aR1. Cytochrome P450 (CYP) 3A4 is the major enzyme responsible for the clearance of avacopan and for the formation and clearance of metabolite M1.
Avacopan is a weak inhibitor of CYP3A4 and CYP2C9 as indicated by a modest increase in the AUC of the probe active substances midazolam (1.81-fold) and celecoxib (1.15-fold), respectively.
In vitro, avacopan is not an inhibitor or an inducer of other CYP enzymes.
Avacopan showed negligible to weak inhibition of common transporters in vitro. Therefore, clinically relevant interactions are unlikely when avacopan is co-administered with substances that are substrates or inhibitors of these transporters.
Based on population pharmacokinetic analysis, the total apparent body clearance (CL/F) of avacopan is 16.3 L/h (95% CI: 13.1-21.1 L/h). The median terminal elimination half-life is 510 hours (21 days) based on population pharmacokinetic analysis. When avacopan is stopped after steady state has been reached, the residual plasma concentration of avacopan is projected to decrease to ~20%, <10%, and <5% of the steady state maximum concentration approximately 4 weeks, 7 weeks, and 10 weeks, respectively, after the last dose.
Following oral administration of radiolabelled avacopan, about 77% and 10% of the radioactivity was recovered in faeces and urine, respectively, and 7% and <0.1% of the radioactive dose was recovered as unchanged avacopan in faeces and urine, respectively. These results suggest that the main route of clearance of avacopan is metabolism followed by biliary excretion of the metabolites into faeces, and that direct excretion of avacopan into urine or faeces via bile is negligible.
Population pharmacokinetic analysis found no significant effect of age (among adults) on the plasma exposure of avacopan; however, there were limited pharmacokinetic data in patients over 75 years of age in clinical studies. No dose adjustment is necessary for elderly patients.
The pharmacokinetic properties of avacopan have been examined in 16 subjects with mild (ChildPugh class A) or moderate (Child-Pugh class B) hepatic impairment. When compared to normal controls, no pharmacologically relevant differences in exposure (mean ratios of Cmax and AUC ≤1.3) of avacopan or its major metabolite M1 was observed; therefore, no dose adjustment is necessary.
Avacopan has not been studied in subjects with severe hepatic impairment (Child-Pugh class C).
Based on population pharmacokinetic analysis, the plasma exposure of avacopan is similar between patients with renal impairment and healthy subjects. Therefore, no dose adjustment is necessary based on renal function.
Avacopan has not been studied in patients with ANCA-associated vasculitis with an eGFR below 15 mL/min/1.73 m², who are on dialysis, in need of dialysis or plasma exchange.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenicity.
Avacopan produced no effects on male or female reproductive performance (fertility) or early development in hamsters at oral doses equivalent up to 6.8-fold the clinical AUC.
Avacopan was not teratogenic when dosed orally to hamsters and rabbits. In hamsters, an increased incidence of skeletal variations (short thoracolumbar supernumerary rib) was observed at exposure equivalent to 5.3-fold the clinical AUC. In rabbits, avacopan caused maternal toxicity (adverse clinical signs and abortions), but no foetal toxicity at 0.6-fold the clinical AUC.
Avacopan did not result in adverse effects in female offspring when administered in hamsters at exposures up to 6.3-fold the clinical AUC during gestation and through lactation until weaning. In males, there was a slight delay in preputial separation at 3.7-fold the clinical AUC. This isolated finding was considered to be of low toxicological significance and was not associated with any impairment of reproductive performance.
Analysis of avacopan plasma levels in the lactating dams and the plasma levels in nursing offspring showed the presence of avacopan, suggesting that avacopan is likely secreted into the milk of lactating hamsters.
The carcinogenic potential of avacopan was evaluated in a 2-year study in both rats and hamsters. In male rats, a slightly increased incidence of C-cell thyroid adenoma was noted in avacopan-treated rats; this increase was not statistically significant, and the incidence was within the historical control range. Avacopan was not carcinogenic in hamsters, the pharmacologically relevant species.
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