Chemical formula: C₂₅H₃₀N₂O₄ Molecular mass: 422.517 g/mol PubChem compound: 90467622
Iptacopan is a proximal complement inhibitor that targets Factor B (FB) to selectively inhibit the alternative pathway. Inhibition of FB in the alternative pathway of the complement cascade prevents the activation of C3 convertase and the subsequent formation of C5 convertase to control both C3-mediated extravascular haemolysis (EVH) and terminal complement-mediated intravascular haemolysis (IVH).
The onset of inhibition of the alternative complement pathway, measured using an ex vivo alternative pathway assay, Bb levels (fragment b of Factor B) and plasma levels of C5b-9, was ≤2 hours after a single iptacopan dose in healthy volunteers.
A comparable effect of iptacopan was observed in patients with PNH previously exposed to anti-C5 agents and treatment-naïve patients.
In treatment-naïve PNH patients, iptacopan 200 mg twice daily reduced LDH by >60% compared to baseline after 12 weeks and maintained the effect through to the end of the study.
In a QTc clinical study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1 200 mg (which provided greater than 4-fold exposure of the 200 mg twice daily dose), showed no effect on cardiac repolarisation or QT interval.
Following oral administration, iptacopan reached peak plasma concentrations approximately 2 hours post dose. At the recommended dosing regimen of 200 mg twice daily, steady state is achieved in approximately 5 days with minor accumulation (1.4-fold). In healthy volunteers, steady-state Cmax,ss (geo-mean (CV)) was 4 020 ng/ml (23.8) and AUCtau,ss was 25 400 ng*hr/ml (15.2%). Inter- and intra-subject variability in iptacopan pharmacokinetics is low to moderate.
Results from a food-effect study with a high-fat high-calorie meal in healthy volunteers indicated that Cmax and area under the curve (AUC) of iptacopan were not affected by food. Therefore, iptacopan may be taken with or without food.
Iptacopan showed concentration-dependent plasma protein binding due to binding to the target FB in the systemic circulation. Iptacopan was 75 to 93% protein bound in vitro at the relevant clinical plasma concentrations. After administration of iptacopan 200 mg twice daily, the geo-mean apparent volume of distribution at steady state was approximately 265 litres.
Metabolism is a predominant elimination pathway for iptacopan, with approximately 50% of the dose attributed to oxidative pathways. Metabolism of iptacopan includes N-dealkylation, O-deethylation, oxidation and dehydrogenation, mostly driven by CYP2C8 with a small contribution from CYP2D6. Direct glucuronidation (by UGT1A1, UGT1A3 and UGT1A8) is a minor pathway. In plasma, iptacopan was the major component, accounting for 83% of the AUC0-48h. Two acyl glucuronides were the only metabolites detected in plasma and were minor, accounting for 8% and 5% of the AUC0-48h. Iptacopan metabolites are not considered pharmacologically active.
In a study in healthy volunteers, following a single 100 mg oral dose of [14C]-iptacopan, mean total excretion of radioactivity (iptacopan and metabolites) was 71.5% in the faeces and 24.8% in the urine. Specifically, 17.9% of the dose was excreted as parent iptacopan in the urine and 16.8% in faeces. The apparent clearance (CL/F) after administration of iptacopan 200 mg twice daily at steady state is 7 960 ml/min. The half-life (t½) of iptacopan at steady state is approximately 25 hours after administration of iptacopan 200 mg twice daily.
At doses between 25 and 100 mg twice daily, the pharmacokinetics of iptacopan were overall less than dose proportional. However, oral doses of 100 mg and 200 mg were approximately dose proportional. Non-linearity was primarily attributed to the saturable binding of iptacopan to its target FB in plasma.
A dedicated interaction study in which iptacopan was co‑administered with other medicinal products was conducted in healthy volunteers and did not demonstrate any clinically relevant interactions.
CYP2C8 inhibitors:
When iptacopan is co‑administered with clopidogrel (a moderate CYP2C8 inhibitor), the iptacopan Cmax and the AUC increased by 5% and 36%, respectively.
OATP1B1/OATP1B3 inhibitors:
When iptacopan is co‑administered with ciclosporin (a strong OATP 1B1/1B3 inhibitor, and a PgP and BCRP inhibitor), the iptacopan Cmax and AUC increased by 41% and 50%, respectively.
PgP substrates:
In the presence of iptacopan, the Cmax of digoxin (a PgP substrate) increased by 8% while its AUC was unchanged.
OATP substrates:
In the presence of iptacopan, the Cmax and AUC of rosuvastatin (an OATP substrate) remained unchanged.
A population pharmacokinetic (PK) analysis was conducted on data from 234 patients. Age (18 to 84 years), body weight, eGFR, race and gender did not significantly influence iptacopan PK. Studies that included Asian subjects showed that the PK of iptacopan were similar to Caucasian (white) subjects.
The effect of renal impairment on the clearance of iptacopan was assessed using a population PK analysis. There were no clinically relevant differences in the clearance of iptacopan between patients with normal renal function and patients with mild (eGFR between 60 and 90 ml/min) or moderate (eGFR between 30 and 60 ml/min) renal impairment and no dose adjustment is required. Patients with severe renal impairment or on dialysis have not been studied.
Based on a study in subjects with mild (Child-Pugh A, n=8), moderate (Child-Pugh B, n=8) or severe (Child-Pugh C, n=6) hepatic impairment, a negligible effect on the total systemic exposure of iptacopan was observed compared to subjects with normal hepatic function. Unbound iptacopan Cmax increased 1.4-, 1.7- and 2.1-fold, and unbound iptacopan AUCinf increased by 1.5-, 1.6- and 3.7-fold in subjects with mild, moderate and severe hepatic impairment, respectively.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
In oral dose animal fertility studies, iptacopan did not impact fertility in male rats up to the highest dose tested (750 mg/kg/day), which corresponds to 6-fold the MRHD based on AUC. Reversible effects on the male reproductive system (testicular tubular degeneration and hypospermatogenesis) were observed in repeated dose toxicity studies after oral administration in rats and dogs at doses >3- fold the MRHD based on AUC, with no apparent effects on sperm numbers, morphology or motility, or fertility.
In the female fertility and early embryonic developmental study in rats, iptacopan-related findings were limited to increased pre-and post-implantation losses and, consequently, decreased numbers of live embryos only at the highest dose of 1 000 mg/kg/day orally, which corresponds to ~5-fold the MRHD based on total AUC. The dose of 300 mg/kg/day is the no-observed-adverse-effect level (NOAEL) which corresponds to ~2-fold the MRHD based on AUC.
Animal reproduction studies in rats and rabbits demonstrated that oral administration of iptacopan during organogenesis did not induce adverse embryo or foetal toxicity up to the highest doses, which correspond to 5-fold (for rats) and 8-fold (for rabbits) the MRHD of 200 mg twice daily based on AUC.
In the pre- and postnatal development study in rats, with iptacopan administered orally to females during gestation, parturition and lactation (from gestational day 6 to lactation day 21), there were no adverse effects on pregnant dams or offspring up to the highest dose tested of 1 000 mg/kg/day (estimated 5-fold the MRHD based on AUC).
In the chronic toxicity study, one male dog at the highest dose level (margin to clinical exposure near 20-fold), was sacrificed 103 days after completed iptacopan administration due to irreversible nonregenerative severe anaemia associated with bone marrow fibrosis. During the treatment phase, haematology findings indicating inflammation and dyserythropoiesis were observed. No mechanism for the observed findings has been identified and a relation to treatment cannot be excluded.
Iptacopan was not genotoxic or mutagenic in a battery of in vitro and in vivo assays.
Carcinogenicity studies conducted with iptacopan in mice and rats via oral administration did not identify any carcinogenic potential. The highest doses of iptacopan studied in mice (1 000 mg/kg/day) and rats (750 mg/kg/day) were approximately 4- and 12-fold the MRHD based on AUC, respectively.
In vitro and in vivo phototoxicity tests were equivocal. In the in vivo phototoxicity study, with iptacopan at doses between 100 and 1 000 mg/kg (equivalent to 38-fold the human total Cmax at the MRHD), some mice showed a non-dose-response pattern of transient minimal erythema, scabs and dryness and slight increase in average ear weight subsequent to irradiation.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
