Chemical formula: C₉₀H₁₂₀N₂₀O₂₂S₂ Molecular mass: 1,896.833 g/mol PubChem compound: 162462321
Icotrokinra is a peptide that selectively binds to the IL-23 receptor (IL-23R) with a dissociation constant of 7 pM and antagonizes the binding of IL-23. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Icotrokinra inhibits the IL-23/IL-23R-dependent release of proinflammatory cytokines.
Icotrokinra reduced serum levels of proinflammatory cytokines, IL-17A, IL-17F, IL-19, IL-22 and β-defensin-2, relative to pretreatment levels in evaluated subjects with moderate-to-severe plaque psoriasis based on exploratory analysis of the pharmacodynamic markers. A decrease from baseline was observed in the expression of mRNA related to IL-23/Th17 pathway and psoriasis, including molecular targets IL17A, IL17F, IL19, IL22, IL23A, and DEFB4A, in lesional skin biopsies up to 24 weeks post treatment in an exploratory analysis of subjects with moderate-to-severe plaque psoriasis. The relationship between these pharmacodynamic markers and the mechanism(s) by which icotrokinra exerts its clinical effects is not fully understood.
At 5 times the maximum recommended dose of icotrokinra, clinically significant QTc interval prolongation was not observed.
Following the administration of icotrokinra 200 mg, the mean (standard deviation) maximum concentration (Cmax) is 3.62 (1.48) ng/mL and total systemic exposure (AUCinf) is 44.8 (11.4) ng*h/mL. Icotrokinra Cmax and AUC increase in a dose-proportional manner between 0.05 to 5 times the recommended dosage in healthy subjects. Following multiple dose administration accumulation for Cmaxwas up to 1.6-fold and for AUC was up to 1.5-fold. Icotrokinra steady state is reached in approximately 3 days.
No clinically relevant differences in icotrokinra pharmacokinetics were observed between healthy subjects and patients with moderate-to-severe plaque psoriasis.
Icotrokinra median (min, max) time to maximum plasma concentration (Tmax) is 2 (0.25, 8) hours.
Icotrokinra AUC decreased by 43% and Cmaxdecreased by 59% following administration with a high-fat meal (1000 calories, 50% fat).
No clinically significant differences in icotrokinra pharmacokinetics were observed following administration of caffeine.
Icotrokinra is 52% bound to plasma protein. Blood to plasma partition ratio is 0.53. Icotrokinra steady state apparent (oral) volume of distribution is 92800 L.
Icotrokinra median elimination half-life is 12 hours with an apparent (oral) clearance of 6550 L/h.
Icotrokinra is a peptide and it is metabolized by peptide catabolism into smaller peptides.
Following oral administration of icotrokinra to healthy subjects, approximately 37% to 81% of the dose was recovered in feces within 24 hours as unchanged icotrokinra, and 0.001% of the dose was recovered in urine as unchanged icotrokinra.
No clinically significant differences in the pharmacokinetics of icotrokinra were observed based on age (range: 12 to 87 years), body weight (range: 39 to 211 kg), sex, race (76% White, 20.1% Asian, 1.7% Black), ethnicity, immunogenicity, mild (eGFR ≥60 to <90 mL/min, [calculated according to Chronic Kidney Disease Epidemiology Collaboration]) renal impairment. The effect of mild (Child-Pugh Class A) to severe (Child-Pugh Class C) hepatic impairment on icotrokinra pharmacokinetics is unknown. Hepatic impairment is unlikely to affect icotrokinra elimination since the drug is not metabolized hepatically. However, patients with severe hepatic impairment were not studied in clinical trials.
No clinically relevant differences in icotrokinra pharmacokinetics were observed in pediatric patients with moderate-to-severe plaque psoriasis 12 years of age and older who weigh at least 40 kg compared to adults.
Icotrokinra AUC increased by 2.47-fold in patients with moderate (eGFR ≥30 to <60 mL/min, [calculated according to Chronic Kidney Disease Epidemiology Collaboration]) and 2.78-fold in severe (eGFR ≥15 to <30 mL/min) renal impairment. No clinically significant differences in the pharmacokinetics of icotrokinra were observed in patients with mild renal impairment (eGFR ≥60 to <90 mL/min) based on population pharmacokinetic analysis.
Drug Interaction Studies
No formal drug-drug interaction studies have been conducted with icotrokinra. No clinically significant drug interactions have been identified.
CYP450 Enzymes: Icotrokinra does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Icotrokinra does not induce CYP1A2, CYP2B6, and CYP3A4.
Transporter systems: Icotrokinra is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, and MATE2-K. Icotrokinra does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, and BSEP.
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